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.
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...
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2020-01-01
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| author | Anouk von Borstel Wayel H Abdulahad Gerjan Dekkema Abraham Rutgers Coen A Stegeman Johanna Veldman Peter Heeringa Jan Stephan Sanders |
| author_facet | Anouk von Borstel Wayel H Abdulahad Gerjan Dekkema Abraham Rutgers Coen A Stegeman Johanna Veldman Peter Heeringa Jan Stephan Sanders |
| author_sort | Anouk von Borstel |
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| description | 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. |
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| spelling | doaj-art-67c7b00a6b624a2eab916a5d1c3865632025-08-20T02:00:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01157e023574310.1371/journal.pone.0235743Mycophenolic acid and 6-mercaptopurine both inhibit B-cell proliferation in granulomatosis with polyangiitis patients, whereas only mycophenolic acid inhibits B-cell IL-6 production.Anouk von BorstelWayel H AbdulahadGerjan DekkemaAbraham RutgersCoen A StegemanJohanna VeldmanPeter HeeringaJan Stephan SandersGranulomatosis 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0235743&type=printable |
| spellingShingle | Anouk von Borstel Wayel H Abdulahad Gerjan Dekkema Abraham Rutgers Coen A Stegeman Johanna Veldman Peter Heeringa Jan Stephan Sanders 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. PLoS ONE |
| title | 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0235743&type=printable |
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