ALTERNATIVE G1M, G2M AND G3M ALLOTYPES OF IGHG GENES CORRELATE WITH ATOPIC AND NONATOPIC PATHWAYS OF IMMUNE REGULATION IN CHILDREN WITH BRONCHIAL-ASTHMA

Most generic studies of bronchial asthma deal with IgE responsiveness. The manner by which allergens trigger IgE production and activate mas t cells suggests that several genetic loci may be involved. Several re ports of candidate genes include chromosome 6 and HLA antigens, chromo some 14q11 and the alpha chain of the T cell receptor, chromosome 11q3 2 and the beta chain of the high-affinity IgE receptor and chromosome 5 and the gene cluster for IL-4, respectively In addition, the immunog lobulin heavy chain G (IGHG) genes on chromosome 14q32 have been assoc iated with both atopic and non atopic bronchial asthma in children. In order to further investigate the role of IGHG genes in asthmatic chil dren, the phenotypes of patients with homozygous but alternative IGHG genes were investigated. IGHG gene expression of patients with childho od asthma was determined by serum Gm allotypes with a quantitative com petitive indirect ELISA method. The groups consisted of 24 children wi th the homozygous G3m(b/b)-G1m(f/f)-G2m(nln) and 16 with the alternati ve G3m(g/g)-G1m(a/a)-G2m(-n/-n) genes. The two different genotypes wer e investigated for serum IgE (PRIST), serum IgG subclass levels (radia l immunodiffusion), Gm allotype levels (competitive ELISA), IgA and Ig M levels (radial immunodiffusion), peripheral blood eosinophils, speci fic IgE antibodies (skin prick test, SPT, or radioallergosorbent test; RAST), number of peripheral blood CD lymphocyte markers (flow cytomet ry) and serum IL-4 and IFN-gamma levels (ELISA). Comparison of the two genotypes in children;vith bronchial asthma revealed significantly in creased IgE (p<0.001), increased specific IgE (p<0.001), as investigat ed by SPT or RAST (n = 10 allergens tested), increased number of perip heral blood eosinophils (p<0.01), increased serum IgG1(f/f)(p<0.001), IgG2(n/n) (p<0.001) and IgG3(b/b)(p<0.01) levels, and decreased CD8 gi ven in percent of the total number of peripheral lymphocytes, (p<0.02) in the G3m(b/b)-G1m(f/f)-G2m(n/n) genotype. The asthmatic children wi th the G3m(g/g)-G1m(a/a)-G2m(-n/-n) genes instead showed low IgE level s, practically no specific IgE antibodies, a lower number of periphera l blood eosinophils, lower IgG1(a/a), IgG2(-n/-n) and IgG3(g/g) serum levels and higher CD8 lymphocyte numbers. The results show that the IG HG3(b/b)-IGHG1(f/f)-IGHG2(n/n) genes are in linkage disequilibrium wit h allergen-specific high-responding IGHE genes and present the atopic phenotype of bronchial asthma, while the IGHG3(g/g)-IGHG1(a/a)-IGHG2(- n/-n) genes present the nonatopic phenotype of childhood asthma. The t wo genotypes with different amino acid epitopes of their constant heav y gamma 1, gamma 2 and gamma 3 chains presented qualitatively differen t IgG1, IgG2 and IgG3 molecules, respectively, and also different seru m IgG1, IgG2 and IgG3 levels, together with different numbers of perip heral blood eosinophils and CD8 lymphocytes. The two IGHG genotypes re present different pathways of human immune regulation. An association of atopic IGHG gene type with other candidate genes for atopy could be suggested.