Human IGHC locus restriction fragment length polymorphisms in IgG4 deficiency: evidence for a structural IGHC defect

In man, IgG4 is the least abundant of the four IgG subclasses, and its serum levels vary considerably from one subject to another. Its deficiency has been thought to lead to recurrent infections; nevertheless, it is also commonly found in healthy individuals (1/400 in the Italian population). In 39 subjects with IgG4 serum levels less than 1 microgram/ml, we used 4 different probes (described in the accompanying study, Bottaro et al., Eur. J. Immunol. 1989. 19: 2151) to examine 13 loci within the IGHC region and analyzed the RFLP for 7 of them. No aberrant restriction patterns were identified in any of the subjects, showing the absence of major IGHC structural alterations. The allele frequency of some loci, however, was significantly different from that of a control group of 95 random subjects. This variation was shown to depend on a selective increase in the number of homozygotes for the associated alleles, that reached significant levels for the IGHGP, G2, PG2, PG4 and SG4 loci, but not for SG1 and A2T. The highest value was reached for alleles in the PG4 region, just 5' of SG4. These data indicate that a minor structural IGHC defect is probably the cause of a significant fraction of IgG4 deficiencies. Moreover, the different association levels of the PG4 and SG4 regions suggest that this defect is likely to lie in an upstream regulatory region rather than in the structural G4 gene.