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Ma H, Wang Z, Yu M, Zhai Y, Yan J. Aberrations in peripheral B lymphocytes and B lymphocyte subsets levels in Parkinson disease: a systematic review. Front Immunol 2025; 16:1526095. [PMID: 40230858 PMCID: PMC11994702 DOI: 10.3389/fimmu.2025.1526095] [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: 11/11/2024] [Accepted: 03/10/2025] [Indexed: 04/16/2025] Open
Abstract
Objective The association of B lymphocytes and B lymphocyte subsets and Parkinson's disease (PD) is increasingly acknowledged. However, there is inconsistence in the alterations of B lymphocytes or B lymphocyte subsets in peripheral blood of PD patients. To comprehensively understand its changes in PD patients,it is necessary to conduct a systematic review on this subject. Methods PubMed, Cochrane Library, and MEDLINE databases were searched until 3rd February 2024. Results We included 20 studies (n=2658) to conduct this systematic review. We conducted a qualitative analysis to assess the alterations of B lymphocytes and B lymphocyte subsets in the peripheral blood of individuals with PD. And studies reviewed demonstrated a significant decrease in the number of B cells, as well as immune dysregulation in the B lymphocyte subsets of these patients' peripheral blood. Conclusion Studies reviewed demonstrated that PD is linked to abnormalities in B lymphocytes and/or B lymphocytes subsets in peripheral blood. This study provides a novel perspective into the pathogenesis of PD, and future investigations into the B lymphocytes and/or B lymphocyte subsets as biomarkers and therapeutic targets for PD is warranted.
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Affiliation(s)
- Hongxia Ma
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Ziyuan Wang
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Miao Yu
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Yibo Zhai
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Junqiang Yan
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
- Key laboratory of Neuromolecular Biology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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Lin Z, Jiang B, Wang W, Chen C, Wang Y, Wan J, Xu Y. Clinical outcomes in lupus nephritis patients treated with belimumab in real-life setting: a retrospective comparative study in China. PeerJ 2024; 12:e18028. [PMID: 39308826 PMCID: PMC11416754 DOI: 10.7717/peerj.18028] [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: 05/18/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
Objective The use of belimumab in treating lupus nephritis (LN) patients in China is still in its early stages. This retrospective comparative study aims to delineate the disease activity, associated therapies, clinical outcomes, and adverse events among LN patients treated with belimumab, reflecting real-world experience in southeastern China. Methods From May 2020 to December 2023, 54 LN patients treated with belimumab and 42 LN patients treated with conventional therapy were enrolled. All patients had a follow-up period of more than 3 months. The general information, presenting clinical and laboratory data, and outcomes were collected and compared. Results At 3 months of belimumab treatment, compared to baseline, there was a decrease in proteinuria from 74.1% to 64.8% (p < 0.001), a reduction in hematuria from 59.3% to 37.0% (p = 0.008), and an increase in partial or complete renal response from 53.7% to 75.9% (p < 0.001). The median SLEDAI score decreased from 10 to 5 (p < 0.001), and the proportion of patients achieving low lupus disease activity state (LLDAS) increased from 11.11% to 16.67% (p < 0.001) by the 3-month evaluation. Notably, there were significant reductions in oral corticosteroid dosages, with a median decrease from 30 to 17.5 mg/day (p < 0.001) by 3 months, and the proportion of patients requiring >5 mg/day of steroids decreased from 88.89% at baseline to 79.07% at six months (p < 0.001). Compared to the conventional therapy group, the belimumab group experienced a significant reduction in median steroid dosage and increased the proportion of patients achieving remission or LLDAS. The incidence of treatment-emergent adverse events (TEAEs) was significantly lower in the belimumab group (29.6% vs 52.4%, p = 0.024). Conclusion These findings support the potential of belimumab to improve renal and serological parameters, reduce disease activity, lessen corticosteroid dependence, and decrease the risk of TEAEs, demonstrating its safety and efficacy as an adjunct therapy in LN management.
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Affiliation(s)
- Zishan Lin
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Bingjing Jiang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Wenfeng Wang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Caiming Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yujia Wang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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3
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Zhao L, Wang W, Wu L, Wu T, Tu J, Wu X, Sun F, Ding H, Shen N, Wu H, Zhu J, Sun L, Ye S. Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis. Lupus Sci Med 2024; 11:e001156. [PMID: 38806217 PMCID: PMC11138273 DOI: 10.1136/lupus-2024-001156] [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: 01/24/2024] [Accepted: 05/13/2024] [Indexed: 05/30/2024]
Abstract
OBJECTIVES To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. METHODS This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m2 at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. RESULTS Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. CONCLUSION The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.
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Affiliation(s)
- Liling Zhao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenwen Wang
- Department of Rheumatology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lijun Wu
- Department of Rheumatology＆Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Rheumatoid Arthritis, Urumqi, Xinjiang, China
| | - Tong Wu
- Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, School of Medicine, University Electronic Science and Technology of China, Chengdu, China
| | - Jianxin Tu
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xue Wu
- Department of Rheumatology＆Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Rheumatoid Arthritis, Urumqi, Xinjiang, China
| | - Fangfang Sun
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huihua Ding
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nan Shen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaxiang Wu
- Department of Rheumatology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Zhu
- Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, School of Medicine, University Electronic Science and Technology of China, Chengdu, China
| | - Li Sun
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shuang Ye
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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4
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Xipell M, Lledó GM, Egan AC, Tamirou F, Del Castillo CS, Rovira J, Gómez-Puerta JA, García-Herrera A, Cervera R, Kronbichler A, Jayne DRW, Anders HJ, Houssiau F, Espinosa G, Quintana LF. From systemic lupus erythematosus to lupus nephritis: The evolving road to targeted therapies. Autoimmun Rev 2023; 22:103404. [PMID: 37543287 DOI: 10.1016/j.autrev.2023.103404] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.
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Affiliation(s)
- Marc Xipell
- Department of Nephrology and Renal Transplantation, Clinic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Gema M Lledó
- Department of Autoimmune Diseases, Clínic Barcelona, Spain; Reference Center for Systemic Autoimmune Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Allyson C Egan
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, United Kingdom
| | - Farah Tamirou
- Rheumatology Department, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Belgium
| | | | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José A Gómez-Puerta
- Department of Rheumatology, Clínic Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain
| | - Adriana García-Herrera
- Department of Pathology, Clínic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ricard Cervera
- Department of Autoimmune Diseases, Clínic Barcelona, Spain
| | - Andreas Kronbichler
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - David R W Jayne
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Frédéric Houssiau
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, United Kingdom
| | - Gerard Espinosa
- Department of Autoimmune Diseases, Clínic Barcelona, Spain; Reference Center for Systemic Autoimmune Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
| | - Luis F Quintana
- Department of Nephrology and Renal Transplantation, Clinic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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5
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Olson WJ, Derudder E. The miR-142 miRNAs: Shaping the naïve immune system. Immunol Lett 2023; 261:37-46. [PMID: 37459958 DOI: 10.1016/j.imlet.2023.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 06/21/2023] [Accepted: 07/10/2023] [Indexed: 08/01/2023]
Abstract
Immunity in a naïve organism is tightly controlled. Adequate proportions of the many immune cell subsets must be produced to mount efficient responses to eventual challenges. In addition, a functioning immune system is highly dynamic at steady state. Mature immune cells must be positioned properly and/or circulate to facilitate the detection of dangers. They must also be poised to promptly react to unusual encounters, while ignoring innocuous germs and self. Numerous regulatory mechanisms act at the molecular level to generate such an exquisite structure, including miRNA-mediated repression of protein synthesis. Notably, the miRNAs from the miR-142 locus are preferentially expressed in hematopoietic cells. Their importance is underscored by the deeply disturbed immune system seen upon inactivation of the locus in mice. In this review, we explore reported roles for the miR-142 miRNAs in the shaping of immunity in vertebrates, discussing in particular their contributions to the generation, migration and survival of hematopoietic cells.
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Affiliation(s)
- William J Olson
- Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Emmanuel Derudder
- Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria.
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Li Y, Zhu L, Ko CJ, Yang JY, Wang H, Manyam G, Wang J, Cheng X, Zhao S, Jie Z. TRAF3-EWSR1 signaling axis acts as a checkpoint on germinal center responses. J Exp Med 2023; 220:e20221483. [PMID: 37097293 PMCID: PMC10130905 DOI: 10.1084/jem.20221483] [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: 08/29/2022] [Revised: 12/29/2022] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer's patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B cell generation and IgG production. We further showed that tumor necrosis factor receptor-associated factor (TRAF) 3 serves as a negative regulator of EWSR1. These results established that the TRAF3-EWSR1 signaling axis acts as a checkpoint for Bcl6 expression and GC responses, indicating that this axis is a therapeutic target to tune GC responses and humoral immunity in infectious diseases.
