Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses

Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma

Objective

Human low-affinity Fcγ receptors (FcγR) constitute a clustered gene family located on chromosome 1q23, that consists of FcγRIIA, IIB, IIC, IIIA, and IIIB genes. FcγRIIB is unique in its ability to transmit inhibitory signals, and recent animal studies demonstrated a role for FcγRIIB deficiency in the development of autoimmunity. Genetic variants of FcγRIIA, IIIA, and IIIB and their association with systemic lupus erythematosus (SLE) have been extensively studied in various populations, but the results were inconsistent. To examine the possibility that another susceptibility gene of primary significance exists within the FcγR region, we screened for polymorphisms of the human FCGR2B gene, and examined whether these polymorphisms are associated with SLE.



Methods

Variation screening of FCGR2B was performed by direct sequencing and polymerase chain reaction (PCR)-single-strand conformation polymorphism methods using complementary DNA samples. Genotyping of the detected polymorphism was done using genomic DNA, with a specific genotyping system based on nested PCR and hybridization probing. Association with SLE was analyzed in 193 Japanese patients with SLE and 303 healthy individuals. In addition, the same groups of patients and controls were genotyped for the previously known polymorphisms of FCGR2A, FCGR3A, and FCGR3B.



Results

We detected a single-nucleotide polymorphism in FCGR2B, (c.695T>C), coding for a nonsynonymous substitution, Ile232Thr (I232T), within the transmembrane domain. The frequency of the 232T/T genotype was significantly increased in SLE patients compared with healthy individuals. When the same patients and controls were also genotyped for FCGR2A-131R/H, FCGR3A-176V/F, and FCGR3B-NA1/2 polymorphisms, FCGR3A-176F/F showed significant association. Two-locus analyses suggested that both FCGR2B and FCGR3A may contribute to SLE susceptibility, while the previously reported association of FCGR3B was considered to be secondary and derived from strong linkage disequilibrium with FCGR2B.



Conclusion

These results demonstrate the association of a new polymorphism of FCGR2B (I232T) with susceptibility to SLE in the Japanese.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.10257

Fc gamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus - Contribution of FCGR2B to genetic susceptibility

Diagnosis and Clinical Course of Autoimmune Neutropenia in Infancy: Analysis of 240 Cases

Two groups of receptors for immunoglobulin G (FcgammaR) can be distinguished. Endothelial cells and placental syncytiotrophoblasts express an MHC class I-like FcgammaR important for regulation of IgG half-life and IgG transport, respectively. FcgammaR expressed on leukocytes constitute a heterogeneous family of membrane bound and soluble proteins. The various FcgammaR (sub) classes of this family differ in ligand affinity and specificity, which is determined by primary structure, glycosylation, association with signaling subunits, and environmental factors (such as serine proteases). The finding that polymorphisms of FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb critically affect interaction with antibodies has prompted analysis in patients which provided tantalizing evidence for the relevance of FcgammaR polymorphisms as risk factors for a number of infectious and autoimmune diseases.

Ernst-Ludwig Stein

Papers

Characterization of a New Alloantigen (SH) on the Human Neutrophil Fcγreceptor IIIb

NA gene frequencies in the German population, determined by polymerase chain reaction with sequence-specific primers.