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FcRI (CD89) Alleles Determine the Proinflammatory Potential of Serum IgA¹

Jianming Wu^*, Chuanyi Ji^*, Fenglong Xie^*, Carl D. Langefeld, Kun Qian^*, Andrew W. Gibson^*, Jeffrey C. Edberg^* and Robert P. Kimberly^2,*

^* Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and Department of Public Health Sciences, Wake Forest University, Winston-Salem, NC 27157

The human IgA FcR (FcRI; CD89) mediates a variety of immune system functions including degranulation, endocytosis, phagocytosis, cytokine synthesis, and cytokine release. We have identified a common, nonsynonymous, single nucleotide polymorphism (SNP) in the coding region of CD89 (844AG) (rs16986050), which changes codon 248 from AGC (Ser²⁴⁸) to GGC (Gly²⁴⁸) in the cytoplasmic domain of the receptor. The two different alleles demonstrate significantly different FcRI-mediated intracellular calcium mobilization and degranulation in rat basophilic leukemia cells and cytokine production (IL-6 and TNF-) in murine macrophage P388D1 cells. In the absence of FcR -chain association in P388D1 cells, the Ser²⁴⁸-FcRI allele does not mediate cytokine production, but the Gly²⁴⁸-FcRI allele retains the capacity to mediate a robust production of proinflammatory cytokine. This allele-dependent difference is also seen with FcRI-mediated IL-6 cytokine release by human neutrophils ex vivo. These findings and the enrichment of the proinflammatory Gly²⁴⁸-FcRI allele in systemic lupus erythematosus populations in two ethnic groups compared with their respective non-systemic lupus erythematosus controls suggest that FcRI (CD89) -chain alleles may affect receptor-mediated signaling and play an important role in the modulation of immune responses in inflammatory diseases.

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 by National Institutes of Health Grants R01-AR33062 (to R.P.K.), N01-AI40068, M01-RR00032, and P01-AR49084 (to R.P.K.). The FACS Core Facility of the University of Alabama at Birmingham Arthritis and Musculoskeletal Center was supported by Rheumatic Diseases Core Center (National Institutes of Health Grant P30-AR48311).

² Address correspondence and reprint requests to Dr. Robert P. Kimberly, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 172 Shelby Interdisciplinary Biomedical Science Building, 1825 University Boulevard, Birmingham, AL 35294. E-mail address: rpk{at}uab.edu

³ Abbreviations used in this paper: TM, transmembrane; EC, extracellular; AM, acetoxymethylester; [Ca²⁺]_i, intracellular CA²⁺ concentration; CYT, cytoplasmic; mIgG, murine IgG; RBL, rat basophilic leukemia; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism.

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