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: Tom A Barr, Ping Shen, Sheila Brown, Vicky Lampropoulou, Toralf Roch, Sarah Lawrie, Boli Fan, Richard A O'Connor, Stephen M Anderton, Amit Bar-Or, Simon Fillatreau, David Gray
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 209 Issue 5 Pg. 1001-10 (May 07 2012) ISSN: 1540-9538 [Electronic] United States
• PMID: 22547654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• DNA Primers
• Interleukin-6
• Rituximab

Topics

• Adoptive Transfer
• Analysis of Variance
• Animals
• Antibodies, Monoclonal, Murine-Derived (pharmacology)
• B-Lymphocytes (drug effects, immunology, metabolism)
• DNA Primers (genetics)
• Encephalomyelitis, Autoimmune, Experimental (immunology, physiopathology, therapy)
• Flow Cytometry
• Humans
• Interleukin-6 (deficiency, metabolism)
• Lymphocyte Depletion (methods)
• Mice
• Multiple Sclerosis, Relapsing-Remitting (immunology, therapy)
• Reverse Transcriptase Polymerase Chain Reaction
• Rituximab
• Specific Pathogen-Free Organisms
• Statistics, Nonparametric