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RIIb on Leukocytes and Its Dysregulation in Systemic Lupus Erythematosus1Division of Clinical Immunology and Rheumatology, Departments of Medicine, Cell Biology, and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
Fc
RIIb (CD32B, Online Mendelian Inheritance in Man 604590), an IgG FcR with a tyrosine-based inhibitory motif, plays a critical role in the balance of tolerance and autoimmunity in murine models. However, the high degree of homology between FcRIIb and FcRIIa in humans and the lack of specific Abs to differentiate them have hampered study of the normal expression profile of FcRIIb and its potential dysregulation in autoimmune diseases such as systemic lupus erythematosus (SLE). Using our newly developed anti-FcRIIb mAb 4F5 which does not react with FcRIIa, we found that FcRIIb is expressed on the cell surface of circulating B lymphocytes, monocytes, neutrophils, myeloid dendritic cells (DCs), and at very low levels on plasmacytoid DCs from some donors. Normal donors with the less frequent 2B.4 promoter haplotype have higher FcRIIb expression on monocytes, neutrophils, and myeloid DCs similar to that reported for B lymphocytes, indicating that FcRIIb expression on both myeloid and lymphoid cells is regulated by the naturally occurring regulatory single nucleotide polymorphisms in the FCGR2B promoter. FcRIIb expression in normal controls is up-regulated on memory B lymphocytes compared with naive B lymphocytes. In contrast, in active SLE, FcRIIb is significantly down-regulated on both memory and plasma B lymphocytes compared with naive and memory/plasma B lymphocytes from normals. Similar down-regulation of FcRIIb on myeloid-lineage cells in SLE was not seen. Our studies demonstrate the constitutive regulation of FcRIIb by natural gene polymorphisms and the acquired dysregulation in SLE autoimmunity, which may identify opportunities for using this receptor as a therapeutic target.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants P01 AR49084, R01 AR42476, R01 AR33062, and N01-AI40068 from the National Institutes of Health and in part by the University of Alabama at Birmingham Rheumatic Diseases Core Center (P30 AR48311) and the General Clinical Research Center (M01 RR-00032).
2 Address correspondence and reprint requests to Dr. Robert P. Kimberly, University of Alabama at Birmingham, 1530 Third Avenue South, Shelby Interdisciplinary Biomedical Research Building 172D, Birmingham, AL 35294-2182. E-mail address: rpk{at}uab.edu
3 Abbreviations used in this paper: DC, dendritic cell; mDC, myeloid DC; pDC, plasmacytoid DC; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index; EC, extracellular domain; MFI, mean fluorescence intensity; [Ca2+]i, intracellular Ca2+ concentration; mIgG, mouse IgG; ahIgG, heat-aggregated human IgG; PMN, polymorphonuclear neutrophil.
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