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Xu X, Zhang S, Luo Z, Zheng Y, Kong T, Huang C, Qiu Z. Frontiers and Controversies in De Novo Gastrointestinal Tumors After Organ Transplantation: Current Progress and Future Directions. Ann Surg Oncol 2025; 32:3392-3405. [PMID: 40035907 DOI: 10.1245/s10434-025-16975-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/21/2025] [Indexed: 03/06/2025]
Abstract
The increasing success of organ transplantation has significantly improved survival for patients with end-stage diseases, yet it introduces a complex dilemma: the elevated risk for the development of de novo gastrointestinal (GI) tumors. The sustained immunosuppression required to maintain graft function paradoxically undermines the body's natural defenses against cancer, leading to a higher incidence, aggressive progression, and atypical presentations of GI tumors among transplant recipients compared with the general population. This presents a pressing challenge: balancing the dual imperatives of preventing graft rejection and effectively managing malignancies. Current treatment paradigms, including surgical approaches, chemotherapy, radiation therapy, and the emerging role of immunotherapy, are fraught with complexities due to the altered immune landscape in these patients. This review underscores the critical need to understand the multifaceted relationship between post-transplantation immunosuppression and tumorigenesis, providing a comprehensive exploration of epidemiologic shifts, pathophysiologic insights, and the intricacies of the tumor microenvironment in this unique patient population. Understanding and managing GI tumors in transplant recipients is not only a clinical challenge, but also a necessary frontier in transplant oncology, promising to refine therapeutic strategies and improve the longevity and quality of life for this growing patient cohort.
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Affiliation(s)
- Ximo Xu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shaopeng Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zai Luo
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Zheng
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingting Kong
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Huang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhengjun Qiu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Liao J, Yang Y, Li J, Liu Z, Song S, Zeng Y, Wang Y. Regulatory B cells, the key regulator to induce immune tolerance in organ transplantation. Front Immunol 2025; 16:1561171. [PMID: 40264774 PMCID: PMC12011811 DOI: 10.3389/fimmu.2025.1561171] [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: 01/15/2025] [Accepted: 03/24/2025] [Indexed: 04/24/2025] Open
Abstract
In solid organ transplantation, especially renal transplantation, for the induction of immune tolerance, accumulating evidence has revealed that Regulatory B cells (Breg) play a crucial role in stimulating immune tolerance, alleviating immune responses, and improving graft survival. We describe the heterogeneous nature of Bregs, focusing on their defining surface markers and regulatory functions. Meanwhile, the major cytokine secretion function and the correlation between Breg and Treg or other immune checkpoints to balance the immune responses are addressed. Furthermore, we summarized the intrinsic and extrinsic pathways or costimulatory stimuli for the differentiation from naïve B cells. More importantly, we summarized the progression of the immune tolerance induction role of Breg in solid organ (kidney, liver, heart, lung, and islet) transplantation. This is an up-to-date review from the origin of Breg to the function of Breg in solid organ transplantation and how it induces immune tolerance in both murine models and human solid organ transplantation.
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Affiliation(s)
- Jinfeng Liao
- Department of Dermatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yixin Yang
- Department of Clinical Medicine, The First Clinical Medical College of Norman Bethune University of Medical Sciences, Jilin, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zheng Liu
- Department of Pathology, MD Anderson Cancer Center, Houston, TX, United States
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Yu Zeng
- Department of Hyperbaric Oxygen, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
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Wang L, Vulesevic B, Vigano M, As’sadiq A, Kang K, Fernandez C, Samarani S, Anis AH, Ahmad A, Costiniuk CT. The Impact of HIV on B Cell Compartment and Its Implications for COVID-19 Vaccinations in People with HIV. Vaccines (Basel) 2024; 12:1372. [PMID: 39772034 PMCID: PMC11679862 DOI: 10.3390/vaccines12121372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/28/2024] [Accepted: 11/30/2024] [Indexed: 01/11/2025] Open
Abstract
HIV causes intense polyclonal activation of B cells, resulting in increased numbers of spontaneously antibody-secreting cells in the circulation and hypergammaglobulinemia. It is accompanied by significant perturbations in various B cell subsets, such as increased frequencies of immature/transitional B cells, activated memory B cells, atypical memory B cells, short-lived plasmablasts and regulatory B cells, as well as by decreased frequencies of resting memory and resting naïve B cells. Furthermore, both memory and antigen-inexperienced naïve B cells show exhausted and immune-senescent phenotypes. HIV also drives the expansion and functional impairment of CD4+ T follicular helper cells, which provide help to B cells, crucial for the generation of germinal center reactions and production of long-lived plasma and memory B cells. By suppressing viral replication, anti-retroviral therapy reverses the virus-induced perturbations and functional defects, albeit inadequately. Due to HIV's lingering impact on B cells, immune senescence and residual chronic inflammation, people with HIV (PWH), especially immune non-responders, are immunocompromised and mount suboptimal antibody responses to vaccination for SARS-CoV-2. Here, we review how functionally and phenotypically distinct B cell subsets are induced in response to a vaccine and an infection and how HIV infection and anti-retroviral therapy (ART) impact them. We also review the role played by HIV-induced defects and perturbations in B cells in the induction of humoral immune responses to currently used anti-SARS-CoV-2 vaccines in PWH on ART. We also outline different strategies that could potentially enhance the vaccine-induced antibody responses in PWH. The review will provide guidance and impetus for further research to improve the immunogenicity of these vaccines in this human population.
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Affiliation(s)
- Lixing Wang
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; (L.W.); (C.F.)
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - Branka Vulesevic
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - MariaLuisa Vigano
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Alia As’sadiq
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Kristina Kang
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
| | - Cristina Fernandez
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; (L.W.); (C.F.)
| | - Suzanne Samarani
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
| | - Aslam H. Anis
- Centre for Advancing Health Outcomes Centre for Health Evaluation and Outcome Sciences, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada;
| | - Ali Ahmad
- Centre de Recherche, Hôpital Ste Justine, Montréal, QC H3T 1C5, Canada;
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Cecilia T. Costiniuk
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada (M.V.); (A.A.); (K.K.); (S.S.)
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, Canada
- Division of Infectious Diseases and Chronic Viral Illnesses Service, McGill University Health Centre, Montreal QC H4A 3J1, Canada
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Lipińska-Opałka A, Leszczyńska-Pilich M, Będzichowska A, Tomaszewska A, Rustecka A, Kalicki B. The Role of Regulatory B Lymphocytes in Allergic Diseases. Biomedicines 2024; 12:2721. [PMID: 39767628 PMCID: PMC11726865 DOI: 10.3390/biomedicines12122721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
PURPOSE OF REVIEW Regulatory B cells (Bregs) are a key component in the regulation of the immune system. Their immunosuppressive function, which includes limiting the inflammatory cascade, occurs through interactions with other immune cells and the secretion of cytokines, primarily IL-10. As knowledge about B cells continues to expand, their diversity is becoming more recognized, with many subpopulations identified in both human and animal models. However, identifying specific transcription factors or markers that could definitively distinguish regulatory B cells remains a challenge. This review summarizes recent findings on the role of B regulatory cells in allergic diseases. RECENT FINDINGS In patients with bronchial asthma, atopic dermatitis, and food allergies, the number of regulatory B cells is reduced, and disease severity is inversely proportional to the quantity of these cells. Furthermore, in patients with atopic dermatitis, the ability of regulatory B cells to produce IL-10 in response to IL-6 stimulation is diminished. However, allergen immunotherapy has been shown to induce the formation of regulatory T cells as well as regulatory B cells. SUMMARY The success of future therapies based on B cells may depend on deepening our current understanding of their phenotypes, induction, differentiation, and function. Research in these areas is essential for understanding the mechanisms regulating Breg activity and for developing potential targeted therapies in the treatment of allergic diseases.
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Affiliation(s)
- Agnieszka Lipińska-Opałka
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Michalina Leszczyńska-Pilich
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agata Będzichowska
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agata Tomaszewska
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Agnieszka Rustecka
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
| | - Bolesław Kalicki
- Faculty of Medicine, University of Warsaw, 02-089 Warsaw, Poland; (A.T.); (B.K.)
- Department of Pediatrics, Nephrology and Allergology, Military Institute of Medicine–National Research Institute, 01-141 Warsaw, Poland; (M.L.-P.); (A.B.); (A.R.)
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Beerweiler CC, Salvermoser M, Theodorou J, Böck A, Sattler F, Kulig P, Tosevski V, Schaub B. Farm-dust mediated protection of childhood asthma: Mass cytometry reveals novel cellular regulation. Allergy 2024; 79:3022-3035. [PMID: 39400913 DOI: 10.1111/all.16347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/06/2024] [Accepted: 08/20/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Farm-dust mediated asthma protection in childhood was replicated in numerous epidemiological studies. Central immune mechanisms are not fully understood. This exploratory study aimed to disentangle underlying immunological regulation of farm-dust mediated protection in peripheral blood on a single-cell level. METHODS Single-cell protein expression of in vitro farm-dust stimulated and unstimulated cells from allergic asthmatics and healthy controls were measured using mass cytometry. Analysis of innate and adaptive cellular proportions (linear regression) and T-cell proliferation was performed. Functional marker intensity was investigated using Earth Mover's Distance and the Monte Carlo permutation test. RESULTS Farm-dust stimulation induced cell type-specific regulation: Key-features of farm-dust stimulation comprised opposing regulation of immune-cell frequencies (downregulated innate cell populations (monocytes/DCs (p < .001), NK-cells (p < .05)) and upregulated adaptive populations (B-cells, CD4+ T-cells (both p < .05)), reduced CD4+ CD25- T-cell proliferation, and differential cell type-specific functional marker expression. Following stimulation, functional marker analysis revealed induced activation (CD25) in T-cells and NK-T-cells in both phenotypes even after correction for multiple testing. Cytotoxicity (GZMB) and inflammation (pERK1/2, pp38) related markers were reduced in T-cells exclusively in asthmatic children. Asthma-associated markers (Gata3, RORγ, and HLA-DR) were reduced in T- and innate- cell populations of asthmatics following stimulation. B-cells displayed a phenotypically independent increase of diverse functional markers upon farm-dust stimulation. CONCLUSIONS This study mimicking in vivo environmental exposure identified a novel profile of immune-regulatory markers using mass cytometry demonstrating decreased asthma-associated markers following farm-dust stimulation. These findings may be key for further studies on asthma prevention in childhood.
