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McNee A, Kannan A, Jull P, Shankar S. Expanding Human Breg for Cellular Therapy in Transplantation: Time for Translation. Transplantation 2025; 109:926-937. [PMID: 39439021 PMCID: PMC12091222 DOI: 10.1097/tp.0000000000005243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 07/24/2024] [Accepted: 08/13/2024] [Indexed: 10/25/2024]
Abstract
Regulatory B cells (Breg) are instrumental in protecting allografts in transplantation. Breg signatures are identified in operationally tolerant human kidney transplant recipients and can predict organ survival and acute rejection. Animal models of transplantation and autoimmunity support the use of Breg as an adoptive cellular therapy. Detailed mechanistic studies have identified multiple signaling pathways utilized by Breg in their induction, expansion, and downstream function. These preclinical studies provide the guiding principles, which will inform protocols by which to expand this crucial immunoregulatory population before clinical use. There is an urgent need for novel therapies to improve long-term transplant outcomes and to minimize immunosuppression-related morbidity including life-threatening infection and cancer. Systematic evaluation of the signals, which drive Breg expansion, will be key to transforming the as of yet unharnessed potential of this potent immunoregulatory cell. In this review, we explore the potential avenues of translating Breg subsets from cell culture at the laboratory bench to cell therapy at the patient's bedside. We will discuss the standardization of Breg phenotypes to aid in precursor population selection and quality control of a Breg-cell therapy product. We will evaluate avenues by which to optimize protocols to drive human Breg expansion to levels sufficient for cellular therapy. Finally, we will examine the steps required in process development including scalable culture systems and quality control measures to deliver a viable Breg-cell therapy product for administration to a transplant recipient.
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Affiliation(s)
- Adam McNee
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Ananya Kannan
- Oxford University Medical School, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Patrick Jull
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Sushma Shankar
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
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Zhang Q, Liao J, Liu Z, Song S, Tian L, Wang Y. The immune tolerance role of Bregs in inhibiting human inflammatory diseases, with a focus on diabetes mellitus. Front Immunol 2025; 16:1565158. [PMID: 40370441 PMCID: PMC12074967 DOI: 10.3389/fimmu.2025.1565158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/10/2025] [Indexed: 05/16/2025] Open
Abstract
Regulatory B cells (Bregs) are pivotal modulators of immune tolerance, suppressing inflammation through cytokine secretion and cellular interactions. Their role is particularly significant in inflammatory diseases such as type 1 and type 2 diabetes mellitus (T1DM and T2DM), where immune dysregulation contributes to disease progression. In T1DM, Bregs mitigate β-cell autoimmunity via IL-10 production and FOXP3-mediated pathways, but genetic mutations and dysfunctions in these mechanisms exacerbate autoimmunity. In T2DM, chronic inflammation and metabolic stress impair Breg numbers and function, further fueling insulin resistance. While Bregs play a central role in T1DM by directly preventing β-cell destruction, their role in T2DM is more supportive, modulating inflammation in metabolically stressed tissues. Emerging therapeutic strategies aim to enhance Breg function through IL-10 induction, ex vivo expansion, or targeting Breg-specific pathways using gene-editing and small molecules. Future research should explore Breg heterogeneity, novel markers, and personalized therapies to unlock their full potential. Understanding and leveraging the immune tolerance role of Bregs may offer transformative strategies to inhibit inflammatory diseases like diabetes mellitus.
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Affiliation(s)
- Qi Zhang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan, China
| | - Jinfeng Liao
- Department of Dermatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zheng Liu
- Pathology Department, University of Texas, MD Anderson Cancer Center, Texas, Houston, TX, United States
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Limin Tian
- Center for Geriatrics and Endocrinology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center for Geriatrics and Endocrinology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Center for Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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3
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Altulea D, van den Born J, Bijma T, Bonasia C, Inrueangsri N, Lammerts R, Berger S, Heeringa P, Sanders JS. Comprehensive Phenotyping and Cytokine Production of Circulating B Cells Associate Resting Memory B Cells With Early Antibody-mediated Rejection in Kidney Transplant Recipients. Transplant Direct 2025; 11:e1775. [PMID: 40124243 PMCID: PMC11927649 DOI: 10.1097/txd.0000000000001775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 03/25/2025] Open
Abstract
Background B cells play a crucial role in kidney transplantation through antibody production and cytokine secretion. To better understand their impact on kidney transplantation, this retrospective study aimed to characterize circulating B-cell phenotypes and cytokine production in a cohort of kidney transplant patients to identify whether pretransplant donor-specific antibodies (DSAs) or biopsy-proven rejection is associated with different B-cell profiles. Methods Pretransplant cryopreserved peripheral blood mononuclear cells were obtained from 96 kidney transplant recipients, of whom 42 had pretransplant DSAs. The cells underwent surface marker staining using a 33-color spectral flow cytometry panel for B-cell phenotyping. Simultaneously, cells were stimulated for interleukin-10, tumor necrosis factor-α, and interleukin-6 production, and analyzed with a 6-color panel. Results Rejection was linked to decreased naive B cells and increased plasmablasts, CD27+ memory B cells, and memory B-cell subsets (all P < 0.04) compared with no rejection. Cytokine-producing B cells and immune regulatory molecule expression showed no significant differences. Multivariate analysis identified resting memory B cells (CD27+CD21+) and pretransplant DSAs as significantly associated with rejection (P = 0.01; odds ratio [OR], 1.07; P = 0.02; OR, 3.10, respectively). Cox regression analysis revealed resting memory B cells were associated with early antibody-mediated rejection (P = 0.04; OR, 1.05). Conclusions B-cell subset distributions differed between patients with and without rejection. Resting memory B-cell frequency was associated with increased early antibody-mediated rejection risk, whereas cytokine production and immune checkpoint expression did not influence rejection. The results suggest that B-cell subset composition could aid in rejection risk assessment and serve as a potential pretransplant diagnostic parameter.
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Affiliation(s)
- Dania Altulea
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Joost van den Born
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Theo Bijma
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Carlo Bonasia
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Nanthicha Inrueangsri
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Rosa Lammerts
- Transplantation Immunology, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Stefan Berger
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jan-Stephan Sanders
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Yang B, Tan X, Dong S, Wang M, Wu D, Zhang G, Chen X, Wang M, Yang H, Li Q. The Role of IL-10-Producing Regulatory B Cells in Children With Primary Nephrotic Syndrome. Nephrology (Carlton) 2025; 30:e70008. [PMID: 40052241 DOI: 10.1111/nep.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 05/13/2025]
Abstract
AIM This study aimed to investigate the contribution of interleukin (IL)-10-producing regulatory B cells (B10 cells) to the pathogenesis of PNS. METHODS The percentages of B10 cells, CD19+CD24hiCD27+ B cells, CD19+CD24hiCD38hi B cells, CD19+CD24hiCD27+IL-10+ B cells, CD19+CD24hiCD38hiIL-10+ B cells, Th17 cells, and regulatory T (Treg) cells within the peripheral blood mononuclear cells (PBMCs) from healthy subjects and PNS patients with active disease or in remission were analysed by flow cytometry. RESULTS The percentages and IL-10 production of circulating B10 cells and the two subsets were decreased in children with active PNS and returned to normal levels in PNS patients in remission. B10 cells and their subsets were negatively correlated with the Th17/Treg ratio. The percentages of B10pro+B10 cells, CD19+CD24hiCD27+IL-10+ B cells, CD19+CD24hiCD38hiIL-10+ B cells, Th17 cells, Treg cells, and the Th17/Treg ratio did not significantly differ between groups after CpG and CD40L stimulation. However, in the presence of CpG and anti-CD40L mAb, the percentages of B10pro+B10 cells, CD19+CD24hiCD27+IL-10+ B cells, CD19+CD24hiCD38hiIL-10+ B cells, and Treg cells were significantly reduced, whereas the Th17 cell percentage and the Th17/Treg ratio were significantly increased. Furthermore, the Th17/Treg ratio correlated negatively, whereas the percentages of B10 cells and their subsets correlated positively with serum immunoglobulin G (IgG) concentration. CONCLUSION Our study demonstrates that the numbers of B10 cells and their ability to produce IL-10 are decreased, leading to an imbalance in the Th17/Treg ratio and low IgG levels, which may then contribute to the pathogenesis of PNS.
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Affiliation(s)
- Baohui Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Xiongjun Tan
- Department of Neonatology, The People's Hospital of Baoan, Shenzhen, China
| | - Shifang Dong
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Mo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Daoqi Wu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Gaofu Zhang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Xuelan Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Mei Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Haiping Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
| | - Qiu Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China
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Wei L, Zhang L, Zhao D, Ma Y, Yang L. The characteristic activity of regulatory B cells during the occurrence and development of insulin resistance. Endocrine 2025; 87:562-568. [PMID: 39313706 DOI: 10.1007/s12020-024-04040-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024]
Abstract
PURPOSE To investigate the aberrant distribution and clinical relevance of regulatory B cells (Bregs) subsets in the peripheral blood of individuals with different levels of insulin resistance (IR). METHODS A cohort of 124 subjects were divided into five groups according to their insulin resistance index (HOMA-IR) and diabetes diagnosis. The groups comprised Group 1 (IR- with good glycemic control) and Group 2 (IR- with poor glycemic control) at HOMA-IR < 3, Group 3 (IR+ without T2DM) and Group 4 (IR+ with T2DM), at 3 ≤ HOMA-IR < 6, and Group 5 (IR++ with T2DM) at HOMA-IR ≥ 6. Peripheral blood samples were collected from each group, the percentages of CD19+CD24+CD27+ and CD19+CD24+CD38+ Bregs and the levels of IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ were detected by flow cytometry and flow microsphere matrix method. Additionally, the cytokines levels were validated through ELISA. The activation of Bregs and the production of IL-10 among different groups were analyzed. Spearman correlation analysis was used to analyze the correlation between Bregs activation rate and IR degree. RESULTS The results showed that the levels of CD19+CD24+CD27+ and CD19+CD24+CD38+ cells were increased whether in IR+ without or with type 2 diabetes mellitus (T2DM) groups compared to the IR- groups, with the most significant increase observed in Group 5. Moreover, the plasma levels of IL-6, IL-10, IL-17, TNF-α and IFN-γ in the IR+ group were higher than those in the IR- group. The expression and activation level of Bregs were positively correlated with the severity of IR in T2DM. CONCLUSION These results suggest that the increase level of Bregs is closely related to the severity of IR, highlighting the potential significance of Bregs in the clinical progression of T2DM and its associated insulin resistance.
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Affiliation(s)
- Lingling Wei
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, China
| | - Lijie Zhang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, China
| | - Dong Zhao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, China
| | - Yan Ma
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China.
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, China.
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, China.
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, China.