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Affiliation(s)
- Yanchuan Li
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Lele Zhu
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA
| | - Chun-Jung Ko
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Young Yang
- Department of Biological Sciences, Pusan National University, Busan, Korea
| | - Hongjiao Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Ganiraju Manyam
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xuhong Cheng
- Memorial Hermann-Texas Medical Center, Houston, TX, USA
| | - Shuli Zhao
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zuliang Jie
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
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7
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Guldenpfennig C, Teixeiro E, Daniels M. NF-kB's contribution to B cell fate decisions. Front Immunol 2023; 14:1214095. [PMID: 37533858 PMCID: PMC10391175 DOI: 10.3389/fimmu.2023.1214095] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB. The formidable task of sorting out the mechanisms behind the regulation and outcome of NF-κB signaling remains an important area of immunology research. Here we briefly discuss the role of NF-κB in regulating cell fate decisions at various times in the path of B cell development, activation, and the generation of long-term humoral immunity.
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Affiliation(s)
- Caitlyn Guldenpfennig
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
| | - Emma Teixeiro
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
| | - Mark Daniels
- Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States
- NextGen Precision Health, University of Missouri, Columbia, MO, United States
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Accapezzato D, Caccavale R, Paroli MP, Gioia C, Nguyen BL, Spadea L, Paroli M. Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Int J Mol Sci 2023; 24:6578. [PMID: 37047548 PMCID: PMC10095030 DOI: 10.3390/ijms24076578] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the development of effective targeted therapies, that hold out hope for personalized therapy. However, the new drugs available to date are still an adjunct to conventional therapy, which is known to be toxic in the short and long term. The purpose of this review is to summarize recent advances in understanding the pathogenesis of the disease and discuss the results obtained from the use of new targeted drugs, with a look at future therapies that may be used in the absence of the current standard of care or may even cure this serious systemic autoimmune disease.
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Affiliation(s)
- Daniele Accapezzato
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Rosalba Caccavale
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Pia Paroli
- Eye Clinic, Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy
| | - Chiara Gioia
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Bich Lien Nguyen
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Luca Spadea
- Post Graduate School of Public Health, University of Siena, 53100 Siena, Italy
| | - Marino Paroli
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
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9
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Olson WJ, Jakic B, Labi V, Woelk J, Derudder E, Baier G, Hermann-Kleiter N. A role for the nuclear receptor NR2F6 in peritoneal B cell homeostasis. Front Immunol 2022; 13:845235. [PMID: 36052079 PMCID: PMC9425112 DOI: 10.3389/fimmu.2022.845235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 07/18/2022] [Indexed: 11/19/2022] Open
Abstract
B cells are key mediators of humoral immunity. Mature B cells fall into various sub-classes that can be separated by their ontogeny, expression of cell surface markers, anatomical location, and function. B1 subsets play important roles in natural immunity and constitute the majority of B cells in newborns. In the adult, B1 cells predominate in the pleural and peritoneal cavities, while the mature B2 follicular subset makes up the major fraction of B cells in lymphoid tissue, although important subsets of antibody-secreting B1 cells are also present at these sites. B1 cells are the main producers of natural IgM but can also contribute to elimination of some pathogens, while B2 cells primarily mediate response to foreign antigens. The differential molecular underpinning of the B1 and B2 subsets remains incompletely understood. Here we demonstrate that germline-deficiency of the orphan nuclear receptor NR2F6 causes a partial loss of B1b and B2 B cells in the peritoneum while leaving peritoneal B1a cells unaltered. A competitive bone marrow chimera in Nr2f6+/+ host mice produced similar numbers of Nr2f6+/+ and Nr2f6-/- peritoneal B1b and B2 cells. The proliferation of Nr2f6-/- peritoneal B cells was not altered, while the migration marker CXCR5 was reduced on all subsets but Beta7-integrin was reduced only on peritoneal B1b and B2 cells. Similarly, B1b and B2 but not B1a cells, exhibited significantly reduced survival.
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Affiliation(s)
- William J. Olson
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
- Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Bojana Jakic
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Verena Labi
- Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes Woelk
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Emmanuel Derudder
- Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Gottfried Baier
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Translational Cell Genetics, Department of Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria
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10
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Struemper H, Kurtinecz M, Edwards L, Freimuth WW, Roth DA, Stohl W. Reductions in circulating B cell subsets and immunoglobulin G levels with long-term belimumab treatment in patients with SLE. Lupus Sci Med 2022; 9:9/1/e000499. [PMID: 35131846 PMCID: PMC8823257 DOI: 10.1136/lupus-2021-000499] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 01/08/2022] [Indexed: 11/30/2022]
Abstract
Objective To examine the long-term changes in circulating B cell subsets and IgG levels at 5+ years of continuous belimumab treatment and their correlations with efficacy and safety measures. Methods This was a post hoc analysis of a continuation study (BEL112233; NCT00724867) of eligible US patients who completed the 76-week BLISS-76 Study (BEL110751; NCT00410384), with up to eight calendar-years of follow-up and median (IQR) belimumab exposure of 310 (209, 364) weeks. From week 76, patients initially randomised to intravenous belimumab 1 mg/kg or 10 mg/kg every 4 weeks in BLISS-76 continued to receive the same dose in the continuation study, while those initially randomised to placebo received belimumab 10 mg/kg intravenous every 4 weeks during continuation. All patients continued to receive standard SLE therapy. Biomarker data were collected, and the effects on baseline and early changes (weeks 0–24 after starting belimumab) from baseline in biomarkers on SLE Responder Index (SRI-4) and infection rate were evaluated. Results Of the 819 patients from BLISS-76, 268 self-selecting patients entered BEL112233. Compared with baseline, B cell subset counts decreased by 40%–99% after 312 weeks (6 years), and serum IgG levels decreased by 28% after 284 weeks. Higher baseline naïve B cell counts were associated with greater SRI-4 response rates (p<0.05), whereas higher baseline SLE subset plasma and short-lived plasma B cell counts were associated with lower SRI-4 response rates (p<0.05). Elevated baseline IgG levels were associated with increased infection rates over the treatment period (p<0.05), and early greater decreases in IgG levels were associated with higher SRI-4 response rates (p<0.05). Conclusions Belimumab treatment up to 312 weeks (6 years) resulted in substantial decreases in several circulating B cell subsets and IgG levels. Higher baseline naïve B cell counts and IgG levels were associated with improved SRI-4 response and increased infection rates, respectively.
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Affiliation(s)
- Herbert Struemper
- Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina, USA
| | - Milena Kurtinecz
- Biostatistics, GlaxoSmithKline, Collegeville, Pennsylvania, USA (At the time of the study)
| | - Lisa Edwards
- Biostatistics, GlaxoSmithKline, Chapel Hill, North Carolina, USA (At the time of the study)
| | - William W Freimuth
- Freimuth Biopharmaceutical Consulting, Gaithersburg, Maryland, USA (At the time of the study)
| | - David A Roth
- Research & Development, GlaxoSmithKline, Collegeville, South Carolina, USA
| | - William Stohl
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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11
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BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis. Acta Pharmacol Sin 2021; 42:1665-1675. [PMID: 33483588 PMCID: PMC8463593 DOI: 10.1038/s41401-020-00582-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 11/16/2020] [Indexed: 02/02/2023]
Abstract
B cell activating factor of TNF family (BAFF) is a member of TNF ligand superfamily and plays a key role in B cell homeostasis, proliferation, maturation, and survival. In this study, we detected BAFF level, the expressions of BAFF receptors and important molecules in NF-κB pathway in rheumatoid arthritis (RA) patients and analyzed the correlation between BAFF level and clinical variables, laboratory parameters or X-ray scores in order to elucidate the roles of BAFF in RA. A total of 50 RA patients and 50 healthy controls (HCs) were enrolled. We showed that the serum BAFF level in RA patients was significantly higher than that of HCs, and the percentages of B cell subsets (CD19+ B cells, CD19+CD27+ B cells, CD19+CD20+CD27+ B cells, and CD19+CD20-CD27+ B cells) in the serum of RA patients were significantly increased compared with those of HCs. The percentages of CD19+BAFFR+ B cells, CD19+ BCMA+ B cells, and CD19+ TACI+ B cells in RA patients were significantly increased compared with those in HCs. The expression of important molecules in the NF-κB pathway (MKK3, MKK6, p-P38, p-P65, TRAF2, and p52) was significantly higher in RA patients than in HCs, but p100 level in RA patients was lower than that in HCs. The serum BAFF level was positively correlated with C-reactive protein, rheumatoid factor, disease activity score (in 28 joints), swollen joint counts, tender joint counts, and X-ray scores. When normal B cells were treated with BAFF in vitro, the percentages of the B cell subset and the expression of BAFF receptors were significantly upregulated. BAFF also promoted the expression of MKK3, MKK6, p-P38, p-P65, TRAF2, and p52. In conclusion, this study demonstrates that BAFF level is correlated with the disease activity and bone destruction of RA. BAFF is involved in the differentiation, proliferation, and activation of B cells in RA through NF-κB signaling pathway, suggesting that BAFF might be an ideal therapeutic target for RA.
