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: A Potential Role in Systemic Lupus Erythematosus1
* Department of Medicine and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262;
Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY 10021;
Randall Centre for Molecular Mechanisms of Cell Function, King’s College London, New Hunt’s House, Guy’s Campus, London, United Kingdom;
Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO 80262;
¶ Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089; and
|| Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
Human complement receptor type 2 (CR2/CD21) is a B lymphocyte membrane glycoprotein that plays a central role in the immune responses to foreign Ags as well as the development of autoimmunity to nuclear Ags in systemic lupus erythematosus. In addition to these three well-characterized ligands, C3d/iC3b, EBV-gp350, and CD23, a previous study has identified CR2 as a potential receptor for IFN-
. IFN-, a multifunctional cytokine important in the innate immune system, has recently been proposed to play a major pathogenic role in the development of systemic lupus erythematosus in humans and mice. In this study, we have shown using surface plasmon resonance and ELISA approaches that CR2 will bind IFN- in the same affinity range as the other three well-characterized ligands studied in parallel. In addition, we show that IFN- interacts with short consensus repeat domains 1 and 2 in a region that serves as the ligand binding site for C3d/iC3b, EBV-gp350, and CD23. Finally, we show that treatment of purified human peripheral blood B cells with the inhibitory anti-CR2 mAb 171 diminishes the induction of IFN--responsive genes. Thus, IFN- represents a fourth class of extracellular ligands for CR2 and interacts with the same domain as the other three ligands. Defining the role of CR2 as compared with the well-characterized type 1 IFN- receptor 1 and 2 in mediating innate immune and autoimmune roles of this cytokine should provide additional insights into the biologic roles of this interaction.
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