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Affiliation(s)
- Claudia Carina Beerweiler
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
- Member of German Center for Lung Research - DZL, LMU Munich, Munich, Germany
| | - Michael Salvermoser
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
| | - Johanna Theodorou
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
- Member of German Center for Lung Research - DZL, LMU Munich, Munich, Germany
| | - Andreas Böck
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
- Member of German Center for Child and Adolescent Health-DZKJ, LMU, Munich, Germany
| | - Franziska Sattler
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
| | - Paulina Kulig
- Mass Cytometry Facility, University of Zurich, Zurich, Switzerland
| | - Vinko Tosevski
- Mass Cytometry Facility, University of Zurich, Zurich, Switzerland
| | - Bianca Schaub
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
- Member of German Center for Lung Research - DZL, LMU Munich, Munich, Germany
- Member of German Center for Child and Adolescent Health-DZKJ, LMU, Munich, Germany
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Ahsan NF, Lourenço S, Psyllou D, Long A, Shankar S, Bashford-Rogers R. The current understanding of the phenotypic and functional properties of human regulatory B cells (Bregs). OXFORD OPEN IMMUNOLOGY 2024; 5:iqae012. [PMID: 39346706 PMCID: PMC11427547 DOI: 10.1093/oxfimm/iqae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/13/2024] [Accepted: 09/10/2024] [Indexed: 10/01/2024] Open
Abstract
B cells can have a wide range of pro- and anti- inflammatory functions. A subset of B cells called regulatory B cells (Bregs) can potently suppress immune responses. Bregs have been shown to maintain immune homeostasis and modulate inflammatory responses. Bregs are an exciting cellular target across a range of diseases, including Breg induction in autoimmunity, allergy and transplantation, and Breg suppression in cancers and infection. Bregs exhibit a remarkable phenotypic heterogeneity, rendering their unequivocal identification a challenging task. The lack of a universally accepted and exclusive surface marker set for Bregs across various studies contributes to inconsistencies in their categorization. This review paper presents a comprehensive overview of the current understanding of the phenotypic and functional properties of human Bregs while addressing the persisting ambiguities and discrepancies in their characterization. Finally, the paper examines the promising therapeutic opportunities presented by Bregs as their immunomodulatory capacities have gained attention in the context of autoimmune diseases, allergic conditions, and cancer. We explore the exciting potential in harnessing Bregs as potential therapeutic agents and the avenues that remain open for the development of Breg-based treatment strategies.
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Affiliation(s)
- Nawara Faiza Ahsan
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Stella Lourenço
- Keizo Asami Institute, Federal University of Pernambuco, Recife 50740-520, Brazil
| | - Dimitra Psyllou
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Alexander Long
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Sushma Shankar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Rachael Bashford-Rogers
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
- Oxford Cancer Centre, University of Oxford, Oxford OX3 7LH, United Kingdom
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Sailliet N, Dupuy A, Brinas F, Renaudin K, Colas L, Kerleau C, Nguyen TVH, Fourgeux C, Poschmann J, Gosset C, Giral M, Degauque N, Mai HL, Danger R, Brouard S. Regulatory B Cells Expressing Granzyme B from Tolerant Renal Transplant Patients: Highly Differentiated B Cells with a Unique Pathway with a Specific Regulatory Profile and Strong Interactions with Immune System Cells. Cells 2024; 13:1287. [PMID: 39120317 PMCID: PMC11311295 DOI: 10.3390/cells13151287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 08/10/2024] Open
Abstract
The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB+ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) peripheral blood mononuclear cells (PBMCs), including GZMB+ B cells from renal transplant patients, i.e., patients with stable graft function on conventional immunosuppressive treatment (STA, n = 3), drug-free tolerant patients (TOL, n = 3), and patients with antibody-mediated rejection (ABMR, n = 3), and (2) ex-vivo-induced GZMB+ B cells from these groups. In the patient PBMCs, we first showed that natural GZMB+ B cells were enriched in genes specific to Natural Killer (NK) cells (such as NKG7 and KLRD1) and regulatory B cells (such as GZMB, IL10, and CCL4). We performed a pseudotemporal trajectory analysis of natural GZMB+ B cells and showed that they were highly differentiated B cells with a trajectory that is very different from that of conventional memory B cells and linked to the transcription factor KLF13. By specifically analysing GZMB+ natural B cells in TOLs, we found that these cells had a very specific transcriptomic profile associated with a reduction in the expression of HLA molecules, apoptosis, and the inflammatory response (in general) in the blood and that this signature was conserved after ex vivo induction, with the induction of genes associated with migration processes, such as CCR7, CCL3, or CCL4. An analysis of receptor/ligand interactions between these GZMB+/- natural B cells and all of the immune cells present in PBMCs also demonstrated that GZMB+ B cells were the B cells that carried the most ligands and had the most interactions with other immune cells, particularly in tolerant patients. Finally, we showed that these GZMB+ B cells were able to infiltrate the graft under inflammatory conditions, thus suggesting that they can act in locations where immune events occur.
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Affiliation(s)
- Nicolas Sailliet
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Amandine Dupuy
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - François Brinas
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Karine Renaudin
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- CHU Nantes, Service d’Anatomie et Cytologie Pathologiques, 44000 Nantes, France
| | - Luc Colas
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Clarisse Kerleau
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Thi-Van-Ha Nguyen
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Cynthia Fourgeux
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Jérémie Poschmann
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Clément Gosset
- Service de Néphrologie et Transplantation rénale—CHU Pasteur2, 06000 Nice, France;
| | - Magali Giral
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- Centre d’Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, 44000 Nantes, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Nantes Université, 44000 Nantes, France
| | - Nicolas Degauque
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Hoa Le Mai
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Richard Danger
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
| | - Sophie Brouard
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, 44000 Nantes, France; (N.S.); (F.B.); (K.R.); (L.C.); (C.K.); (T.-V.-H.N.); (C.F.); (J.P.); (M.G.); (N.D.); (H.L.M.); (R.D.)
- Centre d’Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, 44000 Nantes, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Nantes Université, 44000 Nantes, France
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Veh J, Ludwig C, Schrezenmeier H, Jahrsdörfer B. Regulatory B Cells-Immunopathological and Prognostic Potential in Humans. Cells 2024; 13:357. [PMID: 38391970 PMCID: PMC10886933 DOI: 10.3390/cells13040357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 02/24/2024] Open
Abstract
The aim of the following review is to shed light on the putative role of regulatory B cells (Bregs) in various human diseases and highlight their potential prognostic and therapeutic relevance in humans. Regulatory B cells are a heterogeneous group of B lymphocytes capable of suppressing inflammatory immune reactions. In this way, Bregs contribute to the maintenance of tolerance and immune homeostasis by limiting ongoing immune reactions temporally and spatially. Bregs play an important role in attenuating pathological inflammatory reactions that can be associated with transplant rejection, graft-versus-host disease, autoimmune diseases and allergies but also with infectious, neoplastic and metabolic diseases. Early studies of Bregs identified IL-10 as an important functional molecule, so the IL-10-secreting murine B10 cell is still considered a prototype Breg, and IL-10 has long been central to the search for human Breg equivalents. However, over the past two decades, other molecules that may contribute to the immunosuppressive function of Bregs have been discovered, some of which are only present in human Bregs. This expanded arsenal includes several anti-inflammatory cytokines, such as IL-35 and TGF-β, but also enzymes such as CD39/CD73, granzyme B and IDO as well as cell surface proteins including PD-L1, CD1d and CD25. In summary, the present review illustrates in a concise and comprehensive manner that although human Bregs share common functional immunosuppressive features leading to a prominent role in various human immunpathologies, they are composed of a pool of different B cell types with rather heterogeneous phenotypic and transcriptional properties.
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Affiliation(s)
- Johanna Veh
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
| | - Carolin Ludwig
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
| | - Bernd Jahrsdörfer
- Institute for Transfusion Medicine, Ulm University Hospitals and Clinics, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Donation Service Baden-Württemberg-Hessen, 89081 Ulm, Germany
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9
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Onofrio LI, Marin C, Dutto J, Brugo MB, Baigorri RE, Bossio SN, Quiróz JN, Almada L, Ruiz Moreno F, Olivera C, Silvera-Ruiz SM, Ponce NE, Icely PA, Amezcua Vesely MC, Fozzatti L, Rodríguez-Galán MC, Stempin CC, Cervi L, Maletto BA, Acosta Rodríguez EV, Bertone M, Abiega CD, Escudero D, Kahn A, Caeiro JP, Maccioni M, Motrán CC, Gruppi A, Sotomayor CE, Chiapello LS, Montes CL. COVID-19 patients display changes in lymphocyte subsets with a higher frequency of dysfunctional CD8lo T cells associated with disease severity. Front Immunol 2023; 14:1223730. [PMID: 37809093 PMCID: PMC10552777 DOI: 10.3389/fimmu.2023.1223730] [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: 05/16/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
This work examines cellular immunity against SARS-CoV-2 in patients from Córdoba, Argentina, during two major waves characterized by different circulating viral variants and different social behavior. Using flow cytometry, we evaluated the main lymphocyte populations of peripheral blood from hospitalized patients with moderate and severe COVID-19 disease. Our results show disturbances in the cellular immune compartment, as previously reported in different cohorts worldwide. We observed an increased frequency of B cells and a significant decrease in the frequency of CD3+ T cells in COVID-19 patients compared to healthy donors (HD). We also found a reduction in Tregs, which was more pronounced in severe patients. During the first wave, the frequency of GZMB, CD107a, CD39, and PD-1-expressing conventional CD4+ T (T conv) cells was significantly higher in moderate and severe patients than in HD. During the second wave, only the GZMB+ T conv cells of moderate and severe patients increased significantly. In addition, these patients showed a decreased frequency in IL-2-producing T conv cells. Interestingly, we identified two subsets of circulating CD8+ T cells with low and high CD8 surface expression in both HD and COVID-19 patients. While the percentages of CD8hi and CD8lo T cells within the CD8+ population in HD are similar, a significant increase was observed in CD8lo T cell frequency in COVID-19 patients. CD8lo T cell populations from HD as well as from SARS-CoV-2 infected patients exhibited lower frequencies of the effector cytokine-producing cells, TNF, IL-2, and IFN-γ, than CD8hi T cells. Interestingly, the frequency of CD8lo T cells increased with disease severity, suggesting that this parameter could be a potential marker for disease progression. Indeed, the CD8hi/CD8lo index helped to significantly improve the patient's clinical stratification and disease outcome prediction. Our data support the addition of, at least, a CD8hi/CD8lo index into the panel of biomarkers commonly used in clinical labs, since its determination may be a useful tool with impact on the therapeutic management of the patients.