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Xing C, Cui H, Li G, Liu X, Liu K, Wen Q, Huang X, Wang R, Song L. Hspa13 Deficiency Impaired Marginal Zone B Cells Regulatory Function and Contributed to Lupus Pathogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413144. [PMID: 39737854 PMCID: PMC11848637 DOI: 10.1002/advs.202413144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/11/2024] [Indexed: 01/01/2025]
Abstract
Dysregulated IL-10 producing regulatory B cells (Bregs) are associated with the progression of systemic lupus erythematosus. An immunomodulatory role of heat shock proteins (HSPs) is implicated in autoimmune diseases. However, the molecular basis underlying the role of Hspa13 in regulating Bregs function and lupus pathogenesis remains unclear. In this study, Bregs display higher Hspa13 expression than IL-10- B cells. Induction of IL-10 production is weakened in B cells with Hspa13 knockdown or knockout. Hspa13 binds to the IL-10 promoter via the TATA or CAAT box and activates IL-10 transcription in the nucleus. Furthermore, Hspa13 positive cells are enriched in marginal zone (MZ) B cells to regulate IL-10 production. Stimulated B220+ B or MZ B cells from CD19creHspa13fl/fl mice for Breg induction show an impaired capacity to promote CD4+Foxp3+ regulatory T cells (Treg) differentiation. In lupus MRL/lpr mice, a decline in Treg differentiation is accompanied by decreased Hspa13 expression in both Bregs and MZ B cells. Moreover, adoptive transfusion of Bregs and MZ B cells from CD19creHspa13fl/fl mice fails to increase the frequency of Tregs, attenuate renal pathology, or decrease anti-dsDNA antibody levels. These results explain the unique role of Hspa13 in determining MZ regulatory function and affecting lupus pathogenesis.
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MESH Headings
- Animals
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/metabolism
- Lupus Erythematosus, Systemic/genetics
- Lupus Erythematosus, Systemic/pathology
- Mice
- B-Lymphocytes, Regulatory/immunology
- B-Lymphocytes, Regulatory/metabolism
- Interleukin-10/metabolism
- Interleukin-10/genetics
- Mice, Inbred MRL lpr
- HSP70 Heat-Shock Proteins/genetics
- HSP70 Heat-Shock Proteins/metabolism
- HSP70 Heat-Shock Proteins/deficiency
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Mice, Knockout
- Female
- Disease Models, Animal
- Mice, Inbred C57BL
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Affiliation(s)
- Chen Xing
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Haoran Cui
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Ge Li
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Xiaoling Liu
- Department of DermatologyFirst Medical Centre of ChinesePLA General HospitalBeijing100853China
| | - Kun Liu
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Qing Wen
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Xin Huang
- Beijing Institute of Basic Medical SciencesBeijing100850China
| | - Renxi Wang
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and TechnologyCollaborative Innovation Center for Brain DisordersCapital Medical UniversityBeijing100069China
| | - Lun Song
- Beijing Institute of Basic Medical SciencesBeijing100850China
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Song S, Wang C, Chen Y, Zhou X, Han Y, Zhang H. Dynamic roles of tumor-infiltrating B lymphocytes in cancer immunotherapy. Cancer Immunol Immunother 2025; 74:92. [PMID: 39891668 PMCID: PMC11787113 DOI: 10.1007/s00262-024-03936-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 12/27/2024] [Indexed: 02/03/2025]
Abstract
The amazing diversity of B cells within the tumor microenvironment is the basis for the diverse development of B cell-based immunotherapies. Here, we focus on elucidating the mechanisms of tumor intervention mediated by four tumor-infiltrating B lymphocytes. Naive B cells present the initial antigen, germinal center B cell subsets enhance antibody affinity, and immunoglobulin subtypes exert multiple immune effects, while regulatory B cells establish immune tolerance. Together they reflect the complexity of the changing dynamics of cancer immunity. Additionally, we have investigated the dynamic effects of tumor-infiltrating B lymphocytes in immunotherapy and their relationship to prognosis, providing new insights into potential treatment strategies for patients.
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Affiliation(s)
- Shishengnan Song
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Chong Wang
- Department of Thoracic Surgery, Beijing Chest Hospital Affiliated to Capital Medical University (Beijing Tuberculosis and Thoracic Tumor Research Institute), 9 Beiguan Street, Tongzhou, 101149, Beijing, China
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, 999077, NT, China
| | - Xiaorong Zhou
- Department of Immunology, Medical School of Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China.
| | - Yi Han
- Department of Thoracic Surgery, Beijing Chest Hospital Affiliated to Capital Medical University (Beijing Tuberculosis and Thoracic Tumor Research Institute), 9 Beiguan Street, Tongzhou, 101149, Beijing, China.
| | - Haijian Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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Chayé MAM, van Hengel ORJ, Voskamp AL, Ozir-Fazalalikhan A, König MH, Stam KA, Manurung MD, Mouwenda YD, Aryeetey YA, Kurniawan A, Kruize YCM, Sartono E, Buisman AM, Yazdanbakhsh M, Tak T, Smits HH. Multi-dimensional analysis of B cells reveals the expansion of memory and regulatory B-cell clusters in humans living in rural tropical areas. Clin Exp Immunol 2025; 219:uxae074. [PMID: 39129562 PMCID: PMC11771192 DOI: 10.1093/cei/uxae074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 07/06/2024] [Accepted: 08/09/2024] [Indexed: 08/13/2024] Open
Abstract
B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses, and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN, and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B-cell formation, which "normalizes" with age.
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Affiliation(s)
- Mathilde A M Chayé
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Oscar R J van Hengel
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Astrid L Voskamp
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | | | - Marion H König
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Koen A Stam
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Mikhael D Manurung
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Yoanne D Mouwenda
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
- Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon
| | - Yvonne A Aryeetey
- Parasitology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Agnes Kurniawan
- Department of Parasitology, Universitas Indonesia, Jakarta, Indonesia
| | - Yvonne C M Kruize
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Erliyani Sartono
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Anne-Marie Buisman
- Laboratory for Immunology of Infectious Diseases and Vaccines, Center for Infectious Diseases Control, National Institute for Public Health and The Environment, Bilthoven, The Netherlands
| | - Maria Yazdanbakhsh
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Tamar Tak
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
| | - Hermelijn H Smits
- Leiden University Center for Infectious Diseases (LUCID), LUMC, Leiden, The Netherlands
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9
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Cai H, Mu Q, Xiong H, Liu M, Yang F, Zhou L, Zhou B. Regulatory B cells in parasitic infections: roles and therapeutic potential. Parasitol Res 2025; 124:5. [PMID: 39809978 PMCID: PMC11732949 DOI: 10.1007/s00436-024-08450-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 12/28/2024] [Indexed: 01/16/2025]
Abstract
Parasitic infection is a complex process involving interactions among various immune cells. Regulatory B cells (Breg cells), a subset of B lymphocytes with immunosuppressive functions, play a role in modulating immune responses during infection to prevent excessive immune activation. This article reviews the origin, phenotype, and immunoregulatory mechanisms of Breg cells. We summarize the immunomodulatory roles of Breg cells in various parasitic infections. We also discuss the potential applications of activating Breg cells through parasitic infections and their derived molecules in the treatment of certain allergic, autoimmune, and inflammatory diseases. The aim is to provide new perspectives for the future treatment of parasitic diseases and other related conditions.
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Affiliation(s)
- Haojun Cai
- School of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Qianqian Mu
- School of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Haiting Xiong
- School of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Meichen Liu
- School of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Fengjiao Yang
- School of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Ling Zhou
- Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biying Zhou
- School of Basic Medicine, Zunyi Medical University, Zunyi, China.
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Xu J, Si S, Han Y, Zeng L, Zhao J. Genetic insight into dissecting the immunophenotypes and inflammatory profiles in the pathogenesis of Sjogren syndrome. J Transl Med 2025; 23:56. [PMID: 39806364 PMCID: PMC11726950 DOI: 10.1186/s12967-024-05993-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Sjogren syndrome (SS) is a chronic systemic autoimmune disease and its pathogenesis often involves the participation of numerous immune cells and inflammatory factors. Despite increased researches and studies recently focusing on this area, it remains to be fully elucidated. We decide to incorporate genetic insight into investigation of the causal link between various immune cells, inflammatory factors and pathogenesis of Sjogren syndrome (SS). METHODS Our study leveraged the genetic variants of multi-omics statistics extracted from genome-wide association study (GWAS), the University of Bristol and the FinnGen study. We performed a bidirectional Mendelian randomization and mediation study based on randomly allocated instrumental variables to infer causality, followed by external validation with UK Biobank data and Bayesian colocalization. RESULTS We demonstrated that an elevated level of CD27 on IgD + CD24 + B cell, a subset of B cells expressing both IgD and CD24, was associated with a higher risk of SS (OR = 1.119, 95% CI: 1.061-1.179, P < 0.001), while CD3 on CD45RA + CD4 + Treg was a protective factor (OR = 0.917, 95%CI: 0.877-0.959, P < 0.001). Results of meta-analysis and colocalization further supported the significant results identified in the primary analysis. A total of 4 inflammatory cytokines and 7 circulating proteins exhibited potential causal relationships with SS despite no significant result achieved after FDR correction. Finally, results of mediation analysis indicated that CD40L receptor levels had significant mediating effects (β = 0.0314, 95% CI: 0.0004-0.0624, P = 0.0471) at a mediation proportion of 28% (95% CI: 0.364%-55.6%) in causal relationship between CD27 on IgD + CD24 + B cell and SS. CONCLUSIONS By providing a novel genetic insight into unveiling the roles of autoimmunity and inflammation in Sjogren syndrome, our findings may potentially lead to identifying new clinical biomarkers for disease monitoring and therapeutic targets that offer more effective alternatives for treating this condition. Therefore, our study may provide valuable evidence for future clinical intervention and targeted immunotherapy.
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Affiliation(s)
- Jingyi Xu
- Department of Rheumatology and Immunology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China
| | - Shucheng Si
- Research Center of Clinical Epidemiology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China
| | - Yijun Han
- Department of Rheumatology and Immunology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China
| | - Lin Zeng
- Research Center of Clinical Epidemiology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China.
| | - Jinxia Zhao
- Department of Rheumatology and Immunology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China.
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Quan L, Dai J, Luo Y, Wang L, Liu Y, Meng J, Yang F, You X. The 100 top-cited studies in systemic lupus erythematosus: A bibliometric analysis. Hum Vaccin Immunother 2024; 20:2387461. [PMID: 39149877 PMCID: PMC11328883 DOI: 10.1080/21645515.2024.2387461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/12/2024] [Accepted: 07/30/2024] [Indexed: 08/17/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory tissue disease. In view of the explosive growth in research on SLE, bibliometrics was performed to evaluate the 100 top-cited papers in this realm. We performed the search with terms "systemic lupus erythematosus" the Web of Science Core Collection database on May 3, 2023. Relevant literatures were screened. Data were extracted and analyzed by SPSS. The citations of 100 top-cited SLE studies spanned from 472 to 13,557. Most studies (60 out of 100) were conducted in the United States. Total citation times were positively associated with ACY, which was negatively correlated with the length of time since publication. Approximately half of the studies focused on the underlying mechanisms of SLE. New biologic therapies garnered attention and development. Our findings provide valuable insights into the developments in crucial areas of SLE and shed contributions to future studies.
