Drug insight: the mechanism of action of rituximab in autoimmune disease--the immune complex decoy hypothesis.
Inflammatory responses to cell-associated or tissue-associated immune complexes are key elements in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura. Effector cells, such as monocytes, macrophages and neutrophils, bind immune complexes in a process mediated by Fcgamma receptors, and these cells then initiate inflammatory reactions that lead to tissue destruction. Rituximab is an anti-CD20 monoclonal antibody that suppresses inflammation effectively in autoimmune diseases. It was initially approved by the FDA for the treatment of B-cell lymphomas and later for rheumatoid arthritis refractory to anti-tumor necrosis factor therapies. Rituximab is hypothesized to suppress disease injury in autoimmune diseases by promoting rapid and long-term elimination of circulating and possibly lymphoid-tissue-associated B cells. We suggest, however, that a different mechanism may underlie much of the therapeutic action of rituximab in autoimmune diseases: binding of tens of thousands of rituximab-IgG molecules to B cells generates decoy sacrificial cellular immune complexes that efficiently attract and bind Fcgamma receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.
Taylor
Ronald P
RP
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. rpt@virginia.edu
Lindorfer
Margaret A
MA
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000936:Antigen-Antibody Complex / Q000276:immunology; D018501:Antirheumatic Agents / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000936:Antigen-Antibody Complex; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D017452:Receptors, IgG; D000069283:Rituximab