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Affiliation(s)
- Luisina Ines Onofrio
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Constanza Marin
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Jeremías Dutto
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - María Belén Brugo
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Ruth Eliana Baigorri
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Sabrina Noemi Bossio
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Juan Nahuel Quiróz
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Laura Almada
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Federico Ruiz Moreno
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Carolina Olivera
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Silene M. Silvera-Ruiz
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Nicolás Eric Ponce
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Paula Alejandra Icely
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - María Carolina Amezcua Vesely
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Laura Fozzatti
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - María Cecilia Rodríguez-Galán
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Cinthia Carolina Stempin
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Laura Cervi
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Belkys Angélica Maletto
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Eva Virginia Acosta Rodríguez
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Mariana Bertone
- Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Claudio Daniel Abiega
- Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Daiana Escudero
- Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Adrián Kahn
- Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Juan Pablo Caeiro
- Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC), Hospital Privado Universitario de Córdoba, Córdoba, Argentina
| | - Mariana Maccioni
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Claudia Cristina Motrán
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Adriana Gruppi
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Claudia Elena Sotomayor
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Laura Silvina Chiapello
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
| | - Carolina Lucia Montes
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
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Sailliet N, Mai HL, Dupuy A, Tilly G, Fourgeux C, Braud M, Giral M, Robert JM, Degauque N, Danger R, Poschmann J, Brouard S. Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha. Front Immunol 2023; 14:1183714. [PMID: 37588598 PMCID: PMC10425555 DOI: 10.3389/fimmu.2023.1183714] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 07/05/2023] [Indexed: 08/18/2023] Open
Abstract
Introduction Human Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy. Methods We characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells. Results We find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties. Discussion We report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined.
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Affiliation(s)
- Nicolas Sailliet
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Hoa-Le Mai
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Amandine Dupuy
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Gaëlle Tilly
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Cynthia Fourgeux
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Martin Braud
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Magali Giral
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Jean-Michel Robert
- Institut De Recherche En Santé 2, Cibles Et Médicaments Des Infections Et De l’Immunité IICiMed-UR1155, Nantes Université, Nantes, France
| | - Nicolas Degauque
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Richard Danger
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Jeremie Poschmann
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Sophie Brouard
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
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11
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Veh J, Mangold C, Felsen A, Ludwig C, Gerstner L, Reinhardt P, Schrezenmeier H, Fabricius D, Jahrsdörfer B. Phorbol-12-myristate-13-acetate is a potent enhancer of B cells with a granzyme B + regulatory phenotype. Front Immunol 2023; 14:1194880. [PMID: 37588597 PMCID: PMC10426744 DOI: 10.3389/fimmu.2023.1194880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/12/2023] [Indexed: 08/18/2023] Open
Abstract
Introduction The infusion of ex-vivo-generated regulatory B cells may represent a promising novel therapeutic approach for a variety of autoimmune and hyperinflammatory conditions including graft-versus-host disease. Methods Previously, we developed a protocol for the generation of a novel population of regulatory B cells, which are characterized by secretion of enzymatically active granzyme B (GraB cells). This protocol uses recombinant interleukin 21 (IL-21) and goat-derived F(ab)'2 fragments against the human B cell receptor (anti-BCR). Generally, the use of xenogeneic material for the manufacturing of advanced therapy medicinal products should be avoided to prevent adverse immune reactions as well as potential transmission of so far unknown diseases. Results In the present work we demonstrated that phorbol-12-myristate-13-acetate (PMA/TPA), a phorbol ester with a particular analogy to the second messenger diacylglycerol (DAG), is a potent enhancer of IL-21-induced differentiation of pre-activated B cells into GraB cells. The percentage of GraB cells after stimulation of pre-activated B cells with IL-21 and PMA/TPA was not significantly lower compared to stimulation with IL-21 and anti-BCR. Discussion Given that PMA/TPA has already undergone encouraging clinical testing in patients with certain haematological diseases, our results suggest that PMA/TPA may be a safe and feasible alternative for ex-vivo manufacturing of GraB cells.
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Affiliation(s)
- Johanna Veh
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Charlotte Mangold
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Anja Felsen
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Carolin Ludwig
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Lisa Gerstner
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Peter Reinhardt
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Hubert Schrezenmeier
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
| | - Dorit Fabricius
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Bernd Jahrsdörfer
- Department of Transfusion Medicine, Ulm University, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg–Hessen and University Hospital Ulm, Ulm, Germany
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Xue J, Xu L, Zhong H, Bai M, Li X, Yao R, Wang Z, Zhao Z, Li H, Zhu H, Hu F, Su Y. Impaired regulatory function of granzyme B-producing B cells against T cell inflammatory responses in lupus mice. Lupus Sci Med 2023; 10:e000974. [PMID: 37500293 PMCID: PMC10387741 DOI: 10.1136/lupus-2023-000974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 07/01/2023] [Indexed: 07/29/2023]
Abstract
OBJECTIVE Recently, a new subtype of granzyme B (GrB)-producing Breg cells has been identified, which was proven to be involved in autoimmune disease. Our recent report demonstrated that GrB-producing Breg cells were correlated with clinical and immunological features of SLE. However, the effect of GrB-producing Breg cells in lupus mice is unclear. METHODS GrB expression in naïve and lupus mouse B cells was analysed using flow cytometry, PCR, ELISA and ELISpot assays. To study the role of GrB-producing B cells in a lupus model, GrB knockout (KO) and wild-type (WT) mice were intraperitoneally injected with monoclonal cells from the mutant mouse strain B6.C-H-2bm12 (bm12) for 2 weeks. In addition, the function of GrB-producing Breg cells in naïve and lupus mice was further explored using in vitro B cells-CD4+CD25- T cell co-culture assays with GrB blockade/KO of B cells. RESULTS B cells from the spleens of WT C57BL/6 (B6) mice could express and secret GrB (p<0.001). GrB-producing Breg cells from WT mice showed their regulatory functions on CD4+CD25- T cell. While the frequency of GrB-producing Breg cells was significantly decreased (p=0.001) in lupus mice (p<0.001). Moreover, GrB-producing Breg cells in lupus mice failed to suppress T cell-mediated proinflammatory responses, partially due to the impaired capacity of downregulating the T cell receptor-zeta chain and inducing CD4+CD25- T cell apoptosis. CONCLUSION This study further revealed the function and mechanism of GrB-producing Breg cells in regulating T cell homeostasis in lupus mice and highlighted GrB-producing Breg cells as a therapeutic target in SLE.
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Affiliation(s)
- Jimeng Xue
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Liling Xu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Hua Zhong
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Mingxin Bai
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Xin Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Ranran Yao
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Ziye Wang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Zhen Zhao
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Hongchao Li
- Department of Rheumatology and Immunology, Beijing Jishuitan Hospital, Beijing, China
| | - Huaqun Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yin Su
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
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13
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Matsumura Y, Watanabe R, Fujimoto M. Suppressive mechanisms of regulatory B cells in mice and humans. Int Immunol 2022; 35:55-65. [PMID: 36153768 PMCID: PMC9918854 DOI: 10.1093/intimm/dxac048] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/23/2022] [Indexed: 11/14/2022] Open
Abstract
B cells include immune-suppressive fractions, called regulatory B cells (Bregs), which regulate inflammation primarily through an interleukin 10 (IL-10)-mediated inhibitory mechanism. Several B-cell fractions have been reported as IL-10-producing Bregs in murine disease models and human inflammatory responses including autoimmune diseases, infectious diseases, cancer and organ-transplant rejection. Although the suppressive functions of Bregs have been explored through the hallmark molecule IL-10, inhibitory cytokines and membrane-binding molecules other than IL-10 have also been demonstrated to contribute to Breg activities. Transcription factors and surface antigens that are characteristically expressed in Bregs are also being elucidated. Nevertheless, defining Bregs is still challenging because their active periods and differentiation stages vary among disease models. The identity of the diverse Breg fractions is also under debate. In the first place, since regulatory functions of Bregs are mostly evaluated by ex vivo stimulation, the actual in vivo phenotypes and functions may not be reflected by the ex vivo observations. In this article, we provide a historical overview of studies that established the characteristics of Bregs and review the various suppressive mechanisms that have been reported to be used by Bregs in murine and human disease conditions. We are only part-way through but the common phenotypes and functions of Bregs are still emerging.
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Affiliation(s)
- Yutaka Matsumura
- Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Rei Watanabe
- Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan,Department of Integrative Medicine for Allergic and Immunological Diseases, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan
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14
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Laumont CM, Banville AC, Gilardi M, Hollern DP, Nelson BH. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer 2022; 22:414-430. [PMID: 35393541 PMCID: PMC9678336 DOI: 10.1038/s41568-022-00466-1] [Citation(s) in RCA: 285] [Impact Index Per Article: 95.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2022] [Indexed: 01/03/2023]
Abstract
Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically 'hot' tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy.
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Affiliation(s)
- Céline M Laumont
- Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Allyson C Banville
- Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mara Gilardi
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, San Diego, CA, USA
| | - Daniel P Hollern
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, San Diego, CA, USA
| | - Brad H Nelson
- Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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15
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Michée-Cospolite M, Boudigou M, Grasseau A, Simon Q, Mignen O, Pers JO, Cornec D, Le Pottier L, Hillion S. Molecular Mechanisms Driving IL-10- Producing B Cells Functions: STAT3 and c-MAF as Underestimated Central Key Regulators? Front Immunol 2022; 13:818814. [PMID: 35359922 PMCID: PMC8961445 DOI: 10.3389/fimmu.2022.818814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/11/2022] [Indexed: 12/25/2022] Open
Abstract
Regulatory B cells (Bregs) have been highlighted in very different pathology settings including autoimmune diseases, allergy, graft rejection, and cancer. Improving tools for the characterization of Bregs has become the main objective especially in humans. Transitional, mature B cells and plasma cells can differentiate into IL-10 producing Bregs in both mice and humans, suggesting that Bregs are not derived from unique precursors but may arise from different competent progenitors at unrestricted development stages. Moreover, in addition to IL-10 production, regulatory B cells used a broad range of suppressing mechanisms to modulate the immune response. Although Bregs have been consistently described in the literature, only a few reports described the molecular aspects that control the acquisition of the regulatory function. In this manuscript, we detailed the latest reports describing the control of IL-10, TGFβ, and GZMB production in different Breg subsets at the molecular level. We focused on the understanding of the role of the transcription factors STAT3 and c-MAF in controlling IL-10 production in murine and human B cells and how these factors may represent an important crossroad of several key drivers of the Breg response. Finally, we provided original data supporting the evidence that MAF is expressed in human IL-10- producing plasmablast and could be induced in vitro following different stimulation cocktails. At steady state, we reported that MAF is expressed in specific human B-cell tonsillar subsets including the IgD+ CD27+ unswitched population, germinal center cells and plasmablast.
