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B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly und...

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Autores principales: Barr, Tom A., Shen, Ping, Brown, Sheila, Lampropoulou, Vicky, Roch, Toralf, Lawrie, Sarah, Fan, Boli, O’Connor, Richard A., Anderton, Stephen M., Bar-Or, Amit, Fillatreau, Simon, Gray, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348102/
https://www.ncbi.nlm.nih.gov/pubmed/22547654
http://dx.doi.org/10.1084/jem.20111675
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author Barr, Tom A.
Shen, Ping
Brown, Sheila
Lampropoulou, Vicky
Roch, Toralf
Lawrie, Sarah
Fan, Boli
O’Connor, Richard A.
Anderton, Stephen M.
Bar-Or, Amit
Fillatreau, Simon
Gray, David
author_facet Barr, Tom A.
Shen, Ping
Brown, Sheila
Lampropoulou, Vicky
Roch, Toralf
Lawrie, Sarah
Fan, Boli
O’Connor, Richard A.
Anderton, Stephen M.
Bar-Or, Amit
Fillatreau, Simon
Gray, David
author_sort Barr, Tom A.
collection PubMed
description B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS.
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spelling pubmed-33481022012-11-07 B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells Barr, Tom A. Shen, Ping Brown, Sheila Lampropoulou, Vicky Roch, Toralf Lawrie, Sarah Fan, Boli O’Connor, Richard A. Anderton, Stephen M. Bar-Or, Amit Fillatreau, Simon Gray, David J Exp Med Article B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS. The Rockefeller University Press 2012-05-07 /pmc/articles/PMC3348102/ /pubmed/22547654 http://dx.doi.org/10.1084/jem.20111675 Text en © 2012 Barr et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Barr, Tom A.
Shen, Ping
Brown, Sheila
Lampropoulou, Vicky
Roch, Toralf
Lawrie, Sarah
Fan, Boli
O’Connor, Richard A.
Anderton, Stephen M.
Bar-Or, Amit
Fillatreau, Simon
Gray, David
B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title_full B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title_fullStr B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title_full_unstemmed B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title_short B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells
title_sort b cell depletion therapy ameliorates autoimmune disease through ablation of il-6–producing b cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348102/
https://www.ncbi.nlm.nih.gov/pubmed/22547654
http://dx.doi.org/10.1084/jem.20111675
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