Polymorphic variants of human Fc-gamma-RIIIa, gamma-chain, CTLA-4 and Fc-gamma-RIIb1: Possible implications for systemic lupus erythematosus pathogenesis.

摘要

The purpose of this study was to test the hypothesis that genetically based polymorphic variants exist for four proteins involved in the immune response: FcγRIIIa, γ-chain, CTLA-4, and FcγRIIb1. FcγRIIIa, and the γ-chain are essential in immune complex (IC) clearance, while CTLA-4 and FcγRIIb1 are receptors expressed on T and B cells, respectively, that regulate T cell activation. The hypothesis was tested by amplifying and sequencing full-length cDNA for each gene in 20 normal individuals and 20 individuals with systemic lupus erythematosus (SLE), an IC-mediated autoimmune disease. Specific polymorphisms were selected for functional analysis and frequency determination in an extended population of normals and SLE patients.; For FcγRIIIa, 3 previously reported polymorphisms were found, occurring at nucleotides (nt) T230A/G (amino acid L48H/R), G249A, and T559G (F158V). No polymorphisms were found for the γ-chain. The nt230 polymorphisms were linked to the 559G allele in Caucasians, but did not occur in African Americans. A ligand binding ELISA confirmed the increased affinity of the 5596 (158V) allele over 559T (158F), and showed that the 230 allele also affects ligand binding.; For CTLA-4, one previously reported polymorphism was found at ntA49G (T17A). Studies of 49AA vs 49GG showed that this polymorphism did not affect receptor expression.; For FcγRIIb1, four polymorphisms were found at nt C18T, G336A, G612A and T695C (1232T).; Only two polymorphic states correlated with SLE. The CTLA-4 49AG heterozygous state was associated with SLE in all subjects (0.008), while FcγRIIIa 559T was associated with SLE in Caucasian males (0.018). In contrast, the African American SLE population showed a trend towards an increase of the 5596 allele (0.071). The FcγRIIb1 336A allele showed a trend towards over-representation in SLE Caucasians (0.088).; In conclusion, variation was found in the encoding sequence of three of the four proteins studied. For FcγRIIIa, this included variation that affected protein sequence and function, and appeared to have a physiological role in the development of SLE. For the receptors involved in lymphocyte activation, CTLA-4 and FcγRIIb1, variation was also found to affect protein sequence, but no effect on protein function was identified.