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Drug Insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis

Nature Clinical Practice Rheumatology volume 3, pages 86–95 (2007)Cite this article

Abstract

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 Fcγ 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 Fcγ receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.

Key Points

  • Rituximab has demonstrated therapeutic efficacy in patients with B-cell lymphomas or autoimmune diseases

  • The principal mechanism by which rituximab was postulated to decrease disease activity in autoimmune diseases was its ability to eliminate B cells and thus reduce autoantibody levels

  • Serological changes, however, have not accompanied positive clinical responses in patients treated with rituximab

  • In many autoimmune diseases, binding of tissue-associated immune complexes to monocytes or macrophages is an essential step in the initiation of inflammation and tissue injury

  • Blocking this immune-complex–effector-cell interaction can substantially reduce inflammation and disease pathology in animal models of autoimmune diseases

  • Rituximab-opsonized B cells may act as decoy immune complexes that effectively divert monocytes or macrophages from interactions with tissue-associated immune complexes, which provides an alternative mechanism to explain the therapeutic efficacy of rituximab in autoimmune disease

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Figure 1: Rituximab-opsonized B cells are subject to attack and killing by at least three pathways.
Figure 2: The role of Fcγ receptors in immune-complex-mediated inflammation.
Figure 3: Proposed analogy of the therapeutic mechanisms of IgG anti-RhoD and anti-CD20 monoclonal antibody treatment for immune thrombocytopenic purpura.

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Authors and Affiliations

  1. RP Taylor is Professor of Biochemistry and Molecular Genetics and MA Lindorfer is Research Assistant Professor of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine, Charlottesville, VA, USA.,

    Ronald P Taylor & Margaret A Lindorfer

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Correspondence to Ronald P Taylor.

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Taylor, R., Lindorfer, M. Drug Insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis. Nat Rev Rheumatol 3, 86–95 (2007). https://doi.org/10.1038/ncprheum0424

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