title: B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.
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 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.
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, UK. tom.barr@ed.ac.uk
authors.forename: Tom A
authors.initials: TA
authors.lastname: Barr
authors.forename: Ping
authors.initials: P
authors.lastname: Shen
authors.forename: Sheila
authors.initials: S
authors.lastname: Brown
authors.forename: Vicky
authors.initials: V
authors.lastname: Lampropoulou
authors.forename: Toralf
authors.initials: T
authors.lastname: Roch
authors.forename: Sarah
authors.initials: S
authors.lastname: Lawrie
authors.forename: Boli
authors.initials: B
authors.lastname: Fan
authors.forename: Richard A
authors.initials: RA
authors.lastname: O'Connor
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Simon
authors.initials: S
authors.lastname: Fillatreau
authors.forename: David
authors.initials: D
authors.lastname: Gray
mesh_terms: D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D013047:Specific Pathogen-Free Organisms; D018709:Statistics, Nonparametric
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D017931:DNA Primers; D015850:Interleukin-6; D000069283:Rituximab