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Affiliation(s)
- Liuliu Quan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiawen Dai
- Tianjin Institutes of Health Science, Tianjin, China
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yuan Luo
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Lin Wang
- School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yue Liu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jiaqi Meng
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Fan Yang
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Xin You
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China
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12
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Wang YN, Li R, Huang Y, Chen H, Nie H, Liu L, Zou X, Zhong J, Zheng B, Gong Q. The role of B cells in the pathogenesis of type 1 diabetes. Front Immunol 2024; 15:1450366. [PMID: 39776900 PMCID: PMC11703732 DOI: 10.3389/fimmu.2024.1450366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Type 1 diabetes (T1D) is a metabolic disorder caused by a complete lack of insulin, primarily manifested by hyperglycemia. The mechanisms underlying the onset of T1D are complex, involving genetics, environment, and various unknown factors, leading to the infiltration of various immune components into the islets. Besides T cells, B cells are now considered important contributors to the pathogenesis of T1D, according to recent studies. In non-obese diabetic (NOD) mice, the absence of B cells prevents the development of T1D, and B-cell depletion can even restore the function of pancreatic β cells, emphasizing their involvement in the development of T1D. Naturally, besides pathogenic B cells, regulatory B cells (Bregs) might have a protective function in T1D. This article examines the mechanisms behind B-cell tolerance and the defects in B-cell tolerance checkpoints in T1D. We explored possible functions of B cells in T1D, including the role of islet autoantibodies in T1D, T-B cell interactions, and the role of Bregs in the pathogenesis of T1D. We also summarized the advances of B cell-targeted therapy, exploring new methods for intervention and treatment of T1D.
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Affiliation(s)
- Ya-nan Wang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Ruihua Li
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Yaxuan Huang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Hui Chen
- Department of Laboratory Medicine, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Lian Liu
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Xiaoting Zou
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
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13
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Hashimoto A, Hashimoto S. Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives. Cancers (Basel) 2024; 16:4094. [PMID: 39682280 DOI: 10.3390/cancers16234094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.
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Affiliation(s)
- Ari Hashimoto
- Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Barile R, Rotondo C, Rella V, Trotta A, Cantatore FP, Corrado A. Fibrosis mechanisms in systemic sclerosis and new potential therapies. Postgrad Med J 2024:qgae169. [PMID: 39656890 DOI: 10.1093/postmj/qgae169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/20/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024]
Abstract
Systemic sclerosis is a rare rheumatic disease characterized by immune cell activation, tissue fibrosis, and endothelial dysfunction. Extracellular matrix synthesis disorder causes widespread fibrosis, primarily in skin and internal organs. Various factors such as TGFβ, VEGF, Galectin-3, and signaling pathways like Wnt/β-catenin are involved in pathophysiological processes. Treatment lacks a unified approach but combines diverse modalities tailored to disease subtype and progression. Current therapeutic strategies include biologics, JAK inhibitors, and IL-6 pathway modulators. Monoclonal antibodies and hypomethylating agents demonstrate potential in fibrosis inhibition. This review focuses on emerging therapeutic evidence regarding drugs targeting collagen, cytokines, and cell surface molecules in systemic sclerosis, aiming to provide insight into potential innovative treatment strategies.
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Affiliation(s)
- Raffaele Barile
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
| | - Cinzia Rotondo
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
| | - Valeria Rella
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
| | - Antonello Trotta
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
| | - Francesco Paolo Cantatore
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
| | - Addolorata Corrado
- Rheumatology Unit, Department of Medical and Surgical Sciences, University of Foggia, Luigi Pinto 1, 71121, Foggia, Italy
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Bao Y, Liu J, Li Z, Sun Y, Chen J, Ma Y, Li G, Wang T, Liu H, Zhang X, Yan R, Yao Z, Guo X, Fang R, Feng J, Xia W, Xiang AP, Chen X. Ex vivo-generated human CD1c + regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. Mol Ther 2024; 32:4372-4382. [PMID: 39489917 PMCID: PMC11638867 DOI: 10.1016/j.ymthe.2024.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/06/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024] Open
Abstract
IL-10+ regulatory B cells (Bregs) show great promise in treating graft-versus-host disease (GVHD), a life-threatening complication of post-hematopoietic stem cell transplantation. However, obtaining high-quality human IL-10+ Bregs in vitro remains a challenge due to the lack of unique specific markers and the triggering of pro-inflammatory cytokine expression. Here, by uncovering the critical signaling pathways in Breg induction by mesenchymal stromal cells (MSCs), we first established an efficient Breg induction system based on MSCs and GSK-3β blockage (CHIR-99021), which had a robust capacity to induce IL-10+ Bregs while suppressing tumor necrosis factor α (TNF-α) expression. Furthermore, these Breg populations could be identified and enriched by CD1c+. Mechanistically, MSCs induced the expansion of Bregs through the PKA-mediated phosphorylation of cAMP response element-binding protein (CREB). Thus, we developed a chemically defined inducing protocol by PKA-CREB agonist, instead of MSCs, which can also effectively induce CD1c+ Bregs with lower TNF-α expression. Importantly, induced CD1c+ Bregs suppressed the proliferation of peripheral blood mononuclear cells and the inflammatory cytokine secretion of T cells. When adoptively transferred into a humanized mouse model of GVHD, induced CD1c+ Bregs effectively alleviated GVHD. Overall, we established an efficient ex vivo induction system for human Bregs, which has implications for developing novel Bregs-based therapies for GVHD.
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Affiliation(s)
- Yingying Bao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China; Institute of Gene and Cell Therapy, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jialing Liu
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Zhishan Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Yueming Sun
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Junhua Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Yuanchen Ma
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Gang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Tao Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Huanyi Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoran Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Rong Yan
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Zhenxia Yao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China
| | - Xiaolu Guo
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Rui Fang
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Jianqi Feng
- Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518067, Guangdong, China
| | - Wenjie Xia
- Institute of Blood Transfusion, Guangzhou Blood Centre, Guangzhou 510095, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China.
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 5100080, China; National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 5100080, China.
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Su QY, Jiang ZQ, Song XY, Zhang SX. Regulatory B cells in autoimmune diseases: Insights and therapeutic potential. J Autoimmun 2024; 149:103326. [PMID: 39520834 DOI: 10.1016/j.jaut.2024.103326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/06/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Autoimmune diseases are characterized by the body's immune system attacking its own cells, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In recent studies, regulatory B cells (Bregs), which play a vital role in maintaining peripheral tolerance and controlling persistent autoimmune diseases (ADs), have shown great potential in treating ADs. This review synthesizes the latest advancements in targeted therapies for ADs, with a particular emphasis on the subgroups, phenotypic markers, and signal pathways associated with Bregs. Following an examination of these elements, the discussion pivots to innovative Breg-based therapeutic approaches for the management of ADs.
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Affiliation(s)
- Qin-Yi Su
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Shanxi Province, Taiyuan, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, Taiyuan, China
| | - Zhong-Qing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Shanxi Province, Taiyuan, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, Taiyuan, China
| | - Xuan-Yi Song
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Shanxi Province, Taiyuan, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, Taiyuan, China
| | - Sheng-Xiao Zhang
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Shanxi Province, Taiyuan, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, Taiyuan, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.
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Puppa MA, Bennstein SB, Fischer HJ, Rink L. Zinc deficiency impairs the development of human regulatory B cells from purified B cells. J Trace Elem Med Biol 2024; 86:127556. [PMID: 39442468 DOI: 10.1016/j.jtemb.2024.127556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/11/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
Zinc is a vital trace element, important for many different immune processes and adequate functionality. B cell development is known to be dependent on sufficient zinc supply. Recently a regulatory B cell (Breg) population has been identified, as CD19+IL-10+ B cells, able to regulate immune responses by secretion of anti-inflammatory cytokines, such as IL-10. Due to their promotion of an anti-inflammatory milieu, Bregs could reduce or might even prevent excessive pro-inflammatory responses. Hence, having and maintaining Bregs could be interesting for patients suffering from allergies, asthma, and autoimmune diseases. Therefore, understanding Breg generation, required signaling, and their developmental requirements are important. Since our group could previously show that zinc is important for regulatory T cells, we aimed to determine the effect of zinc deficiency on Breg development from human peripheral blood CD19+ B cells. We observed highest Breg generation with a combined stimulus of CD40L and the toll like receptor (TLR) ligand, CpG-ODN2006. Using this stimulus, we observed that zinc deficient medium significantly decreased Breg generation from purified B cells. This was not seen in Bregs generated from peripheral blood mononuclear cells (PBMCs) without B cell enrichment suggesting a compensatory mechanism. In line with literature, our data also confirms Bregs develop from CD19+ B cells, since total CD19+ frequencies remained unchanged, while Breg frequencies varied between stimuli and zinc media conditions. Our study shows for the first time that zinc deficiency significantly impairs Breg development, which provides an important new perspective for clinical applications and therapeutic strategies.
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Affiliation(s)
- Mary-Ann Puppa
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Sabrina B Bennstein
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Henrike J Fischer
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Lothar Rink
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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Lipińska-Opałka A, Leszczyńska-Pilich M, Będzichowska A, Tomaszewska A, Rustecka A, Kalicki B. The Role of Regulatory B Lymphocytes in Allergic Diseases. Biomedicines 2024; 12:2721. [PMID: 39767628 PMCID: PMC11726865 DOI: 10.3390/biomedicines12122721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
PURPOSE OF REVIEW Regulatory B cells (Bregs) are a key component in the regulation of the immune system. Their immunosuppressive function, which includes limiting the inflammatory cascade, occurs through interactions with other immune cells and the secretion of cytokines, primarily IL-10. As knowledge about B cells continues to expand, their diversity is becoming more recognized, with many subpopulations identified in both human and animal models. However, identifying specific transcription factors or markers that could definitively distinguish regulatory B cells remains a challenge. This review summarizes recent findings on the role of B regulatory cells in allergic diseases. RECENT FINDINGS In patients with bronchial asthma, atopic dermatitis, and food allergies, the number of regulatory B cells is reduced, and disease severity is inversely proportional to the quantity of these cells. Furthermore, in patients with atopic dermatitis, the ability of regulatory B cells to produce IL-10 in response to IL-6 stimulation is diminished. However, allergen immunotherapy has been shown to induce the formation of regulatory T cells as well as regulatory B cells. SUMMARY The success of future therapies based on B cells may depend on deepening our current understanding of their phenotypes, induction, differentiation, and function. Research in these areas is essential for understanding the mechanisms regulating Breg activity and for developing potential targeted therapies in the treatment of allergic diseases.
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Affiliation(s)
- Agnieszka Lipińska-Opałka
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Michalina Leszczyńska-Pilich
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agata Będzichowska
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agata Tomaszewska
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agnieszka Rustecka
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Bolesław Kalicki
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
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Nishioka Y, Murayama G, Kusaoi M, Takemasa D, Kaneda K, Kuga T, Hagiwara Y, Saito T, Yamaji Y, Suzuki Y, Nagaoka T, Yamaji K, Tamura N. Enhanced therapeutic efficacy of granulocyte/monocyte adsorption in rats with drug-induced colitis : Insights from a downsized bead column and newly formed B cells. Ther Apher Dial 2024. [PMID: 39568103 DOI: 10.1111/1744-9987.14234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 11/22/2024]
Abstract
INTRODUCTION Granulocyte/monocyte adsorption therapy can manage mild-to-moderate inflammatory bowel disease by removing activated granulocytes and monocytes. We evaluated granulocyte/monocyte adsorption using new columns with reduced bead size and theoretically enhanced adsorption. METHODS We assessed granulocyte/monocyte adsorption in rats with colitis by analyzing cell changes and cytokine production. RESULTS Granulocyte/monocyte adsorption with the new columns improved histology in rats with colitis. Contrary to expectations, the adsorption rate of granulocytes/monocytes into the blood did not show a significant improvement. However, flow cytometry showed increased B cells in peripheral blood mononuclear cells and newly formed B cells in the bone marrow, which produced more interleukin-10 than peripheral blood B cells. Newly formed B cells adoptively transferred into colitis rats accumulated at the inflammation site and tended to inhibit intestinal shortening. CONCLUSIONS Newly formed B cells with strong interleukin-10 production may alleviate inflammation. The new columns suggest potential for controlling colitis.