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Affiliation(s)
| | | | | | | | | | | | - Divi Cornec
- U1227, LBAI, Univ Brest, Inserm, and CHU Brest, Brest, France
| | | | - Sophie Hillion
- U1227, LBAI, Univ Brest, Inserm, and CHU Brest, Brest, France
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16
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Gan X, Gu J, Ju Z, Lu L. Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance. ENGINEERING 2022; 10:44-56. [DOI: 10.1016/j.eng.2021.03.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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17
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Boldrini VO, Marques AM, Quintiliano RPS, Moraes AS, Stella CRAV, Longhini ALF, Santos I, Andrade M, Ferrari B, Damasceno A, Carneiro RPD, Brandão CO, Farias AS, Santos LMB. Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients. Front Immunol 2022; 13:750660. [PMID: 35197967 PMCID: PMC8859463 DOI: 10.3389/fimmu.2022.750660] [Citation(s) in RCA: 3] [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: 07/30/2021] [Accepted: 01/13/2022] [Indexed: 12/02/2022] Open
Abstract
Background Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-β (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring “cytotoxic” subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.
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Affiliation(s)
- Vinícius O. Boldrini
- Autoimmune Research Laboratory, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- *Correspondence: Vinícius O. Boldrini, ; Alessandro S. Farias, ; Leonilda M. B. Santos,
| | - Ana M. Marques
- Autoimmune Research Laboratory, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Raphael P. S. Quintiliano
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Adriel S. Moraes
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Carla R. A. V. Stella
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Department of Neurology, University of Campinas, Campinas, Brazil
| | - Ana Leda F. Longhini
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Department of Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Irene Santos
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marília Andrade
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Breno Ferrari
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | | | - Rafael P. D. Carneiro
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- MS Clinic of Santa Casa de São Paulo (CATEM), Irmandade da Santa Casa de Misericordia de São Paulo, São Paulo, Brazil
| | - Carlos Otávio Brandão
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Department of Neurology, University of Campinas, Campinas, Brazil
| | - Alessandro S. Farias
- Autoimmune Research Laboratory, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- Experimental Medicine Research Cluster (EMRC), São Paulo, Brazil
- *Correspondence: Vinícius O. Boldrini, ; Alessandro S. Farias, ; Leonilda M. B. Santos,
| | - Leonilda M. B. Santos
- Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- *Correspondence: Vinícius O. Boldrini, ; Alessandro S. Farias, ; Leonilda M. B. Santos,
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Abstract
The humoral immune response and antibody-mediated functions of B cells during viral infections are well described. However, we have limited understanding of antibody-independent B cell functions, such as cytokine production and antigen presentation, in acute and chronic viral infections and their role in protection and/or immunopathogenesis. Here, we summarize the current literature on these antibody-independent B cell functions and identify remaining knowledge gaps. B cell subsets produce anti- and pro-inflammatory cytokines, which can have both beneficial and detrimental effects during viral clearance. As professional antigen presenting cells, B cells also play an important role in immune regulation/shaping of the developing adaptive immune responses. Since B cells primarily express TLR7 and TLR9, we specifically discuss the role of Toll-like receptor (TLR)-mediated B cell responses to viral infections and their role in augmenting adaptive immunity through enhanced cytokine production and antigen presentation. However, viruses have evolved strategies to subvert TLR signaling and additional stimulation via B cell receptor (BCR) may be required to overcome the defective TLR response in B cells. To conclude, antibody-independent B cell functions seem to have an important role in regulating both acute and chronic viral infections and may form the basis for novel therapeutic approaches in treatment of viral infections in the future.
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Affiliation(s)
- Vinit Upasani
- Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia
- Department of Medical Microbiology and Infection Prevention, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Izabela Rodenhuis-Zybert
- Department of Medical Microbiology and Infection Prevention, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Tineke Cantaert
- Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia
- * E-mail:
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Désage AL, Karpathiou G, Peoc’h M, Froudarakis ME. The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review. Cancers (Basel) 2021; 13:3205. [PMID: 34206956 PMCID: PMC8269097 DOI: 10.3390/cancers13133205] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.
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Affiliation(s)
- Anne-Laure Désage
- Department of Pulmonology and Thoracic Oncology, North Hospital, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France;
| | - Georgia Karpathiou
- Pathology, North Hospital, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France; (G.K.); (M.P.)
| | - Michel Peoc’h
- Pathology, North Hospital, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France; (G.K.); (M.P.)
| | - Marios E. Froudarakis
- Department of Pulmonology and Thoracic Oncology, North Hospital, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France;
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20
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Xu WL, Wang RL, Liu Z, Wu Q, Li XL, He Q, Zhu JQ. Granzyme B-Producing B Cells Function as a Feedback Loop for T Helper Cells in Liver Transplant Recipients with Acute Rejection. Inflammation 2021; 44:2270-2278. [PMID: 34120305 DOI: 10.1007/s10753-021-01498-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 10/21/2022]
Abstract
Granzyme B-producing B cells have been reportedly reported to be an important regulatory B cell subset in the pathogenesis of many diseases. However, its role in liver transplant recipients with acute rejection has never been well elucidated. Seventeen liver transplant recipients with acute rejection and 25 controls with stable liver function were enrolled in this study to determine the function of granzyme B-producing B cells via flow cytometry. Liver transplant recipients with acute rejection had higher expression of granzyme B in CD19+B cells when compared with controls. Following rejection, the granzyme B production was even elevated although comparison failed to reach significance. The percentages of CD27+granzyme B+CD19+B cells and CD138+granzyme B+CD19+B cells were lower than those of CD27-granzyme B+CD19+B cells and CD138-granzyme B+CD19+B cells in patients with acute rejection, respectively. While the production of CD27 and CD138 was not different between liver transplant recipients with and without acute rejection but increased expression of the two surface markers was observed following rejection. Furthermore, the frequency of granzyme B+CD19+B cells correlated with the level of alanine aminotransferase instead of tacrolimus. CD19+B cells could produce granzyme B when stimulated with IgG + IgM and CpG in the presence of the supernatant of activated CD4+CD25-T cells. In return, granzyme B+CD19+B cells could suppress the proliferation of CD4+CD25-T cells in a granzyme B- and contact-dependent manner. The increased expression of granzyme B in CD19+B cells from liver transplant recipients with acute rejection might function as a feedback loop for the activation of the CD4+CD25-T cells.
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Affiliation(s)
- Wen-Li Xu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Ruo-Lin Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Zhe Liu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Qiao Wu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
| | - Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
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21
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Ibrahim EH, Aly M, Morath C, Sayed DM, Ekpoom N, Opelz G, Süsal C, Daniel V. Relationship of transitional regulatory B and regulatory T cells and immunosuppressive drug doses in stable renal transplant recipients. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:1252-1271. [PMID: 34102006 PMCID: PMC8589411 DOI: 10.1002/iid3.473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 11/10/2022]
Abstract
OBJECTIVES Regulatory B cells (Bregs) and T cells (Tregs) are thought to be involved in the regulation of graft acceptance in renal transplant recipients. However, mechanisms that affect Breg differentiation and interaction with Tregs are rather unclear. METHODS Using eight-color-fluorescence flow cytometry, Tregs and CD19+ CD24hiCD38hi Bregs were analyzed in whole blood samples of 80 stable kidney transplant recipients, 20 end-stage renal disease (ESRD) patients and 32 healthy controls (HC). In addition, differentiation of Bregs and Tregs was studied in different micromilieus using cocultures with strongly enriched B-lymphocytes and autologous peripheral blood mononuclear cells stimulated with CpG and phytohemagglutinin. RESULTS Bregs were higher in HC than in ESRD patients and lowest in transplant recipients. Bregs were higher early as compared to late posttransplant. Posttransplant, high Bregs were associated with higher glomerular filtration rate (GFR) and lower C-reactive protein (CRP). Higher doses and blood levels of ciclosporine, tacrolimus, and mycophenolate mofetil as well as higher doses of steroids were not associated with low Bregs. In contrast, most Treg subsets were lower when blood levels of ciclosporine, tacrolimus, and mycophenolate mofetil were higher. Tregs were not associated with Bregs, GFR, CRP plasma levels, and occurrence of rejection or infection. In vitro, differentiation of Bregs was strongly dependent on T cell support and was blocked by excessive or lacking T-cell help. Tregs were not associated with Breg numbers in vitro. CONCLUSION Bregs appear to be insensitive to high doses of posttransplant immunosuppressive drugs. The protracted Breg decrease posttransplant might be caused by impaired T cell support attributable to immunosuppressive drugs.
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Affiliation(s)
- Eman H Ibrahim
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Pathology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Mostafa Aly
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.,Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany.,Nephrology Unit, Internal Medicine Department, Assiut University, Assiut, Egypt
| | - Christian Morath
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Douaa M Sayed
- Clinical Pathology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Naruemol Ekpoom
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Gerhard Opelz
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Volker Daniel
- Transplantation Immunology, Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
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22
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Catalán D, Mansilla MA, Ferrier A, Soto L, Oleinika K, Aguillón JC, Aravena O. Immunosuppressive Mechanisms of Regulatory B Cells. Front Immunol 2021; 12:611795. [PMID: 33995344 PMCID: PMC8118522 DOI: 10.3389/fimmu.2021.611795] [Citation(s) in RCA: 201] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.
