1. Mycophenolic acid and 6-mercaptopurine both inhibit B-cell proliferation in granulomatosis with polyangiitis patients, whereas only mycophenolic acid inhibits B-cell IL-6 production
- Author
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Coen A. Stegeman, Abraham Rutgers, Anouk von Borstel, Wayel H. Abdulahad, Peter Heeringa, Gerjan J. Dekkema, Jan-Stephan F. Sanders, Johanna Veldman, Translational Immunology Groningen (TRIGR), Groningen Kidney Center (GKC), and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
Male ,B Cells ,AZATHIOPRINE ,Physiology ,medicine.medical_treatment ,Azathioprine ,Pharmacology ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,CYCLOPHOSPHAMIDE ,Medicine and Health Sciences ,VASCULITIS ,Lymphocytes ,Innate Immune System ,B-Lymphocytes ,Multidisciplinary ,biology ,Chemistry ,Mercaptopurine ,Drugs ,Middle Aged ,Flow Cytometry ,Immunosuppressives ,medicine.anatomical_structure ,Cytokine ,Medicine ,Cytokines ,Female ,Cellular Types ,Granulomatosis with polyangiitis ,Immunosuppressive Agents ,medicine.drug ,Research Article ,Adult ,Cyclophosphamide ,Science ,Immune Cells ,Immunology ,B-Lymphocyte Subsets ,Mycophenolic acid ,Autoimmune Diseases ,03 medical and health sciences ,medicine ,Humans ,RITUXIMAB ,Wegener Granulomatosis ,Interleukin 6 ,Antibody-Producing Cells ,B cell ,Aged ,Cell Proliferation ,030203 arthritis & rheumatology ,Blood Cells ,Interleukin-6 ,Granulomatosis with Polyangiitis ,Biology and Life Sciences ,Cell Biology ,Molecular Development ,Mycophenolic Acid ,medicine.disease ,Memory B cells ,Immune System ,biology.protein ,Clinical Immunology ,AUTOANTIBODIES ,Clinical Medicine ,Ex vivo ,030215 immunology ,Developmental Biology - Abstract
Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.
- Published
- 2020