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Affiliation(s)
- Yujin Nishioka
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Goh Murayama
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Makio Kusaoi
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | | | | | - Taiga Kuga
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yukitomo Hagiwara
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takumi Saito
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yu Yamaji
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoshifumi Suzuki
- Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Tetsutaro Nagaoka
- Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Ken Yamaji
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
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Wang X, Tang J, Zhang X, Zeng H. The Protective Effect of Esculentoside A on MPL/lpr Mice by Upregulating the Expression of CD19+IL-35+Breg Cells and Interleukin-35. Int Arch Allergy Immunol 2024; 186:358-368. [PMID: 39500292 DOI: 10.1159/000541812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 09/27/2024] [Indexed: 03/27/2025] Open
Abstract
INTRODUCTION Esculentoside A (EsA) is one of the main components of the traditional Chinese medicine Phytolacca esculenta. The possible mechanism of action of EsA in the treatment of lupus nephritis (LN) was explored by observing the effects of EsA on CD19+ IL-35+regulatory B (IL-35+Breg) cells. METHODS Twenty-four MRL/lpr mice were randomly divided into control, EsA, and EsA+IL-12p35 antibody groups. Mice were administered the respective treatments intraperitoneally once a day for 4 weeks. The urine protein/creatinine ratio (UPCR) and blood creatinine (Cr) and IL-35, IL-10, and IL-17 expression levels were measured. Body and spleen weight were measured to calculate the splenic index (SI). Flow cytometry was performed to determine the proportion of CD19+ IL-35+ Breg cells in the spleen. Hematoxylin-eosin and PASM-Masson staining of renal tissues were performed, and the "Austin" acute index (AI) system for LN was determined. RESULTS The most severe conditions were seen in mice in the control group, with the highest UPCR, Cr, and IL-17 levels and SI and AI scores; the most severe renal histopathology, and the lowest proportion of CD19+ IL-35+ Breg cells and IL-35 and IL-10 levels. This was followed by the EsA+IL-12p35 antibody group. The EsA group had the lowest UPCR, Cr, and IL-17 levels and SI and AI scores; the mildest renal lesions; and the highest proportion CD19+ IL-35+ Breg cells and IL-35 and IL-10 levels. CONCLUSION EsA delayed the progression of LN by promoting the proliferation of CD19+ IL-35+ Breg cells, upregulating the expression of IL-35, and decreasing the secretion of IL-17.
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Affiliation(s)
- Xing Wang
- Department of Nephrology and Rheumatology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China,
| | - Jieyin Tang
- Department of Nephrology and Rheumatology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
| | - Xianggui Zhang
- Department of Nephrology and Rheumatology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
| | - Huilin Zeng
- Department of Nephrology and Rheumatology, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
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21
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Bradford HF, Mauri C. Diversity of regulatory B cells: Markers and functions. Eur J Immunol 2024; 54:e2350496. [PMID: 39086053 DOI: 10.1002/eji.202350496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024]
Abstract
Regulatory B cells (Bregs) are a functionally distinct B-cell subset involved in the maintenance of homeostasis and inhibition of inflammation. Studies, from the last two decades, have increased our understanding of cellular and molecular mechanisms involved in their generation, function, and to a certain extent phenotype. Current research endeavours to unravel the causes and consequences of Breg defects in disease, with increasing evidence highlighting the relevance of Bregs in promoting tumorigenic responses. Here we provide historical and emerging findings of the significance of Bregs in autoimmunity and transplantation, and how these insights have translated into the cancer field.
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Affiliation(s)
- Hannah F Bradford
- Division of Infection and Immunity and Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
| | - Claudia Mauri
- Division of Infection and Immunity and Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
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22
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Tian S, Xia J, Liu K, Ma Y, Tian H, Wang W, Zhang R, Zhao C, Gong S. The role of CD24 hiCD27 + regulatory B cells in human chronic rhinosinusitis with/without nasal polyps. Immunobiology 2024; 229:152854. [PMID: 39340956 DOI: 10.1016/j.imbio.2024.152854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/31/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Regulatory B cells (Bregs) reduce allergic and autoimmune inflammation. However, their role in chronic rhinosinusitis (CRS) remains unknown. This study investigated the frequency and function of Breg subsets in the peripheral blood of patients with CRS. METHODS The demographic and clinical characteristics were compared among control, CRSsNP, neCRSwNP, and eCRSwNP groups. The expression of various Breg subtypes was evaluated in peripheral blood mononuclear cells (PBMCs) of patients with eosinophilic CRS with nasal polyps (eCRSwNP), non-eosinophilic CRS with nasal polyps (neCRSwNP), CRS without nasal polyps (CRSsNP). CD19+CD24hiCD27+ B cells (B10 cells) were isolated by flow cytometry, followed by RNA sequencing (RNA-seq). Finally, IL-10 secreted by B10 cells were evaluated through the intracellular stain. RESULTS A higher number of eosinophils in peripheral blood and nasal polyps were found in eCRSwNP compared with neCRSwNP, CRSsNP, and control groups. The frequency of B10 in the peripheral blood B cells (B10%) of patients with eCRSwNP was significantly lower than that in the neCRSwNP and control groups. B10% was negatively correlated with the quantity of tissue eosinophils, and the percentage and absolute value of peripheral blood eosinophils. The eCRSwNP, neCRSwNP and control groups had 1403 differentially expressed genes, 35 of which were identified in four highly enriched pathways. Additionally, the frequency of IL-10+B10 cells in peripheral blood was lower in patients with eCRSwNP than in the neCRSwNP and control groups. CONCLUSION This study is the first to reveal differences in both the quantity and IL-10 secretion of B10 cells in patients with eCRSwNP and neCRSwNP. These variations were strongly negatively associated with eosinophils in nasal polyps and peripheral blood. IL-10+B10 cells may play a key role in the pathological mechanisms of CRS, particularly the recurrence of eCRSwNP.
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Affiliation(s)
- Shiyu Tian
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jiao Xia
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ke Liu
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Youxiang Ma
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Tian
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Weiwei Wang
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ruxiang Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Chunli Zhao
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shusheng Gong
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Zou J, Nov P, Du K. Mendelian randomization analysis of the causal relationship between immune cells and keloid. Dermatol Reports 2024; 17. [PMID: 40420724 DOI: 10.4081/dr.2024.10106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Indexed: 05/28/2025] Open
Abstract
Immune cells play complex roles in the formation of keloid. We aimed to investigate the causal relationship between immune cells and keloid and provide genetic evidence for the association between immune cells and keloid risk. Based on data from a genome-wide association study (GWAS), we performed a comprehensive two-sample Mendelian randomization (MR) analysis of 731 immune cell traits in 481,912 keloid cases. We used the inverse-variance weighting (IVW) method as the primary analysis. Then, a comprehensive sensitivity analysis was adopted to verify the results' robustness, heterogeneity, and horizontal pleiotropy. Finally, reverse MR analysis was performed. The IVW method in forward MR analysis showed that CD66b++ myeloid cell AC was negatively associated with keloid risk (OR<1, p<0.05). Consistently, reverse MR analysis showed that keloid risk was negatively associated with CD66b++ myeloid cell AC (OR=0.85, p=0.012). No significant horizontal pleiotropy or heterogeneity was observed. The results of MR analysis demonstrate a bidirectional causal association between CD66b++ myeloid cell AC and keloid formation, suggesting that CD66b++ myeloid cell AC is a protective factor against keloid.
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Affiliation(s)
- Jingwen Zou
- Department of Dermatologic Surgery, Dermatology Hospital of Southern Medical University, Guangzhou
| | - Pengkhun Nov
- Department of Radiation Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou
| | - Kunpeng Du
- Department of Radiation Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou
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24
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Huang SW, Jiang W, Xu S, Zhang Y, Du J, Wang YQ, Yang KY, Zhang N, Liu F, Zou GR, Jin F, Wu HJ, Zhou YY, Zhu XD, Chen NY, Xu C, Qiao H, Liu N, Sun Y, Ma J, Liang YL, Liu X. Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit: biomarker analysis from the phase 3 CONTINUUM and DIPPER trials. Signal Transduct Target Ther 2024; 9:285. [PMID: 39438442 PMCID: PMC11496634 DOI: 10.1038/s41392-024-01988-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/09/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.
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Affiliation(s)
- Sai-Wei Huang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Wei Jiang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Sha Xu
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Yuan Zhang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Juan Du
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Ya-Qin Wang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Kun-Yu Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Ning Zhang
- Department of Radiation Oncology, The First People's Hospital of Foshan, Foshan, PR China
| | - Fang Liu
- Department of Pathology, The First People's Hospital of Foshan, Foshan, PR China
| | - Guo-Rong Zou
- Department of Oncology, Panyu Central Hospital, Guangzhou, PR China
| | - Feng Jin
- Department of Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, PR China
| | - Hai-Jun Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, PR China
| | - Yang-Ying Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, PR China
| | - Xiao-Dong Zhu
- Department of Radiation Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China
| | - Nian-Yong Chen
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Cheng Xu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Han Qiao
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Na Liu
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Ying Sun
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Jun Ma
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
| | - Ye-Lin Liang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
| | - Xu Liu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
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25
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Blevins LK, Khan DIO, Crawford RB, O’Neill C, Bach AP, Zhou J, Karmaus PW, Ang DC, Thapa R, Kaminski NE. CD9 and Aryl Hydrocarbon Receptor Are Markers of Human CD19+CD14+ Atypical B Cells and Are Dysregulated in Systemic Lupus Erythematous Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:1076-1092. [PMID: 39212542 PMCID: PMC11458359 DOI: 10.4049/jimmunol.2400193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024]
Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose expression regulates immune cell differentiation. Single-cell transcriptomic profiling was used to ascertain the heterogeneity of AHR expression in human B cell subpopulations. We identified a unique population of B cells marked by expression of AHR, CD9, and myeloid genes such as CD14 and CXCL8. Results were confirmed directly in human PBMCs and purified B cells at the protein level. TLR9 signaling induced CD14, CD9, and IL-8 protein expression in CD19+ B cells. CD14-expressing CD9+ B cells also highly expressed AHR and atypical B cell markers such as CD11c and TBET. In patients with active lupus disease, CD14+ and CD9+ B cells are dysregulated, with loss of CD9+ B cells strongly predicting disease severity and demonstrating the relevance of CD9+ B cells in systemic lupus erythematosus and autoimmune disease.
