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Michael Holers, MD


University of Colorado Denver, AMC and DC

Medicine and Immunology


The CR2:C3d receptor: ligand interaction as a therapeutic target in lupus

In a properly orchestrated humoral immune response to foreign antigens, complement receptor type 2 (CR2/CD21) and its primary C3 activation fragment-derived ligand designated C3d play a central role in the development of high affinity antibodies. The primary B cell receptors for antigen-bound C3 fragments are CR2 and complement receptor type 1 (CR1/CD35). As opposed to humans, where unique genes encode these proteins, mouse CR2 and CR1 are derived through alternative splicing from a common gene designated Cr2. The larger CR1 protein in both species is the primary receptor for the C3b form of C3 as well as antigen-bound C4b, while the smaller CR2 protein only binds C3d. High affinity autoantibodies and B lymphocytes play central roles in the immunopathogenesis of human systemic lupus erythematosus (SLE). In principle, given our current understanding of the immune basis for the development of SLE through subversion of normal tolerance checkpoints, one might expect a similar humoral autoimmune enhancing role for CR2 through its interactions with C3d-bound self-antigens in SLE. However, prior studies using gene-targeted Cr2-/- mice, which lack both CR2 and CR1, in murine models of SLE have not supported this presumption in that normal tolerance to self-antigens is lost. It is well understand how CR1 could play this role as the high affinity receptor for C4b, which is itself necessary to maintain tolerance to self-antigen in mice and humans. However, no similar experimentally supported role exists for CR2, and thus whether expression of this particular receptor protects from or enhances autoimmune disease development in SLE has not been formally established. To address this question, we have developed new highly specific and informative mouse anti-mouse monoclonal antibodies (mAbs). The first is a non-B cell depleting mAb that recognizes and blocks only CR2/CD21 function without directly affecting CR1 interactions with C4b or C3b. The second mAb recognizes the C3d fragment and blocks its interaction with CR2 without affecting C3b or C4b interactions with CR1. With these novel tools and by pursuing the following specific aims, we will for the first time be able to test the hypothesis that disruption of the critical C3d-CR2 ligand-receptor binding step alone will ameliorate, rather than enhance, autoimmunity and clinical disease in SLE: Specific Aim #1. Evaluate the effects of specific monoclonal antibody-mediated blockade of CR2/CD21 function on the evolution of autoimmunity and clinical outcomes in the (NZBxNZW)F1 model of human lupus; and Specific Aim #2. Using a novel C3d-specific monoclonal antibody to interrupt the interaction by C3d-bearing autoantigen complexes with CR2/CD21, characterize the ameliorative effects of this strategy on the evolution of disease. We expect that these studies will lead to new therapeutic strategies in SLE that target the CR2-C3d interaction and eliminate its amplifying effect on high affinity autoantibody generation.

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