FcalphaRI (CD89) alleles determine the proinflammatory potential of serum IgA.
The human IgA FcR (FcalphaRI; 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 (844A-->G) (rs16986050), which changes codon 248 from AGC (Ser(248)) to GGC (Gly(248)) in the cytoplasmic domain of the receptor. The two different alleles demonstrate significantly different FcalphaRI-mediated intracellular calcium mobilization and degranulation in rat basophilic leukemia cells and cytokine production (IL-6 and TNF-alpha) in murine macrophage P388D1 cells. In the absence of FcR gamma-chain association in P388D1 cells, the Ser(248)-FcalphaRI allele does not mediate cytokine production, but the Gly(248)-FcalphaRI allele retains the capacity to mediate a robust production of proinflammatory cytokine. This allele-dependent difference is also seen with FcalphaRI-mediated IL-6 cytokine release by human neutrophils ex vivo. These findings and the enrichment of the proinflammatory Gly(248)-FcalphaRI allele in systemic lupus erythematosus populations in two ethnic groups compared with their respective non-systemic lupus erythematosus controls suggest that FcalphaRI (CD89) alpha-chain alleles may affect receptor-mediated signaling and play an important role in the modulation of immune responses in inflammatory diseases.
Wu
Jianming
J
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
Ji
Chuanyi
C
Xie
Fenglong
F
Langefeld
Carl D
CD
Qian
Kun
K
Gibson
Andrew W
AW
Edberg
Jeffrey C
JC
Kimberly
Robert P
RP
D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology*; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology; D020125:Mutation, Missense; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D051381:Rats; D011961:Receptors, Fc / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015703:Antigens, CD; C036832:Fc(alpha) receptor; C508600:IL6 protein, human; D007070:Immunoglobulin A; D015850:Interleukin-6; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha