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

David Gray, Tom Barr, Ping Shen, Sheila Brown, Vicky Lampropoulou, Toralf Roch, Sarah Lawrie, Boli Fan, Richard O'Connor, Stephen Anderton, Amit Bar-Or, Simon Fillatreau

Research output: Contribution to journalArticlepeer-review

Abstract

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 mecha- nisms 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.
Original languageEnglish
Pages (from-to)1001-1010
Number of pages10
JournalJournal of Experimental Medicine
Volume209
Issue number5
Early online date30 Apr 2012
DOIs
Publication statusPublished - 7 May 2012
EventEuropean Congress of Immunology - Glasgow
Duration: 5 Sep 20128 Sep 2012

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