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Affiliation(s)
- Lance K. Blevins
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
| | - D.M. Isha O. Khan
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI USA 48824
| | - Robert B. Crawford
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
| | - Christine O’Neill
- Atrium Health Wake Forest Baptist School of Medicine, Winston Salem, NC USA 27157
| | - Anthony P. Bach
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
| | - Jiajun Zhou
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI USA 48824
| | - Peer W. Karmaus
- National Institute of Environmental Health Sciences, Research Triangle Park, NC USA 27709
| | - Dennis C. Ang
- Atrium Health Wake Forest Baptist School of Medicine, Winston Salem, NC USA 27157
| | - Rupak Thapa
- Atrium Health Wake Forest Baptist School of Medicine, Winston Salem, NC USA 27157
| | - Norbert E. Kaminski
- Institute of Integrative Toxicology, Michigan State University, East Lansing, MI USA 48824
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI USA 48824
- Center for Research on Ingredient Safety, Michigan State University, East Lansing, MI USA 48824
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Baert L, Mahmudul HM, Stegall M, Joo H, Oh S. B Cell-mediated Immune Regulation and the Quest for Transplantation Tolerance. Transplantation 2024; 108:2021-2033. [PMID: 38389135 DOI: 10.1097/tp.0000000000004948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients.
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Affiliation(s)
- Laurie Baert
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | | | - Mark Stegall
- Department of Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
| | - HyeMee Joo
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | - SangKon Oh
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
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27
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Li JY, Feng TS, Gao J, Yang XX, Li XC, Deng ZH, Xia YX, Wu ZS. Differentiation and immunosuppressive function of CD19 +CD24 hiCD27 + regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway. Hepatobiliary Pancreat Dis Int 2024; 23:472-480. [PMID: 38724321 DOI: 10.1016/j.hbpd.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 04/12/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.
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Affiliation(s)
- Jin-Yang Li
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Tian-Shuo Feng
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Ji Gao
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Xin-Xiang Yang
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Xiang-Cheng Li
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Zhen-Hua Deng
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Yong-Xiang Xia
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China
| | - Zheng-Shan Wu
- Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing 210029, China.
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Ma Y, Ji J, Liu X, Zheng X, Xu L, Zhou Q, Li Z, Yang L. Integrative Analysis by Mendelian Randomization and Large-Scale Single-Cell Transcriptomics Reveals Causal Links between B Cell Subtypes and Diabetic Kidney Disease. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:327-345. [PMID: 39430286 PMCID: PMC11488840 DOI: 10.1159/000539689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 06/03/2024] [Indexed: 10/22/2024]
Abstract
Introduction The increasing incidence of diabetic kidney disease (DKD) and the challenges in its management highlight the necessity for a deeper understanding of its pathogenesis. While recent studies have underscored the substantial impact of circulating immunity on the development of diabetic microvascular complications such as retinopathy and neuropathy, research on circulating immunity in DKD remains limited. Methods This study utilized Mendelian randomization analysis to explore the potential independent causal relationships between circulating immune cells and DKD pathogenesis. Additionally, a combination of single-cell disease relevance score (scDRS) and immune cell infiltration analysis was employed to map the circulating immunity landscape in DKD patients. Results Ten immune traits, including 5 of B cells, 2 of T cells, 2 of granulocytes, and one of monocytes, were defined to be associated with the pathogenesis of DKD. Notably, IgD - CD27 - B cell Absolute Count (IVW: OR, 1.102 [1.023-1.189], p = 0.011) and IgD - CD24 - B cell Absolute Count (IVW: OR, 1.106 [1.030-1.188], p = 0.005) were associated with promoting DKD pathogenesis, while CD24 + CD27 + B cell %B cell (IVW: OR, 0.943 [0.898-0.989], p = 0.016) demonstrated a protective effect against DKD onset. The presence of B cell-activating factor receptor (BAFF-R) on CD20 - CD38 - B cell (IVW: OR, 0.946 [0.904-0.989], p = 0.015) and BAFF-R on IgD - CD38 + B cell (IVW: OR, 0.902 [0.834-0.975], p = 0.009) also indicated a potential role in preventing DKD. scDRS analysis revealed that two main subsets of B cells, naïve B and memory B cells, had a higher proportion of DKD-related cells or a higher scDRS score of DKD phenotype, indicating their strong association with DKD. Furthermore, immune infiltrate deconvolution analysis showed a notable decrease in the circulating memory B cells and class-switched memory B cells in DKD patients compared to those of DM patients without DKD. Conclusion Our study revealed the causal relations between circulating immunity and DKD susceptibility, particularly highlighted the potential roles of B cell subtypes in DKD development. Further studies addressing the related mechanisms would broaden the current understanding of DKD pathogenesis.
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Affiliation(s)
- Yuan Ma
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Ji
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xintong Liu
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xizi Zheng
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Lingyi Xu
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Qingqing Zhou
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Zehua Li
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Yang
- Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Ahsan NF, Lourenço S, Psyllou D, Long A, Shankar S, Bashford-Rogers R. The current understanding of the phenotypic and functional properties of human regulatory B cells (Bregs). OXFORD OPEN IMMUNOLOGY 2024; 5:iqae012. [PMID: 39346706 PMCID: PMC11427547 DOI: 10.1093/oxfimm/iqae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/13/2024] [Accepted: 09/10/2024] [Indexed: 10/01/2024] Open
Abstract
B cells can have a wide range of pro- and anti- inflammatory functions. A subset of B cells called regulatory B cells (Bregs) can potently suppress immune responses. Bregs have been shown to maintain immune homeostasis and modulate inflammatory responses. Bregs are an exciting cellular target across a range of diseases, including Breg induction in autoimmunity, allergy and transplantation, and Breg suppression in cancers and infection. Bregs exhibit a remarkable phenotypic heterogeneity, rendering their unequivocal identification a challenging task. The lack of a universally accepted and exclusive surface marker set for Bregs across various studies contributes to inconsistencies in their categorization. This review paper presents a comprehensive overview of the current understanding of the phenotypic and functional properties of human Bregs while addressing the persisting ambiguities and discrepancies in their characterization. Finally, the paper examines the promising therapeutic opportunities presented by Bregs as their immunomodulatory capacities have gained attention in the context of autoimmune diseases, allergic conditions, and cancer. We explore the exciting potential in harnessing Bregs as potential therapeutic agents and the avenues that remain open for the development of Breg-based treatment strategies.
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Affiliation(s)
- Nawara Faiza Ahsan
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Stella Lourenço
- Keizo Asami Institute, Federal University of Pernambuco, Recife 50740-520, Brazil
| | - Dimitra Psyllou
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Alexander Long
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Sushma Shankar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Rachael Bashford-Rogers
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Oxford Cancer Centre, University of Oxford, Oxford OX3 7LH, United Kingdom
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30
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Tran B, Voskoboynik M, Bendell J, Gutierrez M, Lemech C, Day D, Frentzas S, Garrido-Laguna I, Standifer N, Wang F, Ferte C, Wang Y, Das M, Carneiro BA. A phase 1 study of the CD40 agonist MEDI5083 in combination with durvalumab in patients with advanced solid tumors. Immunotherapy 2024; 16:759-774. [PMID: 39264730 PMCID: PMC11421296 DOI: 10.1080/1750743x.2024.2359359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 05/21/2024] [Indexed: 09/14/2024] Open
Abstract
Aim: This first-in-human study evaluated safety and efficacy of CD40 agonist MEDI5083 with durvalumab in patients with advanced solid tumors.Methods: Patients received MEDI5083 (3-7.5 mg subcutaneously every 2 weeks × 4 doses) and durvalumab (1500 mg every 4 weeks) either sequentially (N = 29) or concurrently (N = 9). Primary end point was safety; secondary end points included efficacy.Results: Thirty-eight patients received treatment. Most common adverse events (AEs) were injection-site reaction (ISR; sequential: 86%; concurrent: 100%), fatigue (41%; 33%), nausea (20.7%; 55.6%) and decreased appetite (24.1%; 33.3%). Nine patients had MEDI5083-related grade ≥3 AEs with ISR being the most common. Two patients experienced dose limiting toxicities (ISR). One death occurred due to a MEDI5083-related AE. MEDI5083 maximum tolerated dose was 5 mg. Objective response rate was 2.8% (1 partial response and 11 stable disease).Conclusion: MEDI5083 toxicity profile limits its further development.
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Affiliation(s)
- Ben Tran
- Peter MacCallum Cancer Centre, Melbourne, 8006, Australia
| | - Mark Voskoboynik
- Nucleus Network, Melbourne, 3004, Australia
- Monash University, Melbourne, 3004, Australia
| | - Johanna Bendell
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN 37203, USA
| | | | - Charlotte Lemech
- Scientia Clinical Research, Randwick, 2031, Australia
- The University of New South Wales, Sydney, 2052, Australia
| | - Daphne Day
- Monash University, Melbourne, 3004, Australia
- Monash Medical Centre, Clayton, 3800, Australia
| | - Sophia Frentzas
- Monash University, Melbourne, 3004, Australia
- Monash Medical Centre, Clayton, 3800, Australia
| | | | - Nathan Standifer
- Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, South San Francisco, CA 94080, USA
| | - Fujun Wang
- Oncology Biometrics, AstraZeneca, Gaithersburg, MD 20878,USA
| | | | - Yue Wang
- AstraZeneca, Gaithersburg, MD 20878,USA
| | | | - Benedito A Carneiro
- Legorreta Cancer Center at Brown University, Lifespan Cancer Institute, Providence, RI 02903,USA
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31
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Martínez LE, Comin-Anduix B, Güemes-Aragon M, Ibarrondo J, Detels R, Mimiaga MJ, Epeldegui M. Characterization of unique B-cell populations in the circulation of people living with HIV prior to non-Hodgkin lymphoma diagnosis. Front Immunol 2024; 15:1441994. [PMID: 39324141 PMCID: PMC11422120 DOI: 10.3389/fimmu.2024.1441994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 08/20/2024] [Indexed: 09/27/2024] Open
Abstract
People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10+CD27- B cells, CD20+CD27- B cells, and B-cell populations with aberrant features (CD20+CD27+CXCR4+CD71+ B cells and CD20+CXCR4+cMYC+ B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20+CD27+CD24+CXCR4+CXCR5+ B cells, CD20+CD27+CD10+CD24+CXCR4+cMYC+ B cells, and a cluster of CD20+CXCR4hiCD27-CD24+CXCR5+CD40+CD4+AICDA+ B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20+CXCR4+CXCR5+cMYC+AICDA+ B cells and a cluster of germinal center B-cell-like cells (CD19-CD20+CXCR4+Bcl-6+PD-L1+cMYC+) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19+CD24hiCD38hi cMYC+ AICDA+ B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.
