Imbalanced switch of the IGHG (immunoglobulin constant heavy G chain) Gm(bfn) genes in atopic childhood asthma.

Abstract

The IGHG genes on chromosome 14q32, 5'micron delta gamma3 gamma1alpha1 gamma2 gamma4 epsilon alpha2 3', as studied by Gm allotypes, are involved in the inheritance of atopy. The 5'micron delta b f alpha1 n gamma4 epsilon alpha2 3', Gm(bfn) haplotype of the genetic B1-cell variant has been found to be associated with the atopic phenotype of children with bronchial asthma. An indirect competitive enzyme-linked immunosorbent assay for quantitation in serum of the alternative serum Gm allotypes from the gamma3-, gamma1-, and gamma2 loci and radial immunodiffusion for quantitation of IgG subclasses were used. Children with the genetic B1-cell variants B1/B1 (= Gm[bfn/bfn]), B1/B2 (=Gm[bfn/bf-n]), and B1/B4 (=Gm[bfn/ga-n]) and bronchial asthma were investigated and compared to healthy children of the same age and B-cell type. The three groups with B1/B1, B1/B2, and B1/B4 cells exhibited increased IgE. In both homozygous and heterozygous B1 or Gm(bfn), the serum G1m(f) levels from gamma1 loci were significantly downregulated to 75% of normal, while G2m(n) from gamma2 loci were significantly upregulated to about double the normal level. In heterozygous patients with additional B2 or B4 cells, the G2m(-n) levels from gamma2 loci were instead downregulated. G1m(a) from gamma1 of B4 cells was also downregulated. Children with atopic bronchial asthma demonstrated an imbalanced class switch in rearrangement of the genes for IgG. The activity of G1m(f) from the gamma1 locus was downregulated, but G2m(n) from gamma2 was upregulated together with the closely situated epsilon locus downstream of the IGH genes. Low levels of G1m(f), Glm(a), and G2m(-n) indicated a low pressure of infections. The imbalanced activation of the IGH genes in more hygienic environments might be one explanation of the increased prevalence of atopy in children in recent decades.