The demonstration of immune response genes in man has been difficult, although there is evidence for genes linked to the MHC in mouse and guinea pig that control both the specificity and magnitude of immune responses. A number of features of the antibody response to the Rh D antigen, such as the failure of some individuals at risk to respond, the restricted immunoglobulin class, subclass, and light chain type of the antibody produced, and the presumed minor structural difference between Rh D antigen and its allelic product, all suggest that one or at most a few immune response genes are involved. Typing for the four MHC-linked complement genes BF, C2, C4A, and C4B was carried out in 52 independently ascertained Caucasian individuals with significant anti-D titers. A control population of 623 normal Caucasian chromosomes was also studied. In patients with anti-D antibodies, the frequency of BF F1 (0.04 vs 0.0064 for 623 chromosomes, p less than 0.003); of C4A 3 (0.769 vs 0.631, p less than 0.006); and of C4B Q0 (0.25 vs 0.104, p less than 0.00004) were all increased. These three alleles are found in the common complotype BF 8F1,C2 C,C2A 3, C4B Q0, and presumably represent a single extended haplotype of 6p associated with (and presumably containing a gene for) the immune response to RhD. This complotype has a 0.6% frequency in 623 normal control chromosomes, but is also increased in patients with insulin-dependent diabetes mellitus and with membranous glomerulonephritis.

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