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12
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Doshi BS, Rana J, Castaman G, Shaheen MA, Kaczmarek R, Butterfield JS, Meeks SL, Leissinger C, Biswas M, Arruda VR. B cell-activating factor modulates the factor VIII immune response in hemophilia A. J Clin Invest 2021; 131:142906. [PMID: 33651716 PMCID: PMC8262462 DOI: 10.1172/jci142906] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 02/23/2021] [Indexed: 01/19/2023] Open
Abstract
Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell-activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody-mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.
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Affiliation(s)
- Bhavya S Doshi
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Divison of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jyoti Rana
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Giancarlo Castaman
- Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy
| | - Mostafa A Shaheen
- Divison of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Radoslaw Kaczmarek
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - John Ss Butterfield
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shannon L Meeks
- Department of Pediatrics, Aflac Cancer Center and Blood Disorders Center at Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Cindy Leissinger
- Section of Hematology/Oncology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Moanaro Biswas
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Valder R Arruda
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Divison of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Raymond G. Perelman Center for Cellular and Molecular Therapies, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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13
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Agarwal D, Luning Prak ET, Bharani T, Everly M, Migone TS, Cancro M, Allman D, Choe I, Kearns JD, Trofe-Clark J, Naji A, Kamoun M. BLyS neutralization results in selective anti-HLA alloantibody depletion without successful desensitization. Transpl Immunol 2021; 69:101465. [PMID: 34506905 DOI: 10.1016/j.trim.2021.101465] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/05/2021] [Accepted: 09/05/2021] [Indexed: 11/15/2022]
Abstract
Pre-existing anti-HLA allo-antibodies (allo-Abs) are a major barrier to successful kidney transplantation, resulting in an elevated risk for antibody-mediated rejection (AMR) and eventual graft loss. The cytokine B lymphocyte stimulator (BLyS) promotes B cell maturation and plasma cell survival; consequently, anti-BLyS therapy represents a potential therapeutic opportunity in diminishing pre-existing allo-Abs. Here we report that in our 1-year pilot trial, BLyS neutralization failed to reduce total anti-HLA allo-Ab levels in highly sensitized candidates awaiting kidney transplant in a clinically meaningful way. Additionally, we performed a post hoc analysis using sera from trial candidates which revealed selective depletion of anti-HLA class I and class II Abs in response to belimumab treatment, restricted to certain allele specificities and IgG subclasses. Altogether, we observed that BLyS blockade only results in selective depletion of anti-HLA Abs recognizing a few discrete HLA allele specificities.
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Affiliation(s)
- Divyansh Agarwal
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Division of Transplantation, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eline T Luning Prak
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tina Bharani
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | | | - Thi-Sau Migone
- Iconic Therapeutics, Shoreline Court, South San Francisco, CA 94080, USA
| | - Michael Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David Allman
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Insuk Choe
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jane D Kearns
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jennifer Trofe-Clark
- Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.; Department of Medicine, Division of Renal, Electrolyte and Hypertension, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery, Division of Transplantation, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Malek Kamoun
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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14
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Müller-Winkler J, Mitter R, Rappe JCF, Vanes L, Schweighoffer E, Mohammadi H, Wack A, Tybulewicz VLJ. Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival. J Exp Med 2021; 218:211510. [PMID: 33119032 PMCID: PMC7604764 DOI: 10.1084/jem.20191393] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 07/22/2020] [Accepted: 09/14/2020] [Indexed: 01/23/2023] Open
Abstract
Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.
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15
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Lau AWY, Turner VM, Bourne K, Hermes JR, Chan TD, Brink R. BAFFR controls early memory B cell responses but is dispensable for germinal center function. J Exp Med 2021; 218:211511. [PMID: 33119033 PMCID: PMC7604765 DOI: 10.1084/jem.20191167] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/15/2020] [Accepted: 09/03/2020] [Indexed: 11/04/2022] Open
Abstract
The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell-intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, amplification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.
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Affiliation(s)
- Angelica W Y Lau
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Vivian M Turner
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Katherine Bourne
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Jana R Hermes
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Tyani D Chan
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.,St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
| | - Robert Brink
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.,St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
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16
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Cancro MP, Tomayko MM. Memory B cells and plasma cells: The differentiative continuum of humoral immunity. Immunol Rev 2021; 303:72-82. [PMID: 34396546 DOI: 10.1111/imr.13016] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/16/2022]
Abstract
Immunological memory is a composite of lasting antibody titers maintained by plasma cells in conjunction with memory T and B cells. Memory B cells are a critical reservoir for plasma cell generation in the secondary response. Identification of memory B cells requires that they be distinguished from naïve, activated, and germinal center precursors and from plasma cells. Memory B cells are heterogeneous in isotype usage, immunoglobulin mutational content, and phenotypic marker expression. Phenotypic subsets of memory B cells are defined by PD-L2, CD80, and CD73 expression in mice, by CD27 and FCRL4 expression in humans and by T-bet in both mice and humans. These subsets display marked functional heterogeneity, including the ability to rapidly differentiate into plasma cells versus seed germinal centers in the secondary response. Memory B cells are located in the spleen, blood, other lymphoid organs, and barrier tissues, and recent evidence indicates that some memory B cells may be dedicated tissue-resident populations. Open questions about memory B cell longevity, renewal and progenitor-successor relationships with plasma cells are discussed.
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Affiliation(s)
- Michael P Cancro
- Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Mary M Tomayko
- Departments of Dermatology and Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
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17
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Schweighoffer E, Tybulewicz VL. BAFF signaling in health and disease. Curr Opin Immunol 2021; 71:124-131. [PMID: 34352467 DOI: 10.1016/j.coi.2021.06.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/09/2021] [Accepted: 06/18/2021] [Indexed: 11/29/2022]
Abstract
BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells. BAFFR cooperates with other receptors, notably the B cell antigen receptor (BCR), a process which is critical for the expansion of autoimmune and CLL cells. This crosstalk may be mediated by TRAF3 which interacts with BAFFR and with CD79A, a signalling subunit of the BCR and the downstream SYK kinase, inhibiting its activity. BAFF binding to BAFFR leads to degradation of TRAF3 which may relieve inhibition of SYK activity transducing signals to pathways required for B cell survival. BAFFR activates both canonical and non-canonical NF-κB signalling and both pathways play important roles in the survival of B cells and CLL cells.
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Affiliation(s)
| | - Victor Lj Tybulewicz
- The Francis Crick Institute, London NW1 1AT, UK; Department of Immunology & Inflammation, Imperial College London, London W12 0NN, UK.
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18
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Canny SP, Jackson SW. B Cells in Systemic Lupus Erythematosus: From Disease Mechanisms to Targeted Therapies. Rheum Dis Clin North Am 2021; 47:395-413. [PMID: 34215370 PMCID: PMC8357318 DOI: 10.1016/j.rdc.2021.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
B cells exert a prominent contribution to the pathogenesis of systemic lupus erythematosus (SLE). Here, we review the immune mechanisms underlying autoreactive B cell activation in SLE, focusing on how B cell receptor and Toll-like receptor signals integrate to drive breaks in tolerance to nuclear antigens. In addition, we discuss autoantibody-dependent and autoantibody-independent B cell effector functions during lupus pathogenesis. Finally, we address efforts to target B cells therapeutically in human SLE. Despite initial disappointing clinical trials testing B cell depletion in lupus, more recent studies show promise, emphasizing how greater understanding of underlying immune mechanisms can yield clinical benefits.
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Affiliation(s)
- Susan P Canny
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, USA
| | - Shaun W Jackson
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA.
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19
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Smets I, Prezzemolo T, Imbrechts M, Mallants K, Mitera T, Humblet-Baron S, Dubois B, Matthys P, Liston A, Goris A. Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis. Front Immunol 2021; 12:676619. [PMID: 34122439 PMCID: PMC8187869 DOI: 10.3389/fimmu.2021.676619] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/07/2021] [Indexed: 01/12/2023] Open
Abstract
Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
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Affiliation(s)
- Ide Smets
- Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.,Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Teresa Prezzemolo
- Department of Microbiology, Immunology and Transplantation, Laboratory for Adaptive Immunology, KU Leuven, Belgium.,VIB Center for Brain & Disease Research, Leuven, Belgium
| | - Maya Imbrechts
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Klara Mallants
- Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.,Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Tania Mitera
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Stéphanie Humblet-Baron
- Department of Microbiology, Immunology and Transplantation, Laboratory for Adaptive Immunology, KU Leuven, Belgium
| | - Bénédicte Dubois
- Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.,Leuven Brain Institute, KU Leuven, Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Patrick Matthys
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Immunobiology, KU Leuven, Leuven, Belgium
| | - Adrian Liston
- Department of Microbiology, Immunology and Transplantation, Laboratory for Adaptive Immunology, KU Leuven, Belgium.,VIB Center for Brain & Disease Research, Leuven, Belgium.,Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom
| | - An Goris
- Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.,Leuven Brain Institute, KU Leuven, Leuven, Belgium
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20
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Abstract
As one of the most important weapons against infectious diseases, vaccines have saved countless lives since their first use in the late eighteenth century. Antibodies produced by effector B cells upon vaccination play a critical role in mediating protection. The past several decades of research have led to a revolution in our understanding of B cell response to vaccination. Vaccines against SARS-CoV-2 coronavirus were developed at an unprecedented speed to power our global fight against COVID-19 pandemic. Nevertheless, we still face many challenges in the development of vaccines against many other deadly viruses, such as human immunodeficiency virus (HIV) and influenza virus. In this review, we summarize the latest findings on B cell response to vaccination and pathogen infection. We also discuss the current challenges in the field and the potential strategies targeting B cell response to improve vaccine efficacy.Key abbreviations box: BCR: B cell receptor; bNAb: broadly neutralizing antibody; DC: dendritic cells; DZ: dark zone; EF response: extrafollicular response; FDC: follicular dendritic cell; GC: germinal center; HIV: human immunodeficiency virus; IC: immune complex; LLPC: long-lived plasma cell; LZ: light zone; MBC: memory B cell; SLPB: short-lived plasmablast; TFH: T follicular helper cells; TLR: Toll-like receptor.