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Affiliation(s)
- Diego Catalán
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Instituto Milenio en Inmunología e Inmunoterapia, Santiago, Chile
| | - Miguel Andrés Mansilla
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Ashley Ferrier
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Instituto Milenio en Inmunología e Inmunoterapia, Santiago, Chile
| | - Lilian Soto
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile.,Unidad de Dolor, Hospital Clínico, Universidad de Chile (HCUCH), Santiago, Chile
| | | | - Juan Carlos Aguillón
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
| | - Octavio Aravena
- Programa Disciplinario de Inmunología, Facultad de Medicina, Instituto de Ciencias Biomédicas (ICBM), Universidad de Chile, Santiago, Chile
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23
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Wang W, Zou R, Qiu Y, Liu J, Xin Y, He T, Qiu Z. Interaction Networks Converging on Immunosuppressive Roles of Granzyme B: Special Niches Within the Tumor Microenvironment. Front Immunol 2021; 12:670324. [PMID: 33868318 PMCID: PMC8047302 DOI: 10.3389/fimmu.2021.670324] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Granzyme B is a renowned effector molecule primarily utilized by CTLs and NK cells against ill-defined and/or transformed cells during immunosurveillance. The overall expression of granzyme B within tumor microenvironment has been well-established as a prognostic marker indicative of priming immunity for a long time. Until recent years, increasing immunosuppressive effects of granzyme B are unveiled in the setting of different immunological context. The accumulative evidence confounded the roles of granzyme B in immune responses, thereby arousing great interests in characterizing detailed feature of granzyme B-positive niche. In this paper, the granzyme B-related regulatory effects of major suppressor cells as well as the tumor microenvironment that defines such functionalities were longitudinally summarized and discussed. Multiplex networks were built upon the interactions among different transcriptional factors, cytokines, and chemokines that regarded to the initiation and regulation of granzyme B-mediated immunosuppression. The conclusions and prospect may facilitate better interpretations of the clinical significance of granzyme B, guiding the rational development of therapeutic regimen and diagnostic probes for anti-tumor purposes.
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Affiliation(s)
- Weinan Wang
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Rui Zou
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Ye Qiu
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Jishuang Liu
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Yu Xin
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Tianzhu He
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China.,School of Basic Medical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Zhidong Qiu
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
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24
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Le Berre L, Chesneau M, Danger R, Dubois F, Chaussabel D, Garand M, Brouard S. Connection of BANK1, Tolerance, Regulatory B cells, and Apoptosis: Perspectives of a Reductionist Investigation. Front Immunol 2021; 12:589786. [PMID: 33815360 PMCID: PMC8015775 DOI: 10.3389/fimmu.2021.589786] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/06/2021] [Indexed: 12/07/2022] Open
Abstract
BANK1 transcript is upregulated in whole blood after kidney transplantation in tolerant patients. In comparison to patients with rejection, tolerant patients display higher level of regulatory B cells (Bregs) expressing granzyme B (GZMB+) that have the capability to prevent effector T cells proliferation. However, BANK1 was found to be decreased in these GZMB+ Bregs. In this article, we investigated seven different transcriptomic studies and mined the literature in order to make link between BANK1, tolerance and Bregs. As for GZMB+ Bregs, we found that BANK1 was decreased in other subtypes of Bregs, including IL10+ and CD24hiCD38hi transitional regulatory B cells, along with BANK1 was down-regulated in activated/differentiated B cells, as in CD40-activated B cells, in leukemia and plasma cells. Following a reductionist approach, biological concepts were extracted from BANK1 literature and allowed us to infer association between BANK1 and immune signaling pathways, as STAT1, FcγRIIB, TNFAIP3, TRAF6, and TLR7. Based on B cell signaling literature and expression data, we proposed a role of BANK1 in B cells of tolerant patients that involved BCR, IP3R, and PLCG2, and a link with the apoptosis pathways. We confronted these data with our experiments on apoptosis in total B cells and Bregs, and this suggests different involvement for BANK1 in these two cells. Finally, we put in perspective our own data with other published data to hypothesize two different roles for BANK1 in B cells and in Bregs.
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Affiliation(s)
- Ludmilla Le Berre
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Mélanie Chesneau
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Richard Danger
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | - Florian Dubois
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
| | | | - Mathieu Garand
- Systems Biology and Immunology, Sidra Medicine, Doha, Qatar
| | - Sophie Brouard
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
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25
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Xiang W, Xie C, Guan Y. The identification, development and therapeutic potential of IL-10-producing regulatory B cells in multiple sclerosis. J Neuroimmunol 2021; 354:577520. [PMID: 33684831 DOI: 10.1016/j.jneuroim.2021.577520] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 01/27/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022]
Abstract
Regulatory B cells are a rare B-cell subset widely known to exert their immunosuppressive function via the production of interleukin-10 (IL-10) and other mechanisms. B10 cells are a special subset of regulatory B cells with immunoregulatory function that is fully attributed to IL-10. Their unique roles in the animal model of multiple sclerosis (MS) have been described, as well as their relevance in MS patients. This review specifically focuses on the identification and development of B10 cells, the signals that promote IL-10 production in B cells, the roles of B10 cells in MS, and the potential and major challenges of the application of B10-based therapies for MS.
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Affiliation(s)
- Weiwei Xiang
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Rd, Shanghai 200127, China
| | - Chong Xie
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Rd, Shanghai 200127, China
| | - Yangtai Guan
- Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Rd, Shanghai 200127, China.
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26
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Chesneau M, Le Mai H, Brouard S. New Method for the Expansion of Highly Purified Human Regulatory Granzyme B-Expressing B Cells. Methods Mol Biol 2021; 2270:203-216. [PMID: 33479900 DOI: 10.1007/978-1-0716-1237-8_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Granzyme B (GZMB)-expressing B cells inhibit CD4+ T-lymphocyte proliferation in a contact- and GZMB-dependent manner, through degradation of TCR zeta or induction of T-cell apoptosis. This regulatory B-cell population is present in human healthy individuals and represents about 1% of circulating B cells. Their small proportion requires the development of expansion methods to enable their study and envision clinical applications. We describe here how to expand GZMB-expressing B cells to obtain more than 90% of highly purified GZMB+ B cells, and the protocol of B/T cells coculture for the evaluation of the suppressive function of the GZMB+ B-cell population.
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Affiliation(s)
- Mélanie Chesneau
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
| | - Hoa Le Mai
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
| | - Sophie Brouard
- CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France. .,Labex IGO, Nantes, France. .,Centre d'Investigation Clinique en Biothérapie, Centre de ressources biologiques (CRB), Nantes, France.
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27
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Ma S, Satitsuksanoa P, Jansen K, Cevhertas L, van de Veen W, Akdis M. B regulatory cells in allergy. Immunol Rev 2020; 299:10-30. [PMID: 33345311 DOI: 10.1111/imr.12937] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/25/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022]
Abstract
B cells have classically been recognized for their unique and indispensable role in the production of antibodies. Their potential as immunoregulatory cells with anti-inflammatory functions has received increasing attention during the last two decades. Herein, we highlight pioneering studies in the field of regulatory B cell (Breg) research. We will review the literature on Bregs with a particular focus on their role in the regulation of allergic inflammation.
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Affiliation(s)
- Siyuan Ma
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
| | | | - Kirstin Jansen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Lacin Cevhertas
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Department of Medical Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Turkey
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
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28
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Chesneau M, Mai HL, Danger R, Le Bot S, Nguyen TVH, Bernard J, Poullaouec C, Guerrif P, Conchon S, Giral M, Charreau B, Degauque N, Brouard S. Efficient Expansion of Human Granzyme B–Expressing B Cells with Potent Regulatory Properties. THE JOURNAL OF IMMUNOLOGY 2020; 205:2391-2401. [DOI: 10.4049/jimmunol.2000335] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 08/10/2020] [Indexed: 01/12/2023]
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29
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Ran Z, Yue-Bei L, Qiu-Ming Z, Huan Y. Regulatory B Cells and Its Role in Central Nervous System Inflammatory Demyelinating Diseases. Front Immunol 2020; 11:1884. [PMID: 32973780 PMCID: PMC7468432 DOI: 10.3389/fimmu.2020.01884] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/13/2020] [Indexed: 12/15/2022] Open
Abstract
Regulatory B (Breg) cells represent a population of suppressor B cells that participate in immunomodulatory processes and inhibition of excessive inflammation. The regulatory function of Breg cells have been demonstrated in mice and human with inflammatory diseases, cancer, after transplantation, and particularly in autoinflammatory disorders. In order to suppress inflammation, Breg cells produce anti-inflammatory mediators, induce death ligand-mediated apoptosis, and regulate many kinds of immune cells such as suppressing the proliferation and differentiation of effector T cell and increasing the number of regulatory T cells. Central nervous system Inflammatory demyelinating diseases (CNS IDDs) are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. With the advent of monoclonal antibodies directed against B cells, breakthroughs have been made in the treatment of CNS IDDs. Therefore, the number and function of B cells in IDDs have attracted attention. Meanwhile, increasing number of studies have confirmed that Breg cells play a role in alleviating autoimmune diseases, and treatment with Breg cells has also been proposed as a new therapeutic direction. In this review, we focus on the understanding of the development and function of Breg cells and on the diversification of Breg cells in CNS IDDs.
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Affiliation(s)
- Zhou Ran
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Luo Yue-Bei
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Zeng Qiu-Ming
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Yang Huan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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30
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Dubois F, Limou S, Chesneau M, Degauque N, Brouard S, Danger R. Transcriptional meta-analysis of regulatory B cells. Eur J Immunol 2020; 50:1757-1769. [PMID: 32529638 DOI: 10.1002/eji.201948489] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 05/01/2020] [Accepted: 06/09/2020] [Indexed: 12/26/2022]
Abstract
Regulatory B cells (Bregs) have the ability to regulate inflammation in various pathological situations, making them key players in immune regulation. Several mechanisms have been described and we recently identified a GZMB expressing Breg population in kidney transplanted patients who tolerate a kidney graft. To further investigate their biology and mechanisms, we conducted a transcriptomic analysis by RNAseq of these cells and we performed the first weighted meta-analysis of publicly available transcriptomic data from published Breg studies both in humans and mice. We identified two distinct and unique transcriptional signatures of 126 and 93 genes, respectively, associated with these Bregs. While we highlighted genes coding for proteins with potent involvement in regulatory functions, proliferation, and coding for transcription factors, the comparison between humans and mice did not allow identifying a common pattern. Thus, our results suggest distinct species-restricted Breg transcriptional signatures in humans and mice.
