1. Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity.
- Author
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Maurer MA, Rakocevic G, Leung CS, Quast I, Lukačišin M, Goebels N, Münz C, Wardemann H, Dalakas M, and Lünemann JD
- Subjects
- Aged, Autoantibodies immunology, Autoantigens immunology, Autoimmune Diseases of the Nervous System immunology, Clinical Trials as Topic statistics & numerical data, Clone Cells immunology, Double-Blind Method, Female, Humans, Immunoglobulin M immunology, Male, Middle Aged, Myelin-Associated Glycoprotein immunology, Rituximab, Severity of Illness Index, Somatic Hypermutation, Immunoglobulin, Treatment Outcome, Antibodies, Monoclonal, Murine-Derived pharmacology, Autoimmune Diseases of the Nervous System drug therapy, B-Lymphocyte Subsets drug effects, Immunologic Memory, Lymphocyte Depletion methods
- Abstract
The B cell-depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti-myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell-depleting therapies for autoimmune diseases.
- Published
- 2012
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