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Affiliation(s)
- Wei Luo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Qian Yin
- Institute for Immunity, Transplantation & Infection, Stanford University School of Medicine, Stanford, California, USA
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21
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Abstract
Although BAFF/BLyS and its receptor, BAFFR, play critical roles in naive B cell survival, the pathways involved in the persistence of memory B cells are largely unknown. In this issue of JEM, two groups, Müller-Winkler et al. (https://doi.org/10.1084/jem.20191393) and Lau et al. (https://doi.org/10.1084/jem.20191167), take complementary approaches to identify an essential role for BAFFR in the survival of memory B cells.
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Affiliation(s)
| | - Julie Zikherman
- Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA
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22
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Rönnberg C, Lugaajju A, Nyman A, Hammar U, Bottai M, Lautenbach MJ, Sundling C, Kironde F, Persson KEM. A longitudinal study of plasma BAFF levels in mothers and their infants in Uganda, and correlations with subsets of B cells. PLoS One 2021; 16:e0245431. [PMID: 33465125 PMCID: PMC7815132 DOI: 10.1371/journal.pone.0245431] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 01/03/2021] [Indexed: 01/05/2023] Open
Abstract
Malaria is a potentially life-threatening disease with approximately half of the world’s population at risk. Young children and pregnant women are hit hardest by the disease. B cells and antibodies are part of an adaptive immune response protecting individuals continuously exposed to the parasite. An infection with Plasmodium falciparum can cause dysregulation of B cell homeostasis, while antibodies are known to be key in controlling symptoms and parasitemia. BAFF is an instrumental cytokine for the development and maintenance of B cells. Pregnancy alters the immune status and renders previously clinically immune women at risk of severe malaria, potentially due to altered B cell responses associated with changes in BAFF levels. In this prospective study, we investigated the levels of BAFF in a malaria-endemic area in mothers and their infants from birth up to 9 months. We found that BAFF-levels are significantly higher in infants than in mothers. BAFF is highest in cord blood and then drops rapidly, but remains significantly higher in infants compared to mothers even at 9 months of age. We further correlated BAFF levels to P. falciparum-specific antibody levels and B cell frequencies and found a negative correlation between BAFF and both P. falciparum-specific and total proportions of IgG+ memory B cells, as well as CD27− memory B cells, indicating that exposure to both malaria and other diseases affect the development of B-cell memory and that BAFF plays a part in this. In conclusion, we have provided new information on how natural immunity against malaria is formed.
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Affiliation(s)
- Caroline Rönnberg
- Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Division of Infectious Diseases, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Allan Lugaajju
- Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Makerere University, Kampala, Uganda
| | - Anna Nyman
- Department of Laboratory Medicine, Lund University, Skåne University Hospital, Lund, Sweden
| | - Ulf Hammar
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matteo Bottai
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Maximilian Julius Lautenbach
- Division of Infectious Diseases, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Christopher Sundling
- Division of Infectious Diseases, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Fred Kironde
- Makerere University, Kampala, Uganda
- Habib Medical School, Islamic University in Uganda (IUIU), Mbale, Uganda
| | - Kristina E. M. Persson
- Department of Laboratory Medicine, Lund University, Skåne University Hospital, Lund, Sweden
- * E-mail:
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23
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BAFF Inhibition Effectively Suppresses the Development of Anti-HLA.A2 Antibody in the Highly Sensitized Mouse Model. Int J Mol Sci 2021; 22:ijms22020861. [PMID: 33467096 PMCID: PMC7830620 DOI: 10.3390/ijms22020861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/13/2021] [Accepted: 01/13/2021] [Indexed: 11/23/2022] Open
Abstract
B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (Δ-13.62 vs. Δ27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (≤2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.
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24
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Ding X, Xiang W, He X. IFN-I Mediates Dysfunction of Endothelial Progenitor Cells in Atherosclerosis of Systemic Lupus Erythematosus. Front Immunol 2020; 11:581385. [PMID: 33262760 PMCID: PMC7686511 DOI: 10.3389/fimmu.2020.581385] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/14/2020] [Indexed: 12/14/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.
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Affiliation(s)
- Xuewei Ding
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Xiang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, NHC Key Laboratory of Control of Tropical diseases (Hainan Medical University), Haikou, China
| | - Xiaojie He
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
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25
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Yu M, Agarwal D, Korutla L, May CL, Wang W, Griffith NN, Hering BJ, Kaestner KH, Velazquez OC, Markmann JF, Vallabhajosyula P, Liu C, Naji A. Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes. Nat Metab 2020; 2:1013-1020. [PMID: 32895576 PMCID: PMC7572844 DOI: 10.1038/s42255-020-0269-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/21/2020] [Indexed: 01/19/2023]
Abstract
The intrahepatic milieu is inhospitable to intraportal islet allografts1-3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet-islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.
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Affiliation(s)
- Ming Yu
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Divyansh Agarwal
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
- Medical Scientist Training Program, Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Laxminarayana Korutla
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Catherine L May
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Wang
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Bernhard J Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Klaus H Kaestner
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Omaida C Velazquez
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - James F Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Chengyang Liu
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
| | - Ali Naji
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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26
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Sachinidis A, Xanthopoulos K, Garyfallos A. Age-Associated B Cells (ABCs) in the Prognosis, Diagnosis and Therapy of Systemic Lupus Erythematosus (SLE). Mediterr J Rheumatol 2020; 31:311-318. [PMID: 33163863 PMCID: PMC7641025 DOI: 10.31138/mjr.31.3.311] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/21/2022] Open
Abstract
The term “age-associated B cells” (ABCs) refers to a heterogeneous B cell subset (CD19+,CD21−, CD11c+,T-bet+) which is expanded in the elderly, but also accumulates prematurely in patients with autoimmune disorders and/or infectious diseases. In healthy individuals, ABCs represent a low prevalence population that positively impacts immunosenescence. In autoimmunity and infections though, ABCs expand dramatically and produce high titers of antibodies, thus playing a role in the regulation of humoral responses. Despite the fact that these observations were made on both mice and humans, the functional features of ABCs and their exact role in human health and disease are still elusive. This review focuses on ABC and ABC-like sub-populations found in Systemic Lupus Erythematosus (SLE) patients (such as the double negative 2;DN2 population: CD19+,IgD−,CD27−, CXCR5−,T-bet+) and broaches the subject of their potential use as prognostic and/or diagnostic markers. The identification of novel biomarkers, via correlating the cell populations with the clinical profile of the patients, should enable better patient stratification and monitoring. Moreover, the necessity and importance of elucidating the role of transcription factor T-bet (TBX21) in the pathogenesis of human autoimmunity are addressed. T-bet, whose expression is upregulated in both mouse and human ABCs, is considered to play a major role in various aspects of autoimmunity, such as the production of autoreactive IgG, the enhanced antigen presentation to T cells and also the formation of spontaneous germinal centres (GC). Shedding light to its role in human disease, in conjunction with the characterisation of genes and pathways associated with the transcription factor itself, may lead to the discovery of novel druggable targets.