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Affiliation(s)
- Florian Dubois
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
| | - Sophie Limou
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Ecole Centrale de Nantes, Computer Sciences and Mathematics department, Nantes, France
| | - Mélanie Chesneau
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
| | - Nicolas Degauque
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
| | - Sophie Brouard
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France.,Centre d'Investigation Clinique en Biothérapie, Centre de ressources biologiques (CRB), Nantes, France
| | - Richard Danger
- Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.,Labex IGO, Nantes, France
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31
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Massive activity of cytotoxic cells during refractory Neuromyelitis Optica spectrum disorder. J Neuroimmunol 2020; 340:577148. [PMID: 31986375 DOI: 10.1016/j.jneuroim.2020.577148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/02/2020] [Accepted: 01/09/2020] [Indexed: 01/15/2023]
Abstract
Our group is interested in the cytotoxic mechanism during autoimmune neuroinflammation. Unexpectedly, we come across a case that presents a massive enhancement of cytotoxic behavior in lymphocytes, either in peripheral blood and cerebrospinal fluid. Interestingly, this specific patient was refractory to Methylprednisolone treatment. Hypothetically, the cytotoxic activity could represent a novel and complementary effector mechanism to NMOSD pathogenesis. Nevertheless, further investigation is needed to evaluate the extension and the clinical relevance of our finds.
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32
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Alhabbab RY, Nova-Lamperti E, Aravena O, Burton HM, Lechler RI, Dorling A, Lombardi G. Regulatory B cells: Development, phenotypes, functions, and role in transplantation. Immunol Rev 2019; 292:164-179. [DOI: 10.1111/imr.12800] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/27/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Rowa Y. Alhabbab
- Infectious Disease Unit and Division of Applied Medical Sciences King Fahad Centre for medical research King Abdulaziz University Jeddah Saudi Arabia
- Peter Gorer Department of Immunobiology MRC Centre for Transplantation School of Immunology & Mucosal Biology King's College LondonKing's Health PartnersGuy's Hospital London UK
| | - Estefanía Nova-Lamperti
- Molecular and Translational Immunology Laboratory Department of Clinical Biochemistry and Immunology Pharmacy Faculty Universidad de Concepción Concepción Chile
| | - Octavio Aravena
- Programa Disciplinario de Immunología Instituto de Ciencias Biomédicas Facultad de Medicina Universidad de Chile Santiago Chile
| | - Hannah M. Burton
- Peter Gorer Department of Immunobiology MRC Centre for Transplantation School of Immunology & Mucosal Biology King's College LondonKing's Health PartnersGuy's Hospital London UK
| | - Robert I. Lechler
- Peter Gorer Department of Immunobiology MRC Centre for Transplantation School of Immunology & Mucosal Biology King's College LondonKing's Health PartnersGuy's Hospital London UK
| | - Anthony Dorling
- Peter Gorer Department of Immunobiology MRC Centre for Transplantation School of Immunology & Mucosal Biology King's College LondonKing's Health PartnersGuy's Hospital London UK
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology MRC Centre for Transplantation School of Immunology & Mucosal Biology King's College LondonKing's Health PartnersGuy's Hospital London UK
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33
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Xue D, Yang P, Wei Q, Li X, Lin L, Lin T. IL‑21/IL‑21R inhibit tumor growth and invasion in non‑small cell lung cancer cells via suppressing Wnt/β‑catenin signaling and PD‑L1 expression. Int J Mol Med 2019; 44:1697-1706. [PMID: 31573051 PMCID: PMC6777672 DOI: 10.3892/ijmm.2019.4354] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/02/2019] [Indexed: 11/07/2022] Open
Abstract
Lung cancer is considered to be one of the world's deadliest diseases, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. The present study aimed to investigate the role and underlying mechanisms of interleukin-21 (IL-21), and its receptor IL-21R, in NSCLC. Lung tissues and blood samples of NSCLC were used to measure IL-21, IL-21R and programmed death 1 ligand 1 (PD-L1) expression using ELISA, western blot and immunohistochemistry analyses. Following treatment with different doses of IL-21, the proliferation, invasion and migration of human NSCLC cell line A549 was evaluated using a cell counting kit-8, colony formation, Transwell and scratch wound healing assays, respectively. Additionally, IL-21R and PD-L1 expression in A549 cells was detected using western blot analysis and immunofluorescence. IL-21R silencing was subsequently used to investigate its effects in cell proliferation, invasion and migration. PD-L1, IL-1β and tumor necrosis factor α (TNF-α) expression were measured. Finally, Wnt/β-catenin signaling expression was evaluated using western blot analysis following treatment with IL-21. Cells were then treated with lithium chloride (LiCl), which is an agonist of Wnt/β-catenin signaling, and the levels of PD-L1, IL-1β and TNF-α were detected. The results revealed that IL-21 and IL-21R expression in the lung tissues and blood samples of patients with NSCLC were decreased, while PD-L1 expression was increased, compared with normal tissues or healthy controls. Treatment of A549 cells with IL-21 upregulated IL-21R expression, downregulated PD-L1 and inhibited cell growth and metastasis in a dose-dependent manner. Following IL-21R silencing, the effects of IL-21 treatment were reversed, suggesting that IL-21 acted on A549 cells through binding to IL-21R. In addition, the results demonstrated that IL-21 treatment reduced the expression levels of proteins associated with the Wnt/β-catenin signaling, whereas activation of Wnt/β-catenin signaling with the LiCl agonist upregulated PD-L1, IL-1β and TNF-α expression. In conclusion, the IL-21/IL-21R axis reduced the growth and invasion of NSCLC cells via inhibiting Wnt/β-catenin signaling and PD-L1 expression. The present results may provide a novel molecular target for NSCLC diagnosis and therapy.
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Affiliation(s)
- Dan Xue
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Ping Yang
- Department of Respiratory Medicine, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350001, P.R. China
| | - Qiongying Wei
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xiaoping Li
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Lan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Tingyan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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34
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Mohd Jaya FN, Garcia SG, Borràs FE, Chan GC, Franquesa M. Paradoxical role of Breg-inducing cytokines in autoimmune diseases. J Transl Autoimmun 2019; 2:100011. [PMID: 32743499 PMCID: PMC7388338 DOI: 10.1016/j.jtauto.2019.100011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 07/30/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022] Open
Abstract
Regulatory B cells (Breg) are crucial immunoregulators that maintain peripheral tolerance and suppress inflammatory autoimmune responses. In recent years, our understanding on the nature and mechanism of action of Bregs has revealed the important role of cytokines in promoting the regulatory properties of this unique B cell subset, both in animal and human models. In this review, we compiled the cytokines that have been reported by multiple studies to induce the expansion of Breg. The Breg-inducing cytokines which are currently known include IL-21, IL-6, IL1β, IFNα, IL-33, IL-35, BAFF and APRIL. As cytokines are also known to play a pivotal role in the pathogenesis of autoimmune diseases, in parallel we reviewed the pattern of expression of the Breg-inducing cytokines in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Inflammatory Bowel Diseases (IBD) and Multiple Sclerosis (MS). We show here that Breg-inducing cytokines are commonly implicated in these inflammatory diseases where they typically have a higher expression than in healthy individuals, suggesting their paradoxical nature. Interestingly, despite the general overexpression of Breg-inducing cytokines, it is known that Breg cells are often numerically or functionally impaired in various autoimmune conditions. Considering these alterations, we explored the possible parameters that may influence the function of Breg-inducing cytokines in exhibiting either their regulatory or pro-inflammatory properties in the context of autoimmune conditions.
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Affiliation(s)
- Fatin N. Mohd Jaya
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong
- Corresponding author.
| | - Sergio G. Garcia
- REMAR-IVECAT Group, Health Science Research Institute Germans Trias I Pujol, Can Ruti Campus, 08916, Badalona, Spain
| | - Francesc E. Borràs
- REMAR-IVECAT Group, Health Science Research Institute Germans Trias I Pujol, Can Ruti Campus, 08916, Badalona, Spain
| | - Godfrey C.F. Chan
- Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong
| | - Marcella Franquesa
- REMAR-IVECAT Group, Health Science Research Institute Germans Trias I Pujol, Can Ruti Campus, 08916, Badalona, Spain
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35
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Arabpour M, Rasolmali R, Talei AR, Mehdipour F, Ghaderi A. Granzyme B production by activated B cells derived from breast cancer-draining lymph nodes. Mol Immunol 2019; 114:172-178. [PMID: 31357083 DOI: 10.1016/j.molimm.2019.07.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/21/2019] [Accepted: 07/21/2019] [Indexed: 02/06/2023]
Abstract
B lymphocytes with regulatory or effector functions synthesize granzyme B (GZMB). We investigated the frequency and phenotype of GZMB-producing B cells in breast tumor-draining lymph nodes (TDLNs). Mononuclear cells were isolated from 48 axillary lymph nodes and were stimulated with anti-BCR (B cell receptor), recombinant interleukin (IL)-21 and CD40 L alone or in combination. Flow cytometry was used to evaluate the expression of GZMB in B cells, and in 4 samples the phenotype of GZMB+ B cells was determined. B cells produced GZMB only when stimulated with a combination of IL-21 and anti-BCR for at least 16 h. Adding CD40 L to IL-21 and anti-BCR stimuli resulted in lower GZMB production in B cells. A small fraction of B cells was able to produce perforin in all stimulation conditions, and the majority of GZMB+ B cells were perforin-negative. Both naïve (CD24lowCD27-) and active/memory (CD24hiCD27+) B cells expressed GZMB. In patients with invasive ductal carcinoma, the frequency of GZMB+ B cells was significantly lower in metastatic compared to non-metastatic lymph nodes. The frequency of GZMB+ B cells did not significantly correlate with prognostic factors such as stage, tumor size or Her2 expression. In summary, a subpopulation of both naïve and memory B cells expressed GZMB in breast TDLNs. Our findings underscore the need to investigate the function of GZMB+ B cells in breast tumor immunity.
