title: Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity.
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.
authors.affiliation: Institute of Experimental Immunology, Department of Neuroinflammation, University of Zürich, Zürich, Switzerland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maurer
authors.forename: Goran
authors.initials: G
authors.lastname: Rakocevic
authors.forename: Carol S
authors.initials: CS
authors.lastname: Leung
authors.forename: Isaak
authors.initials: I
authors.lastname: Quast
authors.forename: Martin
authors.initials: M
authors.lastname: Lukačišin
authors.forename: Norbert
authors.initials: N
authors.lastname: Goebels
authors.forename: Christian
authors.initials: C
authors.lastname: Münz
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Marinos
authors.initials: M
authors.lastname: Dalakas
authors.forename: Jan D
authors.initials: JD
authors.lastname: Lünemann
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D020274:Autoimmune Diseases of the Nervous System / Q000188:drug therapy* / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000187:drug effects*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D002999:Clone Cells / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007156:Immunologic Memory; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D000069283:Rituximab; D012720:Severity of Illness Index; D027041:Somatic Hypermutation, Immunoglobulin; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; D018992:Myelin-Associated Glycoprotein; D000069283:Rituximab