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Affiliation(s)
- Laura E. Martínez
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Begoña Comin-Anduix
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, United States
- Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, CA, United States
| | - Miriam Güemes-Aragon
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Javier Ibarrondo
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, CA, United States
| | - Roger Detels
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States
| | - Matthew J. Mimiaga
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States
| | - Marta Epeldegui
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
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32
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Meng Q, Ma J, Cui J, Gu Y, Shan Y. Subpopulation dynamics of T and B lymphocytes in Sjögren's syndrome: implications for disease activity and treatment. Front Immunol 2024; 15:1468469. [PMID: 39290700 PMCID: PMC11405198 DOI: 10.3389/fimmu.2024.1468469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Sjögren's syndrome (SS) is an autoimmune disorder primarily affecting the body's exocrine glands, particularly the salivary and lacrimal glands, which lead to severe symptoms of dry eyes and mouth. The pathogenesis of SS involves the production of autoantibodies by activated immune cells, and secretion of multiple cytokines, which collectively lead to tissue damage and functional impairment. In SS, the Immune interaction among T and B cells is particularly significant. Lymphocytic infiltration in the salivary glands is predominantly composed of CD4+ T cells, whose activation cause the death of glandular epithelial cells and subsequent tissue destruction. The excessive activity of T cells contributes significantly to the disease mechanism, with helper T cells (CD4+) differentiating into various subgroups including Th1/Th2, Th17, as well as Treg, each contributing to the pathological process through distinct cytokine secretion. In patients with SS, B cells are excessively activated, leading to substantial production of autoantibodies. These antibodies can attack self-tissues, especially the lacrimal and salivary glands, causing inflammation and tissue damage. Changes in B cell subpopulations in SS patients, such as increases in plasmablasts and plasma cells, correlate positively with serum autoantibody levels and disease progression. Therapies targeting T cells and B cells are extensively researched with the aim of alleviating symptoms and improving the quality of life for patients. Understanding how these cells promote disease development through various mechanisms, and further identifying novel T and B cell subgroups with functional characterization, will facilitate the development of more effective strategies to treat SS.
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Affiliation(s)
- Qingliang Meng
- Department of Rheumatism, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Junfu Ma
- Department of Rheumatism, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Jiakang Cui
- Department of Rheumatism, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yangyi Gu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Shan
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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33
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Yang Y, Chen X, Pan J, Ning H, Zhang Y, Bo Y, Ren X, Li J, Qin S, Wang D, Chen MM, Zhang Z. Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes. Cell 2024; 187:4790-4811.e22. [PMID: 39047727 DOI: 10.1016/j.cell.2024.06.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 04/25/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024]
Abstract
Characterizing the compositional and phenotypic characteristics of tumor-infiltrating B cells (TIBs) is important for advancing our understanding of their role in cancer development. Here, we establish a comprehensive resource of human B cells by integrating single-cell RNA sequencing data of B cells from 649 patients across 19 major cancer types. We demonstrate substantial heterogeneity in their total abundance and subtype composition and observe immunoglobulin G (IgG)-skewness of antibody-secreting cell isotypes. Moreover, we identify stress-response memory B cells and tumor-associated atypical B cells (TAABs), two tumor-enriched subpopulations with prognostic potential, shared in a pan-cancer manner. In particular, TAABs, characterized by a high clonal expansion level and proliferative capacity as well as by close interactions with activated CD4 T cells in tumors, are predictive of immunotherapy response. Our integrative resource depicts distinct clinically relevant TIB subsets, laying a foundation for further exploration of functional commonality and diversity of B cells in cancer.
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Affiliation(s)
- Yu Yang
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Xueyan Chen
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Jieying Pan
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Huiheng Ning
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yufei Bo
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Xianwen Ren
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Jiesheng Li
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Shishang Qin
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China
| | - Dongfang Wang
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China.
| | - Min-Min Chen
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China.
| | - Zemin Zhang
- Biomedical Pioneering Innovation Center (BIOPIC), Academy for Advanced Interdisciplinary Studies, and School of Life Sciences, Peking University, Beijing 100871, China.
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Barbado J. Mesenchymal stem cell transplantation may be able to induce immunological tolerance in systemic lupus erythematosus. Biomed J 2024; 47:100724. [PMID: 38616015 PMCID: PMC11340565 DOI: 10.1016/j.bj.2024.100724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/24/2024] [Accepted: 04/06/2024] [Indexed: 04/16/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a common, potentially fatal autoimmune disease involving a significant inflammatory response. SLE is characterised by failure of self-tolerance and activation of autoreactive lymphocytes, leading to persistent disease. Although current treatments achieve some improvement in patients, some SLE patients are refractory and others relapse after drug withdrawal. The toxicity of current drug regimens, with recurrent infections, together with ongoing inflammation, contribute significantly to the progressive decline in organ function. Therefore, the clinical management of SLE requires more effective and less toxic treatments, ideally inducing complete remission and self-tolerance. In this context, recently developed cell therapies based on mesenchymal stem cells (MSCs) represent a promising and safe strategy in SLE. MSCs inhibit the activation of B cells, prevent the differentiation of CD4⁺ T cells into autoreactive T cells, reprogram macrophages with anti-inflammatory effects and inhibit dendritic cells (DCs), limiting their activity as antigen-presenting cells. In addition, MSCs could induce antigen-specific tolerance by enhancing anergy processes in autoreactive cells - by inhibiting the maturation of antigen-presenting DCs, blocking the T cell receptor (TcR) pathway and secreting inhibitory molecules -, increasing apoptotic activity to eliminate them, and activating regulatory T cells (Tregs) to enhance their proliferation and induction of tolerogenic DCs. Thus, induction of self-tolerance leads to immune balance, keeping inflammation under control and reducing lupus flares.
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Affiliation(s)
- Julia Barbado
- Autoimmune Diseases Unit, Internal Medicine Department, University Hospital Rio Hortega, Valladolid, Spain.
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Sailliet N, Dupuy A, Brinas F, Renaudin K, Colas L, Kerleau C, Nguyen TVH, Fourgeux C, Poschmann J, Gosset C, Giral M, Degauque N, Mai HL, Danger R, Brouard S. Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells. Cells 2024; 13:1287. [PMID: 39120317 PMCID: PMC11311295 DOI: 10.3390/cells13151287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 08/10/2024] Open
Abstract
The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB+ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) peripheral blood mononuclear cells (PBMCs), including GZMB+ B cells from renal transplant patients, i.e., patients with stable graft function on conventional immunosuppressive treatment (STA, n = 3), drug-free tolerant patients (TOL, n = 3), and patients with antibody-mediated rejection (ABMR, n = 3), and (2) ex-vivo-induced GZMB+ B cells from these groups. In the patient PBMCs, we first showed that natural GZMB+ B cells were enriched in genes specific to Natural Killer (NK) cells (such as NKG7 and KLRD1) and regulatory B cells (such as GZMB, IL10, and CCL4). We performed a pseudotemporal trajectory analysis of natural GZMB+ B cells and showed that they were highly differentiated B cells with a trajectory that is very different from that of conventional memory B cells and linked to the transcription factor KLF13. By specifically analysing GZMB+ natural B cells in TOLs, we found that these cells had a very specific transcriptomic profile associated with a reduction in the expression of HLA molecules, apoptosis, and the inflammatory response (in general) in the blood and that this signature was conserved after ex vivo induction, with the induction of genes associated with migration processes, such as CCR7, CCL3, or CCL4. An analysis of receptor/ligand interactions between these GZMB+/- natural B cells and all of the immune cells present in PBMCs also demonstrated that GZMB+ B cells were the B cells that carried the most ligands and had the most interactions with other immune cells, particularly in tolerant patients. Finally, we showed that these GZMB+ B cells were able to infiltrate the graft under inflammatory conditions, thus suggesting that they can act in locations where immune events occur.
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Affiliation(s)
- Nicolas Sailliet
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Amandine Dupuy
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - François Brinas
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Karine Renaudin
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- CHU Nantes, Service d’Anatomie et Cytologie Pathologiques, 44000 Nantes, France
| | - Luc Colas
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Clarisse Kerleau
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Thi-Van-Ha Nguyen
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Cynthia Fourgeux
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Jérémie Poschmann
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Clément Gosset
- Service de Néphrologie et Transplantation rénale—CHU Pasteur2, 06000 Nice, France;
| | - Magali Giral
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- Centre d’Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, 44000 Nantes, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Nantes Université, 44000 Nantes, France
| | - Nicolas Degauque
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Hoa Le Mai
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Richard Danger
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Sophie Brouard
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- Centre d’Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, 44000 Nantes, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Nantes Université, 44000 Nantes, France
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Niu Q, Wang M, Liu XS. The evolving landscape of IL-10, IL-22 and IL-26 in pleurisy especially in tuberculous pleurisy. Respir Res 2024; 25:275. [PMID: 39003443 PMCID: PMC11245850 DOI: 10.1186/s12931-024-02896-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/29/2024] [Indexed: 07/15/2024] Open
Abstract
Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.
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Affiliation(s)
- Qian Niu
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Meng Wang
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Pathology, Baoji Gaoxin Hospital, Baoji, 721000, China
| | - Xian-Sheng Liu
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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37
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Gewurz B, Guo R, Lim M, Shah H, Paulo J, Zhang Y, Yang H, Wang LW, Strebinger D, Smith N, Li M, Leong M, Lutchenkov M, Liang JH, Li Z, Wang Y, Puri R, Melnick A, Green M, Asara J, Papathanassiu A, Gygi S, Mootha V. Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9. RESEARCH SQUARE 2024:rs.3.rs-4413958. [PMID: 38854072 PMCID: PMC11160916 DOI: 10.21203/rs.3.rs-4413958/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.
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Affiliation(s)
| | | | - Matthew Lim
- Department of Cell Biology, Harvard Medical School
| | | | | | | | - Haopeng Yang
- Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center
| | | | | | | | - Meng Li
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine
| | | | | | | | | | | | - Rishi Puri
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University
| | | | - Michael Green
- Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center
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38
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Fouza A, Fylaktou A, Tagkouta A, Daoudaki M, Vagiotas L, Kasimatis E, Stangou M, Xochelli A, Nikolaidou V, Katsanos G, Tsoulfas G, Skoura L, Papagianni A, Antoniadis N. Evaluation of Regulatory B Cell Subpopulations CD24++CD38++, CD24++CD27+, Plasmablasts and Their Correlation with T Regs CD3+CD4+CD25+FOXP3+ in Dialysis Patients and Early Post-Transplant Rejection-Free Kidney Recipients. J Clin Med 2024; 13:3080. [PMID: 38892795 PMCID: PMC11173263 DOI: 10.3390/jcm13113080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/11/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Background: B and T regulatory cells, also known as Bregs and Tregs, are involved in kidney transplantation. The purpose of this study is to monitor changes in the frequency and absolute numbers of Tregs (CD3+CD4+CD25+FoxP3+), transitional Bregs (tBregs) (CD24++CD38++), memory Bregs (mBregs) (CD24++CD27+), and plasmablasts before (T0) and six months (T6) after transplantation. Additionally, we aim to investigate any correlation between Tregs and tBregs, mBregs, or plasmablasts and their relationship with graft function. Methods: Flow cytometry was used to immunophenotype cells from 50 kidney recipients who did not experience rejection. Renal function was assessed using the estimated glomerular filtration rate (eGFR). Results: At T6, there was a significant decrease in the frequency of Tregs, plasmablasts, and tBregs, as well as in the absolute number of tBregs. The frequency of mBregs, however, remained unchanged. Graft function was found to have a positive correlation with the frequency of tBregs and plasmablasts. A significant correlation was observed between the frequency and absolute number of tBregs only when the eGFR was greater than 60 but not at lower values. At an eGFR greater than 60, there was a positive correlation between the absolute numbers of Tregs and mBregs but not between Tregs and tBregs. No correlation was observed for any cell population in dialysis patients. Conclusions: The data show a correlation between the frequency and absolute number of tBregs and the absolute number of Tregs and mBregs with good renal function in the early post-transplant period.