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Affiliation(s)
- Athanasios Sachinidis
- Department of Pharmacognosy-Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Xanthopoulos
- Department of Pharmacognosy-Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexandros Garyfallos
- 4 Department of Internal Medicine, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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27
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Kaneko Y, Fukahori H, Yamagami K, Kawashima T, Ito M, Akamatsu M, Marui T, Kato K, Takahashi F, Morokata T. Effects of AS2819899, a novel selective PI3Kδ inhibitor, in a NZB/W F1 mouse lupus-like nephritis model. Int Immunopharmacol 2020; 87:106764. [PMID: 32736191 DOI: 10.1016/j.intimp.2020.106764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 11/18/2022]
Abstract
Phosphoinositide 3-kinases generate lipid-based second messengers that control an array of intracellular signaling pathways. In particular, phosphoinositide 3-kinases delta (PI3Kδ) is expressed primarily in hematopoietic cells and plays an important role in B-cell development and function. B cells play a critical role in autoimmune diseases by producing autoantibodies. Studies have therefore increasingly focused on PI3Kδ as a therapeutic target for the treatment of inflammatory and autoimmune diseases. One such autoimmune disease is systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease with repeated recurrence and remission, and autoantibodies play an important role in its pathogenesis. Here, we examined the pharmacological profile of the novel PI3Kδ selective inhibitor AS2819899 and investigated its therapeutic potential against SLE in a NZB/W F1 mouse lupus-like nephritis model, a widely-used SLE mouse model. AS2819899 prevented B and T cell activation in vitro, and inhibited antibody production in a T-cell independent de novo antibody production mouse model. In the spontaneous NZB/W F1 mouse model, AS2819899 treatment significantly reduced anti-dsDNA antibody titers and improved kidney dysfunction. Further, AS2819899 inhibited the memory recall reaction in a T-cell dependent antibody production mouse model, suggesting that AS2819899 can potentially maintain remission of SLE. Moreover, we identified a pharmacodynamics marker for AS2819899 that may be useful in clinical studies. These results indicate that AS2819899 may be an attractive therapeutic candidate for SLE, including the maintenance of remission.
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Affiliation(s)
- Yoko Kaneko
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
| | - Hidehiko Fukahori
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Kaoru Yamagami
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Tomoko Kawashima
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Misato Ito
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Masahiko Akamatsu
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Takanori Marui
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Koji Kato
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Fumie Takahashi
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Tatsuaki Morokata
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
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28
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Parodi C, Barrio A, García Bustos MF, González Prieto AG, Pimentel J, Badano N, Albareda MC, Castro Eiro ME, Laucella SA, de Elizalde de Bracco MM. B-cell profile, B-cell activating factor concentration and IgG levels in human cutaneous and mucosal leishmaniasis. Parasite Immunol 2020; 42:e12759. [PMID: 32460372 DOI: 10.1111/pim.12759] [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: 10/03/2019] [Revised: 04/28/2020] [Accepted: 05/19/2020] [Indexed: 11/26/2022]
Abstract
AIMS The aim of this study was to evaluate characteristics of B cells in human tegumentary leismaniasis (TL) analysing cutaneous leishmaniasis (CL), most prevalent form and mucosal leishmaniasis (ML), aggressive form characterized by the destruction of the oral-nasal-pharyngeal cavities. METHODS AND RESULTS By flow cytometry analysis, we found decreased percentages of non-class-switched memory B cells in TL with the degree of the loss related to clinical severity. Using commercial ELISA, we reported high levels of B-cell activating factor (BAFF) and IgG preferentially in aggressive CL and markedly in ML together with decreased BAFF receptors in the latter. We also found lower levels of BAFF after clinical recovery suggesting a relation between BAFF and disease activity. Mucosal leishmaniasis history of therapeutic failure presented high levels of BAFF accompanied by detectable concentrations of IFN-γ and IL-6 (assayed by commercial ELISA and cytometric bead arrays respectively), cytokines involved in exaggerated inflammatory responses and tissue damage in TL. CONCLUSION We demonstrate B-cell disturbances in TL with the degree of the alterations related to clinical severity. We suggest a relation between excess of BAFF and disease activity and point towards a possible implication of BAFF in the inflammatory phenomenon of ML.
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Affiliation(s)
- Cecilia Parodi
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Alejandra Barrio
- Cátedra de Microbiología, Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
| | - María F García Bustos
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Ana G González Prieto
- Cátedra de Microbiología, Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
| | - Julia Pimentel
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Noel Badano
- Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - María C Albareda
- Instituto Nacional de Parasitología Dr. M. Fatala Chaben, Buenos Aires, Argentina
| | - Melisa E Castro Eiro
- Instituto Nacional de Parasitología Dr. M. Fatala Chaben, Buenos Aires, Argentina
| | - Susana A Laucella
- Instituto Nacional de Parasitología Dr. M. Fatala Chaben, Buenos Aires, Argentina
| | - María M de Elizalde de Bracco
- Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina
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29
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Abstract
The age-associated B cell subset has been the focus of increasing interest over the last decade. These cells have a unique cell surface phenotype and transcriptional signature, and they rely on TLR7 or TLR9 signals in the context of Th1 cytokines for their formation and activation. Most are antigen-experienced memory B cells that arise during responses to microbial infections and are key to pathogen clearance and control. Their increasing prevalence with age contributes to several well-established features of immunosenescence, including reduced B cell genesis and damped immune responses. In addition, they are elevated in autoimmune and autoinflammatory diseases, and in these settings they are enriched for characteristic autoantibody specificities. Together, these features identify age-associated B cells as a subset with pivotal roles in immunological health, disease, and aging. Accordingly, a detailed understanding of their origins, functions, and physiology should make them tractable translational targets in each of these settings.
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Affiliation(s)
- Michael P. Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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30
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Wilson RP, McGettigan SE, Dang VD, Kumar A, Cancro MP, Nikbakht N, Stohl W, Debes GF. IgM Plasma Cells Reside in Healthy Skin and Accumulate with Chronic Inflammation. J Invest Dermatol 2019; 139:2477-2487. [PMID: 31152755 PMCID: PMC6874734 DOI: 10.1016/j.jid.2019.05.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 05/03/2019] [Accepted: 05/13/2019] [Indexed: 12/15/2022]
Abstract
Antibodies are key to cutaneous host defense and inflammation. Despite their importance, the mechanisms by which skin antibodies are sustained are poorly described. Here, we identified that, in addition to antibody production in lymphoid tissues, plasma cells reside in healthy mouse and human skin. In naïve mice, IgM was the predominant isotype produced in skin. Skin plasma cells developed independently of T cells and microbiota. Importantly, chronic skin inflammation promoted the massive accumulation of IgM-secreting cells, and cutaneous immunization directed both T cell-dependent and -independent antigen-specific IgM-secreting cells into skin. Unlike their counterparts in lymphoid tissues, cutaneous IgM-secreting cells were completely dependent on survival factors such as a proliferation-inducing ligand or B cell-activating factor, which were constitutively expressed and upregulated during inflammation in skin. Our data support a model in which skin plasma cells supply natural and adaptive IgM to the cutaneous environment, thereby supporting homeostatic skin barrier functions and providing defense against pathogen intrusion. Our results are also of potential relevance for manipulation of cutaneous plasma cells in inflammatory skin diseases or cutaneous plasma cell malignancies.
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Affiliation(s)
- R Paul Wilson
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shannon E McGettigan
- Department of Microbiology and Immunology, Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Van Duc Dang
- Department of Microbiology and Immunology, Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Cell Biology, Faculty of Biology, VNU University of Science, Hanoi, Vietnam; Vinmec Research Institute of Stem Cell and Gene Technology, Hanoi, Vietnam
| | - Anil Kumar
- Department of Microbiology and Immunology, Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Michael P Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Neda Nikbakht
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - William Stohl
- Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Gudrun F Debes
- Department of Microbiology and Immunology, Sidney Kimmel Medical College and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
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31
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Jackson SW, Davidson A. BAFF inhibition in SLE-Is tolerance restored? Immunol Rev 2019; 292:102-119. [PMID: 31562657 PMCID: PMC6935406 DOI: 10.1111/imr.12810] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
Abstract
The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low-affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM- and IgG-producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.
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Affiliation(s)
- Shaun W Jackson
- Seattle Children's Research Institute, Seattle, WA, USA
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Anne Davidson
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
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32
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Shu JL, Zhang XZ, Han L, Zhang F, Wu YJ, Tang XY, Wang C, Tai Y, Wang QT, Chen JY, Chang Y, Wu HX, Zhang LL, Wei W. Paeoniflorin-6'-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-κB signaling: comparison with biological agents. Acta Pharmacol Sin 2019; 40:801-813. [PMID: 30446734 DOI: 10.1038/s41401-018-0169-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 09/06/2018] [Indexed: 11/09/2022]
Abstract
Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19+ total B cells, CD19+CD27+-activated B cells, CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-κB signaling. Furthermore, we showed that treatment with CP-25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-κB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-κB signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.
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33
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Tomayko MM, Allman D. What B cell memories are made of. Curr Opin Immunol 2019; 57:58-64. [PMID: 30861463 DOI: 10.1016/j.coi.2019.01.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 01/16/2019] [Indexed: 12/21/2022]
Abstract
In many ways, memory B cells represent the ultimate outcome of humoral immunity. Many of these cells express exceptionally high affinity antigen-specific B cell receptors for antigen, and these cells are a critical source of the long-lived plasma cells that secrete protective serum antibodies to protect against secondary exposure to pathogens and other life-threatening antigens. Evidence is now emerging that not all memory B cells are created via the same cellular pathways and molecular events. Similarly, it is becoming clear that different memory B cells can take on different functions, with some producing IgM rather than IgG antibodies upon reactivation, and others preferentially producing plasma cells rather than additional waves of memory B cells. With this review, we discuss the conceptual ides and early studies surrounding early work on B cell memory, then discuss the many pathways and functional attributes of subpopulations of memory B cells and current approaches to characterize these cells directly.