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Affiliation(s)
- Mohsen Arabpour
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Rasolmali
- Department of Pathology, Shiraz Central Hospital, Shiraz, Iran
| | - Abdoul-Rasoul Talei
- Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fereshteh Mehdipour
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Abbas Ghaderi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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36
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Effect of binding immunoglobulin protein on induction of regulatory B cells with killer phenotype during inflammation and disease. Future Sci OA 2019; 5:FSO379. [PMID: 30906571 PMCID: PMC6426174 DOI: 10.4155/fsoa-2018-0121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/14/2019] [Indexed: 12/16/2022] Open
Abstract
Immune responses result from different immune cells acting in synergy to successfully fight infections. This requires a high degree of regulation to prevent excessive production of inflammatory products leading to other disease forms. Regulatory B cells are classified based on surface immunoglobulin expression. These cells are reported to resolve inflammation during chronic or autoimmune diseases. However, during chronic inflammation, their frequencies have been shown to be affected, and they can be induced by exposure to extracellular binding immunoglobulin protein (BiP). This review focuses on the effects on immune cells by extracellular or secreted BiP during various chronic inflammatory responses. For example, cell stress associated with Mycobacterium tuberculosis infection leads to accumulation of unfolded proteins that subsequently activate BiP and its three signal transducers intracellularly. Furthermore, BiP can be translocated from the endoplasmic reticulum to the extracellular environment where it binds immune cells as an autoantigen and leads to functional changes. Immune responses during tuberculosis disease require balanced cell interactions. These include antigen-presenting cells, effector cells and regulatory cells. B lymphocytes can mediate regulatory function during chronic diseases and lead to better disease outcome. These specialized cells mediate this function through both surface and soluble protein expression. Their development can be facilitated by different stimuli including binding immunoglobulin protein. This protein resides in the endoplasmic reticulum where it functions in proper protein folding; however, it can escape this location to the extracellular phase, where it affects immune cell function leading to development of regulatory traits on B cells.
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Qiu L, Yu Q, Zhou Y, Zheng S, Tao J, Jiang Q, Yuan G. Functionally impaired follicular helper T cells induce regulatory B cells and CD14 + human leukocyte antigen-DR - cell differentiation in non-small cell lung cancer. Cancer Sci 2018; 109:3751-3761. [PMID: 30325558 PMCID: PMC6272090 DOI: 10.1111/cas.13836] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 12/18/2022] Open
Abstract
Non‐small cell lung cancer (NSCLC) represents one of the most common and aggressive cancers worldwide, as it typically displays irreversible progression and poor prognosis. Interaction between programmed death 1 (PD‐1) and its ligand, PD‐L1, plays important roles in tumor immunology. Follicular helper T (Tfh) cells have characteristically high PD‐1 expression; thus, in the present study, we investigated the role of circulating Tfh cells and their correlation with disease‐free survival after tumor resection in NSCLC. We found significantly higher number of Tfh cells but lower serum interleukin (IL)‐21 levels in NSCLC patients, especially in those with advanced stage (III and IV), indicating that the function of Tfh cells to produce IL‐21 was impaired. Further analysis showed that the increase in Tfh cells was attributable to an expansion of the PD‐1+‐Tfh2 and PD‐1+‐Tfh17 subtypes. Functional analysis showed that Tfh cells from NSCLC patients induced the differentiation of regulatory B cells and CD14+ human leukocyte antigen (HLA)‐DR− cells. Interestingly, the number of Tfh1 subtypes in NSCLC patients was negatively correlated with disease‐free survival after tumor resection. In short, the high number and abnormal function of Tfh cells could cause further immunosuppression and lead to tumor development in NSCLC. Rescuing Tfh functions therefore represents a potential therapeutic strategy in NSCLC.
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Affiliation(s)
- Liannv Qiu
- Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qinhua Yu
- Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Yonglie Zhou
- Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Sujie Zheng
- Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jiaojiao Tao
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Qian Jiang
- College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guorong Yuan
- Department of Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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38
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Wąsik M, Nazimek K, Bryniarski K. Regulatory B cell phenotype and mechanism of action: the impact of stimulating conditions. Microbiol Immunol 2018; 62:485-496. [PMID: 29998521 DOI: 10.1111/1348-0421.12636] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/29/2018] [Accepted: 07/09/2018] [Indexed: 12/14/2022]
Abstract
A diverse population of regulatory B (Breg) cells reportedly exhibits significant immunomodulatory effects in various models of inflammatory responses and infectious diseases caused by bacteria, viruses or parasites. Breg cells contribute to maintenance of homeostasis via IL-10 production and multiple IL-10-independent mechanisms. The current review describes various phenotypic and functional subsets of Breg cells in autoimmune and infectious diseases and discusses the impacts of experimental conditions that have been found to drive Breg cell differentiation.
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Affiliation(s)
- Magdalena Wąsik
- Department of Immunology, Jagiellonian University College of Medicine, 18 Czysta St., 31-121 Krakow, Poland
| | - Katarzyna Nazimek
- Department of Immunology, Jagiellonian University College of Medicine, 18 Czysta St., 31-121 Krakow, Poland
| | - Krzysztof Bryniarski
- Department of Immunology, Jagiellonian University College of Medicine, 18 Czysta St., 31-121 Krakow, Poland
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39
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Sperk M, Domselaar RV, Neogi U. Immune Checkpoints as the Immune System Regulators and Potential Biomarkers in HIV-1 Infection. Int J Mol Sci 2018; 19:ijms19072000. [PMID: 29987244 PMCID: PMC6073446 DOI: 10.3390/ijms19072000] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 06/29/2018] [Accepted: 07/06/2018] [Indexed: 11/21/2022] Open
Abstract
Immune checkpoints are several co-stimulatory and inhibitory pathways that regulate T cell immune responses. Most of the discoveries about immune checkpoints were made in cancer research where inhibitory immune checkpoints cause immune exhaustion and down-regulate anti-tumor responses. In addition to cancer, immune checkpoints are exploited in chronic infectious diseases. In human immunodeficiency virus (HIV) infection, the immune checkpoint molecule called programmed cell death protein 1 (PD-1) has been determined as being a major regulatory factor for T cell exhaustion. Recent studies with antibodies blocking either PD-1 ligand 1 (PD-L1) or PD-1 show not only promising results in the enhancement of HIV-specific immune responses but even in reducing the latent HIV reservoir. Apart from the therapeutic target for a functional cure of HIV-1, immune checkpoint molecules might be used as biomarkers for monitoring disease progression and therapeutic response. In this review, we will summarize and discuss the inhibitory immune checkpoint molecules PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and T cell immunoglobulin and mucin-domain-containing-3 (TIM3) as well as the co-stimulatory molecules CD40L and CD70, including their role in immunity, with a particular focus on HIV infection, and being potential targets for a functional HIV cure.
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Affiliation(s)
- Maike Sperk
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden.
| | - Robert van Domselaar
- Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, 141 86 Stockholm, Sweden.
| | - Ujjwal Neogi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden.
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40
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Shen M, Sun Q, Wang J, Pan W, Ren X. Positive and negative functions of B lymphocytes in tumors. Oncotarget 2018; 7:55828-55839. [PMID: 27331871 PMCID: PMC5342456 DOI: 10.18632/oncotarget.10094] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/04/2016] [Indexed: 12/20/2022] Open
Abstract
Accumulating evidence indicated that B lymphocytes exerted complex functions in tumor immunity. On the one hand, B lymphocytes can inhibit tumor development through antibody generation, antigen presentation, tumor tissue interaction, and direct killing. On the other hand, B lymphocytes have tumor-promoting functions. A typical type of B lymphocytes, termed regulatory B cells, is confirmed to attenuate immune response in a tumor environment. In this paper, we summarize the current understanding of B-cell functions in tumor immunology, which may shed light on potential therapeutic strategies against cancer.
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Affiliation(s)
- Meng Shen
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Jian Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Wei Pan
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Xiubao Ren
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
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41
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Chu Z, Zou W, Xu Y, Sun Q, Zhao Y. The regulatory roles of B cell subsets in transplantation. Expert Rev Clin Immunol 2018; 14:115-125. [PMID: 29338551 DOI: 10.1080/1744666x.2018.1426461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Zhulang Chu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Department of Pathology, Beijing University of Chinese Medicine, Beijing, China
| | - Weilong Zou
- Surgery of Transplant and Hepatopancrobiliary, The General Hospital of Chinese People’s Armed Police Forces, Beijing, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Qiquan Sun
- Department of Renal Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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42
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Zhang W, Ambikan AT, Sperk M, van Domselaar R, Nowak P, Noyan K, Russom A, Sönnerborg A, Neogi U. Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune-control Mechanisms of HIV-1 Infected Elite Controllers. EBioMedicine 2018; 27:40-50. [PMID: 29269040 PMCID: PMC5828548 DOI: 10.1016/j.ebiom.2017.11.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 11/22/2017] [Accepted: 11/30/2017] [Indexed: 12/21/2022] Open
Abstract
A small subset of HIV-1 infected individuals, the "Elite Controllers" (EC), can control viral replication and restrain progression to immunodeficiency without antiretroviral therapy (ART). In this study, a cross-sectional transcriptomics and targeted proteomics analysis were performed in a well-defined Swedish cohort of untreated EC (n=19), treatment naïve patients with viremia (VP, n=32) and HIV-1-negative healthy controls (HC, n=23). The blood transcriptome identified 151 protein-coding genes that were differentially expressed (DE) in VP compared to EC. Genes like CXCR6 and SIGLEC1 were downregulated in EC compared to VP. A definite distinction in gene expression between males and females among all patient-groups were observed. The gene expression profile between female EC and the healthy females was similar but did differ between male EC and healthy males. At targeted proteomics analysis, 90% (29/32) of VPs clustered together while EC and HC clustered separately from VP. Among the soluble factors, 33 were distinctive to be statistically significant (False discovery rate=0.02). Cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling seem to synergistically play an essential role in HIV-1 control in EC.
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Affiliation(s)
- Wang Zhang
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden
| | - Anoop T Ambikan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Maike Sperk
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Faculty of Medicine, University of Tuebingen, Tuebingen, Germany
| | - Robert van Domselaar
- Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Piotr Nowak
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Kajsa Noyan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Aman Russom
- Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden
| | - Anders Sönnerborg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Huddinge, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ujjwal Neogi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Division of Proteomics and Nanobiotechnology, KTH Royal Institute of Technology, Solna, Stockholm, Sweden.
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43
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Amrouche K, Jamin C. Influence of drug molecules on regulatory B cells. Clin Immunol 2017; 184:1-10. [DOI: 10.1016/j.clim.2017.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
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44
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Dai YC, Zhong J, Xu JF. Regulatory B cells in infectious disease (Review). Mol Med Rep 2017; 16:3-10. [PMID: 28534949 PMCID: PMC5482109 DOI: 10.3892/mmr.2017.6605] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 03/22/2017] [Indexed: 01/06/2023] Open
Abstract
Regulatory B cells (Bregs) are a subset of B cells, which reportedly exert significant immunomodulatory effects through the production of interleukin (IL)‑10, IL‑35 and transforming growth factor‑β. Over the last decade, studies have indicated that Bregs function in autoimmune and allergic diseases through antigen‑specific and non‑specific immunoregulatory mechanisms. However, only a limited number of reviews have focused on the role of Bregs during infection, particularly their functions in intracellular infections. The present review discusses the role of Bregs in infectious diseases in animal models and human studies, and provides an overview of the immunoregulatory mechanisms used by Bregs.