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Affiliation(s)
- Ariadni Fouza
- Department of Transplant Surgery, Center for Research and Innovation in Solid Organ Transplantation School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (G.T.); (N.A.)
| | - Asimina Fylaktou
- National Peripheral Histocompatibility Center, Department of Immunology, Ippokration General Hospital, 54642 Thessaloniki, Greece; (A.F.); (A.X.); (V.N.)
| | - Anneta Tagkouta
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Hygiene, Social-Preventive Medicine & Medical Statistics, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Daoudaki
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Lampros Vagiotas
- Department of Transplant Surgery, Center for Research and Innovation in Solid Organ Transplantation School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (G.T.); (N.A.)
| | - Efstratios Kasimatis
- 1st Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Ippokration General Hospital, 54642 Thessaloniki, Greece; (E.K.); (M.S.); (A.P.)
| | - Maria Stangou
- 1st Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Ippokration General Hospital, 54642 Thessaloniki, Greece; (E.K.); (M.S.); (A.P.)
| | - Aliki Xochelli
- National Peripheral Histocompatibility Center, Department of Immunology, Ippokration General Hospital, 54642 Thessaloniki, Greece; (A.F.); (A.X.); (V.N.)
| | - Vasiliki Nikolaidou
- National Peripheral Histocompatibility Center, Department of Immunology, Ippokration General Hospital, 54642 Thessaloniki, Greece; (A.F.); (A.X.); (V.N.)
| | - Georgios Katsanos
- Department of Transplant Surgery, Center for Research and Innovation in Solid Organ Transplantation School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (G.T.); (N.A.)
| | - Georgios Tsoulfas
- Department of Transplant Surgery, Center for Research and Innovation in Solid Organ Transplantation School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (G.T.); (N.A.)
| | - Lemonia Skoura
- Microbiology Laboratory, Department of Immunology, AHEPA University Hospital, 54636 Thessaloniki, Greece;
| | - Aikaterini Papagianni
- 1st Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Ippokration General Hospital, 54642 Thessaloniki, Greece; (E.K.); (M.S.); (A.P.)
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, Center for Research and Innovation in Solid Organ Transplantation School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (G.T.); (N.A.)
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39
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Li R, Lei Y, Rezk A, Diego A Espinoza, Wang J, Feng H, Zhang B, Barcelos IP, Zhang H, Yu J, Huo X, Zhu F, Yang C, Tang H, Goldstein AC, Banwell BL, Hakonarson H, Xu H, Mingueneau M, Sun B, Li H, Bar-Or A. Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis. Sci Immunol 2024; 9:eadk0865. [PMID: 38701189 DOI: 10.1126/sciimmunol.adk0865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 04/10/2024] [Indexed: 05/05/2024]
Abstract
Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.
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Affiliation(s)
- Rui Li
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Yanting Lei
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Ayman Rezk
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diego A Espinoza
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jing Wang
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Huiru Feng
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Bo Zhang
- Institute of Immunotherapy and Department of Neurology of First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Isabella P Barcelos
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hang Zhang
- Department of Immunology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jing Yu
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Xinrui Huo
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Fangyi Zhu
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Changxin Yang
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hao Tang
- MS Research Unit, Biogen, Cambridge, MA 02142, USA
| | - Amy C Goldstein
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Brenda L Banwell
- Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hongwei Xu
- Department of Immunology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | | | - Bo Sun
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hulun Li
- Department of Neurobiology, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Amit Bar-Or
- Center for Neuroinflammation and Experimental Therapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- MS Research Unit, Biogen, Cambridge, MA 02142, USA
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40
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Carvalho-Santos A, Ballard Kuhnert LR, Hahne M, Vasconcellos R, Carvalho-Pinto CE, Villa-Verde DMS. Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis. PLoS One 2024; 19:e0292028. [PMID: 38691538 PMCID: PMC11062543 DOI: 10.1371/journal.pone.0292028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 04/02/2024] [Indexed: 05/03/2024] Open
Abstract
APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro. Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19+IgM+CD5+ cell population in draining lymph nodes and an increase of CD19+CD21hiCD23hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro.
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Affiliation(s)
- Adriana Carvalho-Santos
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Lia Rafaella Ballard Kuhnert
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Michael Hahne
- Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
| | - Rita Vasconcellos
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Carla Eponina Carvalho-Pinto
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Déa Maria Serra Villa-Verde
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
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41
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Elias C, Chen C, Cherukuri A. Regulatory B Cells in Solid Organ Transplantation: From Immune Monitoring to Immunotherapy. Transplantation 2024; 108:1080-1089. [PMID: 37779239 PMCID: PMC10985051 DOI: 10.1097/tp.0000000000004798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Regulatory B cells (Breg) modulate the immune response in diverse disease settings including transplantation. Despite the lack of a specific phenotypic marker or transcription factor, their significance in transplantation is underscored by their ability to prolong experimental allograft survival, the possibility for their clinical use as immune monitoring tools, and the exciting prospect for them to form the basis for cell therapy. Interleukin (IL)-10 expression remains the most widely used marker for Breg. Several Breg subsets with distinct phenotypes that express this "signature Breg cytokine" have been described in mice and humans. Although T-cell immunoglobulin and mucin family-1 is the most inclusive and functional marker that accounts for murine Breg with disparate mechanisms of action, the significance of T-cell immunoglobulin and mucin family-1 as a marker for Breg in humans still needs to be explored. Although the primary focus of this review is the role of Breg in clinical transplantation, the net modulatory effect of B cells on the immune response and clinical outcomes is the result of the balancing functions of both Breg and effector B cells. Supporting this notion, B-cell IL-10/tumor necrosis factor α ratio is shown to predict immunologic reactivity and clinical outcomes in kidney and liver transplantation. Assessment of Breg:B effector balance using their IL-10/tumor necrosis factor α ratio may identify patients that require more immunosuppression and provide mechanistic insights into potential therapies. In summary, current advances in our understanding of murine and human Breg will pave way for future definitive clinical studies aiming to test them for immune monitoring and as therapeutic targets.
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Affiliation(s)
- Charbel Elias
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chuxiao Chen
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Aravind Cherukuri
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Renal and Electrolyte Division, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
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42
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Hu F, Shi L, Liu X, Chen Y, Zhang X, Jia Y, Liu X, Guo J, Zhu H, Liu H, Xu L, Li Y, Wang P, Fang X, Xue J, Xie Y, Wei C, Song J, Zheng X, Liu YY, Li Y, Ren L, Xu D, Lu L, Qiu X, Mu R, He J, Wang M, Zhang X, Liu W, Li Z. Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis. Ann Rheum Dis 2024; 83:576-588. [PMID: 38302261 DOI: 10.1136/ard-2023-224878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 01/17/2024] [Indexed: 02/03/2024]
Abstract
OBJECTIVES B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.
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Affiliation(s)
- Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lianjie Shi
- Department of Rheumatology and Immunology, Peking University Shougang Hospital, Beijing, China
| | - Xiaohang Liu
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Yingjia Chen
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
| | - Xia Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuan Jia
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xu Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jianping Guo
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Huaqun Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Liling Xu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yingni Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Ping Wang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiangyu Fang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jimeng Xue
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yang Xie
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Chaonan Wei
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jing Song
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Xi Zheng
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Yan-Ying Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuhui Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Limin Ren
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Dakang Xu
- Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liwei Lu
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Xiaoyan Qiu
- Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China
| | - Rong Mu
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Wanli Liu
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
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Li T, Zhang Y, Zhou Z, Zhang Y, Song X, Zhou X, Wan Z, Ruan Y. Causal associations of immune cells with benign prostatic hyperplasia: insights from a Mendelian randomization study. World J Urol 2024; 42:216. [PMID: 38581575 DOI: 10.1007/s00345-024-04913-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 02/29/2024] [Indexed: 04/08/2024] Open
Abstract
BACKGROUND Previous research has focused on the association between immune cells and the development of benign prostatic hyperplasia (BPH). Nevertheless, the causal relationships in this context remain uncertain. METHODS This study employed a comprehensive and systematic two-sample Mendelian randomization (MR) analysis to determine the causal relationships between immunophenotypes and BPH. We examined the causal associations between 731 immunophenotypes and the risk of BPH by utilizing publicly available genetic data. Integrated sensitivity analyses were performed to validate the robustness, assess heterogeneity, and examine horizontal pleiotropy in the results. RESULTS We discovered that 38 immunophenotypes have a causal effect on BPH. Subsequently, four of these immunophenotypes underwent verification using weighted median, weighted mode, and inverse variance weighted (IVW) algorithms, which included CD19 on CD24+ CD27+, CD19 on naive-mature B cell, HLA DR on CD14- CD16+ and HLA DR+ T cell%lymphocyte. Furthermore, BPH exhibited a significant association with three immunophenotypes: CD19 on IgD+ CD38dim (β = -0.152, 95% CI = 0.746-0.989, P = 0.034), CD19 on IgD+ (β = -0.167, 95% CI = 0.737-0.973, P = 0.019), and CD19 on naive-mature B cell (β = -0.166, 95% CI = 0.737-0.972, P = 0.018). CONCLUSIONS Our study provides valuable insights for future clinical investigations by establishing a significant association between immune cells and BPH.
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Affiliation(s)
- Tiewen Li
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Yichen Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Zeng Zhou
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Yu Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Xiaodong Song
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Xuehao Zhou
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China
| | - Zhong Wan
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China.
| | - Yuan Ruan
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Wujin Road 85, Shanghai, 200080, China.
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44
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Tompa A, Faresjö M. Shift in the B cell subsets between children with type 1 diabetes and/or celiac disease. Clin Exp Immunol 2024; 216:36-44. [PMID: 38134245 PMCID: PMC10929695 DOI: 10.1093/cei/uxad136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 12/17/2023] [Indexed: 12/24/2023] Open
Abstract
Our purpose was to characterize the pattern of B cell subsets in children with a combined diagnosis of type 1 diabetes (T1D) and celiac disease (C) since children with single or double diagnosis of these autoimmune diseases may differ in peripheral B cell subset phenotype patterns. B cells were analyzed with flow cytometry for the expression of differentiation/maturation markers to identify transitional, naive, and memory B cells. Transitional (CD24hiCD38hiCD19+) and memory Bregs (mBregs; CD24hiCD27+CD19+, CD1d+CD27+CD19+, and CD5+CD1d+CD19+) were classified as B cells with regulatory capacity. Children with a combined diagnosis of T1D and C showed a pattern of diminished peripheral B cell subsets. The B cells compartment in children with combined diagnosis had higher percentages of memory B subsets and Bregs, including activated subsets, compared to children with either T1D or C. Children with combined diagnosis had a lower percentage of naive B cells (CD27-CD19+; IgD+CD19+) and an increased percentage of memory B cells (CD27+CD19+; IgD-CD19+). A similar alteration was seen among the CD39+ expressing naive and memory B cells. Memory Bregs (CD1d+CD27+CD19+) were more frequent, contrary to the lower percentage of CD5+ transitional Bregs in children with a combined diagnosis. In children with either T1D or C, the peripheral B cell compartment was dominated by naive cells. Differences in the pattern of heterogeneous peripheral B cell repertoire subsets reflect a shifting in the B cell compartment between children with T1D and/or C. This is an immunological challenge of impact on the pathophysiology of these autoimmune diseases.
