FcαRI (CD89) Alleles Determine the Proinflammatory Potential of Serum IgA

Abstract

The human IgA FcR (FcαRI; 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 (Ser248) to GGC (Gly248) in the cytoplasmic domain of the receptor. The two different alleles demonstrate significantly different FcαRI-mediated intracellular calcium mobilization and degranulation in rat basophilic leukemia cells and cytokine production (IL-6 and TNF-α) in murine macrophage P388D1 cells. In the absence of FcR γ-chain association in P388D1 cells, the Ser248-FcαRI allele does not mediate cytokine production, but the Gly248-FcαRI allele retains the capacity to mediate a robust production of proinflammatory cytokine. This allele-dependent difference is also seen with FcαRI-mediated IL-6 cytokine release by human neutrophils ex vivo. These findings and the enrichment of the proinflammatory Gly248-FcαRI allele in systemic lupus erythematosus populations in two ethnic groups compared with their respective non-systemic lupus erythematosus controls suggest that FcαRI (CD89) α-chain alleles may affect receptor-mediated signaling and play an important role in the modulation of immune responses in inflammatory diseases.

Recognition and functional activation of the human IgA receptor (FcαRI) by C-reactive protein

“…RBL cells express the high-affinity IgE receptor, FcεRI, and the FcR γ-chain, and cross-linking of FcεRI by IgE leads to potent degranulation as measured by the release of β-hexosaminidase. This γ-chaindependent degranulation also was observed in G248 cells upon antibody cross-linking of FcαRI (16). Importantly, significant re- Table S1.…”

“…To determine whether the observed solution binding between pentraxins and FcαRI also occurred on cell surfaces, we investigated CRP binding to RBL cells, a rat basophilic leukemia cell line, stably transfected with a Gly-248 variant of FcαRI (referred to as "G248 cells") (16). The expression of FcαRI on G248 cells can be detected readily by an anti-FcαRI antibody, MIP8a, (Fig.…”

“…An RBL cell line was stably transfected with a Gly-248 variant of human FcαRI (16). Human FcαRI exists in two common alleles (Gly and Ser) as a result of an SNP at amino acid 248 in the cytoplasmic domain of the receptor gene.…”

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

“…97 FcRn could be facilitating the 'opsonized' tachyzoite traverse the placenta. 98 The two alleles have significantly different FcaRI-mediated intracellular calcium mobilization and degranulation and cytokine production (IL-6 and TNF-a). In addition, IgA may inhibit IL-6 production by neutrophils from human donors carrying the Ser248 allele.…”

“…Thus, a-chain alleles of FcaRI affect receptor-mediated signaling and have an important role in immune responses modulation in inflammatory diseases. 98 FceRI regulates the concentration of circulating IgE antibodies; among its genetic variants, the C/T transition at À315 in the promoter of the a-chain gene is related to increased IgE levels. 99 Polymorphisms in these FcaRI and FceRI will probably affect the ability of the already-infected embryo/fetus to respond properly to T. gondii, but little can be suspected about their role in vertical transmission, as they are not present in the syncytiotrophoblast.…”