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Affiliation(s)
- Mary M Tomayko
- The Department of Dermatology, Yale University, New Haven, CT 06511, United States
| | - David Allman
- The Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States.
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34
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Allman D, Wilmore JR, Gaudette BT. The continuing story of T-cell independent antibodies. Immunol Rev 2019; 288:128-135. [PMID: 30874357 PMCID: PMC6653682 DOI: 10.1111/imr.12754] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 02/04/2019] [Indexed: 12/12/2022]
Abstract
The purpose of this article is to review the role of extrafollicular and T-cell independent antibody responses in humoral immunity. We consider two interrelated questions: (a) do T-cell independent antibody responses dominated by IgM and/or IgA play unique functions in immunity and homeostasis; and (b) is it typical for these responses to result in lifelong protection? In addressing these questions, we consider the established advantages of T-cell driven responses including the unique role played by germinal center reactions in these responses, and contrast the processes and outcomes of germinal center-centric responses with germinal center- and T-cell independent antibodies. We suggest that T-independent and other extrafollicular responses contribute substantially to highly stable antibody repertoires in both the serum and the intestine, providing relatively constitutive humoral barriers with the collective dual function of protecting against invading pathogens and regulating the composition of non-pathogenic microbial communities.
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Affiliation(s)
- David Allman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Joel R Wilmore
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Brian T Gaudette
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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Bath NM, Ding X, Wilson NA, Verhoven BM, Boldt BA, Sukhwal A, Reese SR, Panzer SE, Djamali A, Redfield RR. Desensitization and treatment with APRIL/BLyS blockade in rodent kidney transplant model. PLoS One 2019; 14:e0211865. [PMID: 30735519 PMCID: PMC6368307 DOI: 10.1371/journal.pone.0211865] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/23/2019] [Indexed: 11/19/2022] Open
Abstract
Alloantibody represents a significant barrier in kidney transplant through the sensitization of patients prior to transplant through antibody mediated rejection (ABMR). APRIL BLyS are critical survival factors for mature B lymphocytes plasma cells, the primary source of alloantibody. We examined the effect of APRIL/BLyS blockade via TACI-Ig (Transmembrane activator calcium modulator cyclophilin lig interactor-Immunoglobulin) in a preclinical rodent model as treatment for both desensitization ABMR. Lewis rats were sensitized with Brown Norway (BN) blood for 21 days. Following sensitization, animals were then sacrificed or romized into kidney transplant (G4, sensitized transplant control); desensitization with TACI-Ig followed by kidney transplant (G5, sensitized + pre-transplant TACI-Ig); kidney transplant with post-transplant TACI-Ig for 21 days (G6, sensitized + post-transplant TACI-Ig); desensitization with TACI-Ig followed by kidney transplant post-transplant TACI-Ig for 21 days (G7, sensitized + pre- post-transplant TACI-Ig). Animals were sacrificed on day 21 post-transplant tissues were analyzed using flow cytometry, IHC, ELISPOT, RT-PCR. Sensitized animals treated with APRIL/BLyS blockade demonstrated a significant decrease in marginal zone non-switched B lymphocyte populations (p<0.01). Antibody secreting cells were also significantly reduced in the sensitized APRIL/BLyS blockade treated group. Post-transplant APRIL/BLyS blockade treated animals were found to have significantly less C4d deposition less ABMR as defined by Banff classification when compared to groups receiving APRIL/BLyS blockade before transplant or both before after transplant (p<0.0001). The finding of worse ABMR in groups receiving APRIL/BLyS blockade before both before after transplant may indicate that B lymphocyte depletion in this setting also resulted in regulatory lymphocyte depletion resulting in a worse rejection. Data presented here demonstrates that the targeting of APRIL BLyS can significantly deplete mature B lymphocytes, antibody secreting cells, effectively decrease ABMR when given post-transplant in a sensitized animal model.
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Affiliation(s)
- Natalie M. Bath
- Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Xiang Ding
- Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Nancy A. Wilson
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Bret M. Verhoven
- Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Brittney A. Boldt
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Adarsh Sukhwal
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Shannon R. Reese
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Sarah E. Panzer
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Arjang Djamali
- Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Robert R. Redfield
- Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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36
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Granja AG, Tafalla C. Different IgM + B cell subpopulations residing within the peritoneal cavity of vaccinated rainbow trout are differently regulated by BAFF. FISH & SHELLFISH IMMUNOLOGY 2019; 85:9-17. [PMID: 28989090 DOI: 10.1016/j.fsi.2017.10.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 10/03/2017] [Accepted: 10/04/2017] [Indexed: 06/07/2023]
Abstract
In teleost fish, IgM+ B cells are one of the main responders against inflammatory stimuli in the peritoneal cavity, as IgM+ B cells dominate the peritoneum after intraperitoneal stimulation, also increasing the levels of secreted IgM. BAFF, a cytokine known to play a major role in B cell biology, has been shown to be up-regulated along with its receptors in the peritoneum of rainbow trout upon antigenic exposure, however, the regulatory mechanisms underneath this response remain unclear. In this study, we have identified two different IgM+ B cell types residing in the peritoneal cavity of previously vaccinated rainbow trout (Oncorhynchus mykiss): IgD+IgMhiMHCIIhi cells, resembling naïve B cells, and IgD-IgMloMHCIIlo cells, resembling antibody-secreting cells. Based on their membrane IgM levels, these cell types were named IgMhi and IgMlo B cells, respectively. As each of these B cell populations showed a distinct expression pattern for the different BAFF receptors, we studied the effect of BAFF individually on each cell subset. Recombinant BAFF promoted the survival of IgMlo but not IgMhi B cells in vitro, resulting in increased levels of IgM-secreting cells. In contrast, BAFF increased the levels of membrane MHC II only on IgMhi B cells, suggesting different functions on these B cell subsets. Moreover, we also showed that peritoneal IgMhi B cells expressed BAFF at levels comparable to those seen on myeloid cells. These results point to BAFF as a main regulator of B cell homeostasis in the peritoneal cavity, suggesting that this cytokine can trigger different signals on different peritoneal B cell subsets in a specific manner.
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Affiliation(s)
- Aitor G Granja
- Centro de Investigación en Sanidad Animal (CISA-INIA), Madrid, Spain.
| | - Carolina Tafalla
- Centro de Investigación en Sanidad Animal (CISA-INIA), Madrid, Spain.
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Tsiantoulas D, Sage AP, Göderle L, Ozsvar-Kozma M, Murphy D, Porsch F, Pasterkamp G, Menche J, Schneider P, Mallat Z, Binder CJ. B Cell-Activating Factor Neutralization Aggravates Atherosclerosis. Circulation 2018; 138:2263-2273. [PMID: 29858401 PMCID: PMC6181204 DOI: 10.1161/circulationaha.117.032790] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell-activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. METHODS To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe-/- and Ldlr-/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, the authors studied atherosclerosis-prone mice that lack the alternative receptor for BAFF: transmembrane activator and calcium modulator and cyclophilin ligand interactor. RESULTS The authors demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell-specific deletion of transmembrane activator and calcium modulator and cyclophilin ligand interactor also results in increased atherosclerosis, while B cell-specific transmembrane activator and calcium modulator and cyclophilin ligand interactor deletion had no effect. Mechanistically, BAFF-transmembrane activator and calcium modulator and cyclophilin ligand interactor signaling represses macrophage IRF7-dependent (but not NF-κB-dependent) Toll-like receptor 9 responses including proatherogenic CXCL10 production. CONCLUSIONS These data identify a novel B cell-independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.
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Affiliation(s)
- Dimitrios Tsiantoulas
- Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.),CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
| | - Andrew P. Sage
- Division of Cardiovascular Medicine, University of Cambridge, UK (A.P.S., D.M., Z.M.)
| | - Laura Göderle
- Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.),CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
| | - Maria Ozsvar-Kozma
- Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.),CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
| | - Deirdre Murphy
- Division of Cardiovascular Medicine, University of Cambridge, UK (A.P.S., D.M., Z.M.)
| | - Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.),CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
| | | | - Jörg Menche
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
| | - Pascal Schneider
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland (P.S.)
| | - Ziad Mallat
- Division of Cardiovascular Medicine, University of Cambridge, UK (A.P.S., D.M., Z.M.).,Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center (PARCC), Paris, France (Z.M.)
| | - Christoph J. Binder
- Department of Laboratory Medicine, Medical University of Vienna (D.T., L.G., M.O.-K., F.P., C.J.B.),CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (D.T., L.G., M.O.-K., F.P., J.M., C.J.B.)