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Affiliation(s)
- You-Chao Dai
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
| | - Jixin Zhong
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jun-Fa Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan, Guangdong 523808, P.R. China
- Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
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45
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Differential expression of serpins may selectively licence distinct granzyme B functions including antigen cross-presentation. Mol Immunol 2017; 87:325-326. [DOI: 10.1016/j.molimm.2017.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 03/06/2017] [Indexed: 11/23/2022]
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46
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Xu L, Liu X, Liu H, Zhu L, Zhu H, Zhang J, Ren L, Wang P, Hu F, Su Y. Impairment of Granzyme B-Producing Regulatory B Cells Correlates with Exacerbated Rheumatoid Arthritis. Front Immunol 2017; 8:768. [PMID: 28713386 PMCID: PMC5491972 DOI: 10.3389/fimmu.2017.00768] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 06/16/2017] [Indexed: 12/24/2022] Open
Abstract
Hyperactivated B cells have been demonstrated the contribution to the development of rheumatoid arthritis (RA). While the recognition of the negative regulatory function of B cells further promoted our understanding of their pathogenic role in RA. Recently, a new population of granzyme B (GrB)-producing B cells was identified, which was proved to be involved in cancer and infectious diseases. However, their characteristics and roles in RA remain to be elucidated. In the present study, we aim to further characterize whether B cells could produce GrB and reveal their potential role in the pathogenesis of RA. Here, we further demonstrated peripheral blood B cells from healthy individuals could produce and secrete GrB, which could be enhanced by IL-21 and/or anti-B-cell receptor stimulation. These cells could negatively regulate Th1 and Th17 cells partly via downregulating TCR zeta chain and inducing T cell apoptosis, which might be termed as GrB-producing regulatory B cells (Bregs). These GrB-producing Bregs were significantly decreased under RA circumstance concomitant of lower levels of IL-21 receptor, with impaired regulatory functions on Th1 and Th17 cells. Moreover, the frequencies of these cells were negatively correlated with RA patient disease activity and clinical features. After effective therapy with disease remission in RA, these GrB-producing Bregs could be recovered. Therefore, our data revealed that B cells could produce GrB with immunosuppressive functions, and the impairment of this Breg subset was correlated with RA pathogenesis.
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Affiliation(s)
- Liling Xu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Xu Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Lei Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Huaqun Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Jian Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Limin Ren
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Pingzhang Wang
- Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China
| | - Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Yin Su
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.,Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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Hu Y, Yu P, Yu X, Hu X, Kawai T, Han X. IL-21/anti-Tim1/CD40 ligand promotes B10 activity in vitro and alleviates bone loss in experimental periodontitis in vivo. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2149-2157. [PMID: 28583714 DOI: 10.1016/j.bbadis.2017.06.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/12/2017] [Accepted: 06/01/2017] [Indexed: 12/20/2022]
Abstract
IL-10-expressing regulatory B cells (B10) play an essential role in immune system balance by suppressing excessive inflammatory responses. In this study, we investigated induction of B 10 cell's IL-10 competency in vitro and its effect on ligature-induced experimental periodontitis in vivo. Spleen B cells were isolated from C57BL/6J mice and cultured for 48h under the following conditions: control, CD40L, IL-21, anti-Tim1, CD40L+IL-21, CD40L+anti-Tim1, CD40L+IL-21+anti-Tim1. Silk ligatures were tied around both maxillary second molars of C57BL/6J mice for two weeks. Optimized combination of CD40L, IL-21 and anti-Tim1 and vehicle were injected into contralateral side of palatal gingiva on days 3, 6 and 9. The palatal gingival tissues and maxillary bone were collected on day 14 to determine expressions of IL-10 and periodontal bone resorption respectively. Our results demonstrated that IL-10 expressions of cultured spleen B cells were significantly increased in the presence of CD40L, IL-21 and anti-Tim1 combination when compared with control groups. Gingival IL-10 mRNA and protein expressions were significantly increased after injection of CD40L, IL-21 and anti-Tim1 combination, when compared to the control side. The gingival RANKL expression and periodontal bone loss were significantly decreased on the combination treatment side, as compared to the control side. These results suggest that combination of IL-21, anti-Tim1 and CD40L treatment induced B10 cell's IL-10 competency in vitro and inhibited periodontal bone loss in ligature-induced experimental periodontitis.
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Affiliation(s)
- Yang Hu
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States; Harvard University, School of Dental Medicine, Cambridge, MA, United States
| | - Pei Yu
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States; State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xinbo Yu
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States; Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xingxue Hu
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States
| | - Toshihisa Kawai
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States; Harvard University, School of Dental Medicine, Cambridge, MA, United States
| | - Xiaozhe Han
- Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, United States; Harvard University, School of Dental Medicine, Cambridge, MA, United States.
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48
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Granzyme B producing B-cells in renal transplant patients. Clin Immunol 2017; 184:48-53. [PMID: 28461110 DOI: 10.1016/j.clim.2017.04.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/27/2017] [Indexed: 11/23/2022]
Abstract
OBJECTIVES A separate subset of Granzyme B (GrB) producing B-cells regulating T-cell mediated immunity has been identified. In the present study, we investigated the role of GrB+ B-cells in renal transplant patients (RTX). METHODS 12 healthy controls (HC) and 26 RTX patients were enrolled. In addition, 19 healthy volunteers treated with cyclosporine A (CsA) were enrolled. GrB+ B-cells were determined via flow cytometry. RESULTS RTX Patients showed a diminished fraction of GrB+ B-cells as compared to HC. CsA treatment of healthy volunteers had no impact on the development of GrB+ B-cells. RTX patients with a history of allograft rejection showed an increased frequency of GrB+ B-cells. RTX patients with at least one episode of CMV viremia tended to have lower GrB+ B-cells as compared to patients without viremic episodes. CONCLUSION We demonstrate that treatment with CsA does not impair the development of GrB+ B-cells. GrB+ B-cells may have a dual role in renal transplantation as regulatory cells to maintain allospecific tolerance and as effector cells enhancing viral control.
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49
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Schlößer HA, Thelen M, Dieplinger G, von Bergwelt-Baildon A, Garcia-Marquez M, Reuter S, Shimabukuro-Vornhagen A, Wennhold K, Haustein N, Buchner D, Heiermann N, Kleinert R, Wahba R, Ditt V, Kurschat C, Cingöz T, Becker J, Stippel DL, von Bergwelt-Baildon M. Prospective Analyses of Circulating B Cell Subsets in ABO-Compatible and ABO-Incompatible Kidney Transplant Recipients. Am J Transplant 2017; 17:542-550. [PMID: 27529836 DOI: 10.1111/ajt.14013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 07/24/2016] [Accepted: 08/09/2016] [Indexed: 01/25/2023]
Abstract
Immunosuppressive strategies applied in renal transplantation traditionally focus on T cell inhibition. B cells were mainly examined in the context of antibody-mediated rejection, whereas the impact of antibody-independent B cell functions has only recently entered the field of transplantation. Similar to T cells, distinct B cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B cell subsets in the peripheral blood of AB0-compatible (n = 27) and AB0-incompatible (n = 10) renal transplant recipients. Activated B cells were transiently decreased and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in AB0-incompatible patients resulted in long-lasting B cell depletion and in a naïve phenotype of repopulating B cells 1 year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B cell subsets. Our study demonstrates the remarkable effects of standard immunosuppression on circulating B cell subsets. Furthermore, the B cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B cell subsets could be of clinical benefit in renal transplantation.
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Affiliation(s)
- H A Schlößer
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Interventional Immunology, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - M Thelen
- Cologne Interventional Immunology, University of Cologne, Köln, Germany
| | - G Dieplinger
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - A von Bergwelt-Baildon
- Cologne Transplant Center, University of Cologne, Köln, Germany.,Department of Internal Medicine II, University of Cologne, Köln, Germany
| | - M Garcia-Marquez
- Cologne Interventional Immunology, University of Cologne, Köln, Germany
| | - S Reuter
- Cologne Interventional Immunology, University of Cologne, Köln, Germany
| | - A Shimabukuro-Vornhagen
- Cologne Interventional Immunology, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - K Wennhold
- Cologne Interventional Immunology, University of Cologne, Köln, Germany
| | - N Haustein
- Cologne Interventional Immunology, University of Cologne, Köln, Germany
| | - D Buchner
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - N Heiermann
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - R Kleinert
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - R Wahba
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - V Ditt
- Institute for Clinical Transfusion Medicine, Merheim Medical Center Cologne, Köln, Germany
| | - C Kurschat
- Cologne Transplant Center, University of Cologne, Köln, Germany.,Department of Internal Medicine II, University of Cologne, Köln, Germany
| | - T Cingöz
- Cologne Transplant Center, University of Cologne, Köln, Germany.,Department of Internal Medicine II, University of Cologne, Köln, Germany
| | - J Becker
- Cologne Transplant Center, University of Cologne, Köln, Germany.,Institute of Pathology, University of Cologne, Köln, Germany
| | - D L Stippel
- Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.,Cologne Transplant Center, University of Cologne, Köln, Germany
| | - M von Bergwelt-Baildon
- Cologne Interventional Immunology, University of Cologne, Köln, Germany.,Department of Internal Medicine I, University of Cologne, Köln, Germany
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Miles B, Miller SM, Connick E. CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection. Front Immunol 2016; 7:659. [PMID: 28082992 PMCID: PMC5187376 DOI: 10.3389/fimmu.2016.00659] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/16/2016] [Indexed: 11/13/2022] Open
Abstract
T follicular helper cells (TFH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in TFH. Paradoxically, TFH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased TFH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in TFH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in TFH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of TFH, other mechanisms that have been linked to TFH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance TFH function in HIV infection include lack of an established phenotype for memory TFH as well as limited understanding of the relationship between peripheral TFH and lymphoid tissue TFH. Interventions to augment TFH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.
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Affiliation(s)
- Brodie Miles
- Division of Infectious Diseases, University of Colorado Denver , Aurora, CO , USA
| | - Shannon M Miller
- Department of Immunology, University of Colorado Denver , Aurora, CO , USA
| | - Elizabeth Connick
- Division of Infectious Diseases, Department of Medicine, University of Arizona , Tucson, AZ , USA
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