Characterization of type I complement C2 deficiency MHC haplotypes. Strong conservation of the complotype/HLA-B-region and absence of disease association due to linked class II genes.

Abstract

Fourteen individuals with complete C2 deficiency from 11 families and 3 heterozygous C2-deficient individuals from two families were investigated. In all the 24 independent C2-deficient haplotypes, the complotype S042 was present and the majority (21/24) was [HLA-B18,S042,DR2]. All carried the type I C2 deficiency C2 pseudogene with its characteristic 28 bp deletion. All but two haplotypes had 10 AC/GT repeats in the TNF alpha microsatellite polymorphism and all but one of the haplotypes were identical at or near HLA-B as assessed by RFLP using BstEII digestion and two genomic probes, R5A and M20A, located 100 and 38 kb centromeric to HLA-B, respectively. The exceptional haplotype was HLA-B40 with four AC/GT repeats at TNF-alpha. Three of the haplotypes were not DR2 based on generic and sequence-specific oligonucleotide typing. Another four haplotypes showed different DO-variants detected by RFLP analysis using BglIIand Mspl digestion. Thus, the [HLA-B18,S042,DR2] haplotype appears to be more fixed in the region between the complement genes and the HLA-B locus (96%) than in the region between the complement genes and DR (88%) and DO loci (71%). Of the 14 individuals studied, six had SLE or SLE-like syndromes and six had a history of severe infections although two were apparently healthy. Three of the six SLE patients and two individuals with repeated infections were homozygous for [HLA-B18,S042,DR2] and also homozygous for DQB1*0602 and the common DO variant. Thus, MHC class II genes linked to the C2 pseudogene do not appear to determine different clinical consequences of C2 deficiency.