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Rodríguez-Carrio J, Alperi-López M, López P, Ballina-García FJ, Suárez A. Profiling of B-Cell Factors and Their Decoy Receptors in Rheumatoid Arthritis: Association With Clinical Features and Treatment Outcomes. Front Immunol 2018; 9:2351. [PMID: 30369929 PMCID: PMC6194314 DOI: 10.3389/fimmu.2018.02351] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/24/2018] [Indexed: 12/27/2022] Open
Abstract
Introduction: B-cell activation is pivotal in rheumatoid arthritis (RA) pathogenesis and represents a relevant therapeutic target. The main aim of this study was to characterize the profiles of B-cell factors and their decoy receptors in RA and evaluate their clinical relevance. Methods: sBLyS, sAPRIL, sBCMA, sTACI, sBLyS-R, and several cytokines' serum levels were measured by immunoassays in 104 RA patients and 33 healthy controls (HC). An additional group of 42 systemic lupus erythematosus (SLE) patients were enrolled as disease controls. Whole blood IFI44, IFI44L, IFI6, and MX1 gene expression was measured and averaged into an IFN-score. BLyS membrane expression (mBLyS) was assessed on blood cell subsets by flow cytometry. Results: increased sAPRIL and sBCMA levels were found in RA, whereas BLyS was elevated in very early RA (VERA). No differences were observed for sTACI and sBLyS-R. An increased sBLyS/sBLyS-R ratio was associated with poor clinical outcome at 6 and 12 months in VERA, whereas a positive association with disease activity was observed in established disease. Increased mBLyS expression was found on monocytes, mDCs, neutrophils and B-cells in RA, to a similar extent that in SLE patients. Cluster analysis identified a specific B-cell factors profile overrepresented in RA and associated with autoantibodies, elevated proinflammatory cytokines (IFNα, MIP1α, TNFα, IL-37, and GM-CSF) and increased type-I IFN signature. Increasing sBCMA and sBLyS serum levels upon treatment and mBLyS expression at baseline on monocytes and mDCs, but not B-cells, were associated with poor clinical outcome upon TNFα-blockade. Conclusions: profound and complex alterations of soluble and membrane-bound B-cell factors are observed in RA associated with clinical outcomes, thus supporting its applicability to guide patient stratification along disease course.
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Affiliation(s)
- Javier Rodríguez-Carrio
- Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
| | - Mercedes Alperi-López
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.,Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Patricia López
- Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
| | - Francisco J Ballina-García
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.,Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana Suárez
- Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
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39
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Smulski CR, Eibel H. BAFF and BAFF-Receptor in B Cell Selection and Survival. Front Immunol 2018; 9:2285. [PMID: 30349534 PMCID: PMC6186824 DOI: 10.3389/fimmu.2018.02285] [Citation(s) in RCA: 231] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/14/2018] [Indexed: 12/16/2022] Open
Abstract
The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
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Affiliation(s)
- Cristian R Smulski
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany
| | - Hermann Eibel
- Faculty of Medicine, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany
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40
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Trentin F, Gatto M, Zen M, Larosa M, Maddalena L, Nalotto L, Saccon F, Zanatta E, Iaccarino L, Doria A. Effectiveness, Tolerability, and Safety of Belimumab in Patients with Refractory SLE: a Review of Observational Clinical-Practice-Based Studies. Clin Rev Allergy Immunol 2018; 54:331-343. [PMID: 29512034 PMCID: PMC6132773 DOI: 10.1007/s12016-018-8675-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
To date, belimumab is the only biological drug approved for the treatment of patients with active refractory SLE. We compared and critically analyzed the results of 11 observational clinical-practice-based studies, conducted in SLE referral centers. Despite the differences in endpoints and follow-up duration, all studies remarked that belimumab provides additional benefits when used as an add-on to existing treatment, allowing a higher rate of patients to reach remission and to taper or discontinue corticosteroids. In the OBSErve studies, 2–9.6% of patients discontinued corticosteroids and 72–88.4% achieved a ≥ 20% improvement by physician’s judgment at 6 months. In Hui-Yuen’s study, 51% of patients attained response by simplified SRI at month 6. In Sthoeger’s study, 72.3% of patients discontinued corticosteroids and 69.4% achieved clinical remission by PGA after a median follow-up of 2.3 years. In the multicentric Italian study, 77 and 68.7% of patients reached SRI-4 response at months 6 and 12, respectively. In all the studies, disease activity indices decreased over time. Retention rates at 6, 9, and 12 months were 82–94.1, 61.2–83.3, and 56.7–79.2%, respectively. The main limitations of these studies include the lack of a control group, the short period of observation (6–24 months) and the lack of precise restrictions regarding concomitant medication management. This notwithstanding, these experiences provide a more realistic picture of real-life effectiveness of the drug compared with the randomized controlled clinical trials, where stringent inclusion/exclusion criteria and changes in background therapy could limit the inference of data to the routine clinical care.
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Affiliation(s)
- Francesca Trentin
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Mariele Gatto
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Margherita Zen
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | | | - Larosa Maddalena
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Linda Nalotto
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Francesca Saccon
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Elisabetta Zanatta
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Luca Iaccarino
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - Andrea Doria
- Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.
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41
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Theodorou E, Nezos A, Antypa E, Ioakeimidis D, Koutsilieris M, Tektonidou M, Moutsopoulos HM, Mavragani CP. B-cell activating factor and related genetic variants in lupus related atherosclerosis. J Autoimmun 2018; 92:87-92. [PMID: 29859654 DOI: 10.1016/j.jaut.2018.05.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 05/04/2018] [Accepted: 05/08/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with an increased atherosclerotic risk compared to healthy population, partially explained by traditional cardiovascular (CV) risk factors. Recent data suggest B-cell activating factor (BAFF) as an important contributor in the pathogenesis of both SLE and atherosclerosis. The aim of the current study is to explore whether serum BAFF levels along with variants of the BAFF gene increase lupus related atherosclerotic risk. PATIENTS-METHODS 250 SLE patients underwent assessment of plaque formation and/or intimal media thickness (IMT) measurements in carotid and femoral arteries by ultrasound. Disease related features and CV traditional risk factors were also assessed. Serum BAFF levels were determined by commercially available ELISA and five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) were evaluated by PCR-based assays in all patients and 200 healthy controls (HC) of similar age and sex distribution. SLE patients were further divided in high and low BAFF groups on the basis of the upper quartile level of the distribution (1358 pg/ml). Genotype and haplotype frequencies in SLE patients and HC were determined by SNPStats and SHEsis software. RESULTS High-BAFF SLE group displayed increased rates of both plaque formation and arterial wall thickening (defined as IMT>0.90 mm) compared to patients with low BAFF levels (58.1% vs 43.6%, p:0.048 and 38.6% vs 23.2%, p-value: 0.024, respectively). The association remained significant after disease related features were taken into account (ORs [95%CI]: 2.2 [1.0-5.1] and 2.5 [1.1-5.5] for plaque formation and arterial wall thickening, respectively). Moreover, the presence of the AA genotype of the rs12583006 BAFF gene variant increased susceptibility for both lupus and lupus related plaque formation (ORs [95%CI]: 2.8 [1.1-7.1], and 4.4 [1.3-15.4] in the codominant model, respectively). Finally, the haplotype TTTAT was found to be protective for plaque formation among SLE patients (OR 0.3 [0.1-0.9]. No associations between BAFF gene variants with arterial wall thickening were detected. CONCLUSIONS High BAFF serum levels in the upper 4th quartile as well as BAFF genetic variants seem to increase susceptibility for both lupus and lupus related subclinical atherosclerosis implying B-cell hyperactivity as a potential contributor in the pronounced lupus related atherosclerotic risk.
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Affiliation(s)
- Evangelos Theodorou
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Athens, Greece
| | - Adrianos Nezos
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleni Antypa
- Department of Radiology, General Hospital of Athens "G.Gennimatas", Athens, Greece
| | - Dimitrios Ioakeimidis
- Department of Rheumatology, General Hospital of Athens "G.Gennimatas", Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Tektonidou
- Rheumatology Unit, First Department of Propaedeutic and Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Haralampos M Moutsopoulos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Clio P Mavragani
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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42
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Schrezenmeier E, Jayne D, Dörner T. Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives. J Am Soc Nephrol 2018; 29:741-758. [PMID: 29326157 DOI: 10.1681/asn.2017040367] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The unique contributions of memory B cells and plasma cells in kidney diseases remain unclear. In this review, we evaluate the clinical experience with treatments directed at B cells, such as rituximab, and at plasma cells, such as proteasome inhibition, to shed light on the role of these two B lineage compartments in glomerular diseases. Specifically, analysis of these targeted interventions in diseases such as ANCA-associated vasculitis, SLE, and antibody-mediated transplant rejection permits insight into the pathogenetic effect of these cells. Notwithstanding the limitations of preclinical models and clinical studies (heterogeneous populations, among others), the data suggest that memory B and plasma cells represent two engines of autoimmunity, with variable involvement in these diseases. Whereas memory B cells and plasma cells appear to be key in ANCA-associated vasculitis and antibody-mediated transplant rejection, respectively, SLE seems likely to be driven by both autoimmune compartments. These conclusions have implications for the future development of targeted therapeutics in immune-mediated renal disease.