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Affiliation(s)
- Andrea Tompa
- Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Jönköping, Sweden
- Division of Diagnostics, Region Jönköping County, Jönköping, Sweden
| | - Maria Faresjö
- Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Jönköping, Sweden
- Department of Life Sciences, Division of Systems and Synthetic Biology, Chalmers University of Technology, Gothenburg, Sweden
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45
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Nicholas DA, Mbongue JC, Garcia-Pérez D, Sorensen D, Ferguson Bennit H, De Leon M, Langridge WHR. Exploring the Interplay between Fatty Acids, Inflammation, and Type 2 Diabetes. IMMUNO 2024; 4:91-107. [PMID: 39606781 PMCID: PMC11600342 DOI: 10.3390/immuno4010006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
Around 285 million people worldwide currently have type 2 diabetes and it is projected that this number will be surpassed by 2030. Therefore, it is of the utmost importance to enhance our comprehension of the disease's development. The regulation of diet, obesity, and inflammation in type 2 diabetes is believed to play a crucial role in enhancing insulin sensitivity and reducing the risk of onset diabetes. Obesity leads to an increase in visceral adipose tissue, which is a prominent site of inflammation in type 2 diabetes. Dyslipidemia, on the other hand, plays a significant role in attracting activated immune cells such as macrophages, dendritic cells, T cells, NK cells, and B cells to visceral adipose tissue. These immune cells are a primary source of pro-inflammatory cytokines that are believed to promote insulin resistance. This review delves into the influence of elevated dietary free saturated fatty acids and examines the cellular and molecular factors associated with insulin resistance in the initiation of inflammation induced by obesity. Furthermore, it explores novel concepts related to diet-induced inflammation and its relationship with type 2 diabetes.
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Affiliation(s)
- Dequina A. Nicholas
- School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Jacques C. Mbongue
- Department of Biological Sciences, School of Arts and Sciences, Oakwood University, Huntsville, AL 35896, USA
| | - Darysbel Garcia-Pérez
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
- Division of Molecular Genetics and Microbiology, School of Medicine Alumni Hall, Loma Linda University, Rm 102, 11021 Campus Street, Loma Linda, CA 92350, USA
| | - Dane Sorensen
- Center for Perinatal Biology, Division of Physiology, Loma Linda School of Medicine, Rm A572, 11234 Anderson Street, Loma Linda, CA 92350, USA
| | - Heather Ferguson Bennit
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - Marino De Leon
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - William H. R. Langridge
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
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46
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Wu P, Song Y, Chen Z, Xia J, Zhou Y. Changes of B cell subsets in different types of diabetes and its effect on the progression of latent autoimmune diabetes in adults. Endocrine 2024; 83:624-635. [PMID: 37755622 DOI: 10.1007/s12020-023-03539-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/13/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters. METHODS A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method. RESULTS We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of β-cell in patients with diabetes. CONCLUSIONS This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients.
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Affiliation(s)
- Peihao Wu
- Department of Clinical Laboratory, Women's Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, 310006, China
| | - Yingxiang Song
- Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China
| | - Zhuo Chen
- Department of Clinical Laboratory, Hangzhou Lin'an Third People's Hospital, Hangzhou, Zhejiang, 311311, China
| | - Jun Xia
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China.
| | - Yu Zhou
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China.
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang province, No.182 Tianmushan Road, Xihu District, Hangzhou, Zhejiang, 310063, China.
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Veh J, Ludwig C, Schrezenmeier H, Jahrsdörfer B. Regulatory B Cells-Immunopathological and Prognostic Potential in Humans. Cells 2024; 13:357. [PMID: 38391970 PMCID: PMC10886933 DOI: 10.3390/cells13040357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 02/24/2024] Open
Abstract
The aim of the following review is to shed light on the putative role of regulatory B cells (Bregs) in various human diseases and highlight their potential prognostic and therapeutic relevance in humans. Regulatory B cells are a heterogeneous group of B lymphocytes capable of suppressing inflammatory immune reactions. In this way, Bregs contribute to the maintenance of tolerance and immune homeostasis by limiting ongoing immune reactions temporally and spatially. Bregs play an important role in attenuating pathological inflammatory reactions that can be associated with transplant rejection, graft-versus-host disease, autoimmune diseases and allergies but also with infectious, neoplastic and metabolic diseases. Early studies of Bregs identified IL-10 as an important functional molecule, so the IL-10-secreting murine B10 cell is still considered a prototype Breg, and IL-10 has long been central to the search for human Breg equivalents. However, over the past two decades, other molecules that may contribute to the immunosuppressive function of Bregs have been discovered, some of which are only present in human Bregs. This expanded arsenal includes several anti-inflammatory cytokines, such as IL-35 and TGF-β, but also enzymes such as CD39/CD73, granzyme B and IDO as well as cell surface proteins including PD-L1, CD1d and CD25. In summary, the present review illustrates in a concise and comprehensive manner that although human Bregs share common functional immunosuppressive features leading to a prominent role in various human immunpathologies, they are composed of a pool of different B cell types with rather heterogeneous phenotypic and transcriptional properties.
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Affiliation(s)
- Johanna Veh
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
| | - Carolin Ludwig
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
| | - Bernd Jahrsdörfer
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
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48
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Lee EG, Oh JE. From neglect to spotlight: the underappreciated role of B cells in cutaneous inflammatory diseases. Front Immunol 2024; 15:1328785. [PMID: 38426103 PMCID: PMC10902158 DOI: 10.3389/fimmu.2024.1328785] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024] Open
Abstract
The skin, covering our entire body as its largest organ, manifests enormous complexities and a profound interplay of systemic and local responses. In this heterogeneous domain, B cells were considered strangers. Yet, recent studies have highlighted their existence in the skin and their distinct role in modulating cutaneous immunity across various immune contexts. Accumulating evidence is progressively shedding light on the significance of B cells in maintaining skin health and in skin disorders. Herein, we integrate current insights on the systemic and local contributions of B cells in three prevalent inflammatory skin conditions: Pemphigus Vulgaris (PV), Systemic Lupus Erythematosus (SLE), and Atopic Dermatitis (AD), underscoring the previously underappreciated importance of B cells within skin immunity. Moreover, we address the potential adverse effects of current treatments used for skin diseases, emphasizing their unintentional consequences on B cells. These comprehensive approaches may pave the way for innovative therapeutic strategies that effectively address the intricate nature of skin disorders.
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Affiliation(s)
- Eun-Gang Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Ji Eun Oh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- BioMedical Research Center, KAIST, Daejeon, Republic of Korea
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49
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Goldmann O, Nwofor OV, Chen Q, Medina E. Mechanisms underlying immunosuppression by regulatory cells. Front Immunol 2024; 15:1328193. [PMID: 38380317 PMCID: PMC10876998 DOI: 10.3389/fimmu.2024.1328193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024] Open
Abstract
Regulatory cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), and myeloid-derived suppressor cells (MDSCs), play a crucial role in preserving immune tolerance and controlling immune responses during infections to prevent excessive immune activation. However, pathogens have developed strategies to hijack these regulatory cells to decrease the overall effectiveness of the immune response and persist within the host. Consequently, therapeutic targeting of these immunosuppressive mechanisms during infection can reinvigorate the immune response and improve the infection outcome. The suppressive mechanisms of regulatory cells are not only numerous but also redundant, reflecting the complexity of the regulatory network in modulating the immune responses. The context of the immune response, such as the type of pathogen or tissue involved, further influences the regulatory mechanisms involved. Examples of these immunosuppressive mechanisms include the production of inhibitory cytokines such as interleukin 10 (IL-10) and transforming growth factor beta (TGF-β) that inhibit the production of pro-inflammatory cytokines and dampen the activation and proliferation of effector T cells. In addition, regulatory cells utilize inhibitory receptors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to engage with their respective effector cells, thereby suppressing their function. An alternative approach involves the modulation of metabolic reprogramming in effector immune cells to limit their activation and proliferation. In this review, we provide an overview of the major mechanisms mediating the immunosuppressive effect of the different regulatory cell subsets in the context of infection.
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Affiliation(s)
| | | | | | - Eva Medina
- Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
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50
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Mishina T, Miyoshi H, Takeuchi M, Miyawaki K, Nakashima K, Yamada K, Moritsubo M, Inoue-Mitsuyama K, Shimasaki Y, Imamoto T, Kawamoto K, Furuta T, Kohno K, Kato K, Akashi K, Ohshima K. Co-expression of regulatory B-cell markers, transforming growth factor β and interleukin-10 as a prognostic factor in diffuse large B-cell lymphoma. Pathol Res Pract 2024; 254:155117. [PMID: 38262270 DOI: 10.1016/j.prp.2024.155117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/25/2024]
Abstract
Regulatory B cells (Bregs) suppress antitumor immunity by producing anti-inflammatory cytokines such as transforming growth factor β (TGF-β) and interleukin-10 (IL-10) and promoting tumor growth. It is unknown whether diffuse large B-cell lymphoma (DLBCL), a common subtype of B-cell malignancy, exhibits characteristics similar to those of Bregs. This study aimed to clarify the features of DLBCLs carrying Breg markers. In 123 DLBCL cases, we evaluated TGF-β and IL-10 expression in tumor biopsy samples using immunohistochemical staining and retrospectively analyzed their clinicopathological characteristics. Fifteen cases (12.2 %) classified as Breg-type DLBCL were positive for both TGF-β and IL-10. Breg-type DLBCL is mainly classified as having activated B cell-like cells of origin. Breg-type DLBCL cases showed significantly worse progression-free survival and overall survival (OS) than other DLBCL cases (P = 0.0016 and P = 0.042, respectively). In multivariate analysis, Breg-type DLBCL significantly affected OS (hazard ratio, 3.13; 95 % confidence interval 1.15-8.55; P = 0.025). Gene expression analysis showed that the expression of follicular dendritic cell-associated genes (FCER2, PIK3CD, FOXO1) was downregulated in Breg-type DLBCLs compared to other DLBCLs. These results suggest that the double expression of Breg markers, TGF-β and IL-10, in tumor cells indicates a poor prognosis in DLBCL patients. Further studies evaluating genomic abnormalities could confirm the characteristics of Breg-type DLBCL.
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Affiliation(s)
- Tatsuzo Mishina
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan; Division of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan
| | - Hiroaki Miyoshi
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.
| | - Mai Takeuchi
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kazutaka Nakashima
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Kyohei Yamada
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Mayuko Moritsubo
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | | | - Yasumasa Shimasaki
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Teppei Imamoto
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan; Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Keisuke Kawamoto
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Takuya Furuta
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Kei Kohno
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
| | - Koji Kato
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Koichi Ohshima
- Department of Pathology, School of Medicine, Kurume University, Kurume, Japan
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