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Affiliation(s)
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Thomas Dörner
- Rheumatology and Clinical Immunology, Department of Medicine, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; and
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43
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Schweighoffer E, Tybulewicz VL. Signalling for B cell survival. Curr Opin Cell Biol 2017; 51:8-14. [PMID: 29149682 DOI: 10.1016/j.ceb.2017.10.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 10/10/2017] [Indexed: 12/21/2022]
Abstract
The number of mature B cells is carefully controlled by signalling from receptors that support B cell survival. The best studied of these are the B cell antigen receptor (BCR) and BAFFR. Recent work has shown that signalling from these receptors is closely linked, involves the CD19 co-receptor, and leads to activation of canonical and non-canonical NF-κB pathways, ERK1, ERK2 and ERK5 MAP kinases, and PI-3 kinases. Importantly, studies show that investigation of the importance of signalling molecules in cell survival requires the use of inducible gene deletions within mature B cells. This overcomes the limitations of many earlier studies using constitutive gene deletions which were unable to distinguish between requirements for a protein in development versus survival.
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Affiliation(s)
| | - Victor Lj Tybulewicz
- The Francis Crick Institute, London NW1 1AT, UK; Imperial College, London W12 0NN, UK.
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44
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Wang X, Zhang Y, Wang Z, Liu X, Zhu G, Han G, Chen G, Hou C, Wang T, Shen B, Li Y, Xiao H, Ma N, Wang R. Anti‑IL‑39 (IL‑23p19/Ebi3) polyclonal antibodies ameliorate autoimmune symptoms in lupus‑like mice. Mol Med Rep 2017; 17:1660-1666. [PMID: 29138852 PMCID: PMC5780108 DOI: 10.3892/mmr.2017.8048] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 06/22/2017] [Indexed: 12/05/2022] Open
Abstract
The interleukin (IL)-12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL-12 family cytokine, IL-39 (IL-23p19/Ebi3) mediates inflammation in lupus-like mice. In the present study, the effect of anti-mouse IL-39 polyclonal antibodies on autoimmune symptoms in lupus-like mice was investigated. Rabbit anti-mouse IL-39 polyclonal antibodies were produced by immunization with recombinant mouse IL-39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupus-like mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of anti-IL-39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The anti-IL-39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that anti-IL-39 polyclonal antibodies ameliorated autoimmune symptoms in lupus-like mice. Therefore, IL-39 may be used as a possible target for the treatment of systemic lupus erythematosus.
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Affiliation(s)
- Xiaoqian Wang
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Yu Zhang
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Zhiding Wang
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Xiaoling Liu
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Gaizhi Zhu
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Gencheng Han
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Guojiang Chen
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Chunmei Hou
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Tianxiao Wang
- College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China
| | - Beifen Shen
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Yan Li
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - He Xiao
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Ning Ma
- Department of Rheumatology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Renxi Wang
- Laboratory of Immunology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China
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Walker JA, Vuyyuru R, Manser T, Alugupalli KR. Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants. Stem Cells Dev 2017; 26:1715-1723. [PMID: 29099340 DOI: 10.1089/scd.2017.0156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Immunodeficient mice transplanted with human hematopoietic stem cells (HSCs) have been referred to as "Human Immune System" (HIS) mice and are a translational platform for studying human immune responses in vivo. Human HSC sources used in generating HIS mice include fetal liver (FL), umbilical cord blood (CB), and adult bone marrow (BM). Since HSCs from FL, CB, and BM are produced at various stages of human development, we tested whether mice transplanted with these three HSCs differ in their immune responses. We found that compared with CB HSCs or FL HSCs, adult BM HSCs reconstitute the immune system poorly. The resulting HIS mice do not mount an antibody response to Borrelia hermsii infection and as a consequence suffer persistently high levels of bacteremia. While both CB and FL HSCs yield comparable levels of immune reconstitution of HIS mice resulting in robust anti-B. hermsii immune responses, FL HSC-transplanted mice exhibited a discernable difference in their human B cell maturity as identified by an increased frequency of CD10+ immature B cells and relatively smaller lymphoid follicles compared with CB HSC-transplanted mice. Although CB HSC-transplanted mice generated robust antibody responses to B. hermsii and specific protein antigens of B. hermsii, they failed to respond to Salmonella typhi Vi polysaccharide, a classical T cell-independent antigen. This situation resembles that seen in human infants and young children. Therefore, CB HSC-transplanted mice may serve as a translation platform to explore approaches to overcome the impaired antipolysaccharide responses characteristic of human infants.
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Affiliation(s)
- Justin A Walker
- Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania
| | - Raja Vuyyuru
- Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania
| | - Tim Manser
- Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania
| | - Kishore R Alugupalli
- Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania
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Abstract
The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.
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Affiliation(s)
- Jiro Sakai
- Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Mustafa Akkoyunlu
- Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Land J, Lintermans LL, Stegeman CA, Muñoz-Elías EJ, Tarcha EJ, Iadonato SP, Heeringa P, Rutgers A, Abdulahad WH. Kv1.3 Channel Blockade Modulates the Effector Function of B Cells in Granulomatosis with Polyangiitis. Front Immunol 2017; 8:1205. [PMID: 29018452 PMCID: PMC5622953 DOI: 10.3389/fimmu.2017.01205] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 09/12/2017] [Indexed: 12/21/2022] Open
Abstract
B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto)antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) from GPA patients, and HCs were stimulated in vitro in the presence and absence of ShK-186. The production of total and antineutrophil cytoplasmic antibodies targeting proteinase 3 (PR3-ANCA) IgG was analyzed by enzyme-linked immunosorbent assay and Phadia EliA, respectively. In addition, effects of ShK-186 on B cell proliferation and cytokine production were determined by flow cytometry. The frequency of circulating switched and unswitched memory B cells was decreased in GPA patients as compared to HC. ShK-186 suppressed the production of both total and PR3-ANCA IgG in stimulated PBMCs. A strong decrease in production of tumor necrosis factor alpha (TNFα), interleukin (IL)-2, and interferon gamma was observed upon ShK-186 treatment, while effects on IL-10 production were less pronounced. As such, ShK-186 modulated the TNFα/IL-10 ratio among B cells, resulting in a relative increase in the regulatory B cell pool. ShK-186 modulates the effector functions of B cells in vitro by decreasing autoantibody and pro-inflammatory cytokine production. Kv1.3 channel blockade may hold promise as a novel therapeutic strategy in GPA and other B cell-mediated autoimmune disorders.
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Affiliation(s)
- Judith Land
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Lucas L Lintermans
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Coen A Stegeman
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | | | | | | | - Peter Heeringa
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Abraham Rutgers
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Wayel H Abdulahad
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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48
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Boothby M, Rickert RC. Metabolic Regulation of the Immune Humoral Response. Immunity 2017; 46:743-755. [PMID: 28514675 DOI: 10.1016/j.immuni.2017.04.009] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 04/15/2017] [Accepted: 04/21/2017] [Indexed: 12/13/2022]
Abstract
Productive humoral responses require that naive B cells and their differentiated progeny move among distinct micro-environments. In this review, we discuss how studies are beginning to address the nature of these niches as well as the interplay between cellular signaling, metabolic programming, and adaptation to the locale. Recent work adds evidence to the expectation that B cells at distinct stages of development or functional subsets are influenced by the altered profiles of nutrients and metabolic by-products that distinguish these sites. Moreover, emerging findings reveal a cross-talk among the external milieu, signal transduction pathways, and transcription factors that direct B cell fate in the periphery.
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Affiliation(s)
- Mark Boothby
- Department of Pathology, Microbiology and Immunology, School of Medicine, Vanderbilt University, and Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, School of Medicine, Vanderbilt University, and Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Robert C Rickert
- Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute (SBP), La Jolla, CA 92037, USA; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
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49
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Immunological aspects of rabies: a literature review. Arch Virol 2017; 162:3251-3268. [PMID: 28726129 DOI: 10.1007/s00705-017-3484-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/27/2017] [Indexed: 02/08/2023]
Abstract
Rabies is a lethal disease caused by the neurotropic virus rabies virus (RABV), and it remains an important public health problem globally. It is known that the host immune response is important for control of viral infection and promoting viral clearance. In this context, it is well documented that, in addition to RABV neutralizing antibody, interferons and cell-mediated immunity also have an important role in preventing the establishment of disease. On the other hand, RABV suppresses host immunity through different mechanisms, for example, direct inhibition of host gene expression, sequestration of pathogen-associated molecular patterns, or modification of cytokine signalling pathways, which hinder the protective host immune responses to RABV infection. Here, we review the immunological aspects of rabies, highlighting innate and adaptive immunity, as well as the host evasion immune mechanisms used by the virus. Finally, we briefly discuss how this knowledge can direct new research and be harnessed for future therapeutic strategies.
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50
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Ma N, Zhang Y, Liu Q, Wang Z, Liu X, Zhu G, Yu D, Han G, Chen G, Hou C, Wang T, Ma Y, Shen B, Li Y, Xiao H, Wang R. B cell activating factor (BAFF) selects IL-10 − B cells over IL-10 + B cells during inflammatory responses. Mol Immunol 2017; 85:18-26. [DOI: 10.1016/j.molimm.2017.02.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 01/24/2017] [Accepted: 02/04/2017] [Indexed: 12/14/2022]
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