Genetic B-cell variation based on immunoglobulin heavy G-chain (Gm) genes.

Abstract

Immunoglobulins are unique products of B cells. The different phases of B-cell development have been studied extensively. Variability in B cells based on the genetic variation of immunoglobulin heavy G-chain (IGHG) genes, could be suggested. The IGHG genes on chromosome 14q32 can be easily studied by the serum expression of Gm allotypes [1] quantitatively [2]. Gm allotypes are defined by minor amino acid epitope differences in the heavy constant chain of the IgG1, IgG2 and IgG3 molecules, and are inherited in the Mendelian way. The IGHG3, IGHG1 and IGHG2 genes, the order in which they appear on the chromosome, are characterized by two Gm allotypes from two alternatives on every IgG subclass locus [1]. The alternative Gm allotypes are: for IgG3, G3m(g) and G3m(b); for IgG1, G1m(a) and G1m(f); and for IgG2, G2 m(n) and G2m(-n). Four variants of IGHG genes are known according to Gm haplotypes namely: 1/Gm(b,f,n), 2/Gm(b,f,-n), 3/Gm(g,a,n) and 4/Gm(g,a,-n). The variation in a Caucasian population is the combination of these four haplotypes found in 10 different genotypes some of which are common and others very rare. The different genotypes are found in the following proportions: Gm(b,f,n)/(b,f,n), 22.3%; Gm(b,f,n)/(b,f,-n), 20.4%; Gm(b,f,-n)/ (b,f,-n), 7.0%; Gm(g,a,n)/(g,a,n), 1.3%; Gm(g,a,n)/g,a,-n), 0%; Gm(g,a,-n)/g,a,-n), 14%; Gm(g,a,n)/(b,f,n), 3.8%; Gm(g,a,n) (b,f,-n), 0%; Gm(g,a,-n)(b,f,n), 19.1%; and Gm(g,a,-n)/(b,f,-n), 12.1% [3]. Different pathways of immune regulation were evident when investigating two groups of bronchial asthmatic children, one expressing homozygous Gm(b,f,n) genotype and the other the opposite homozygous Gm(g,a,-n) genotype, representing B cells producing qualitatively different IgG molecules The Gm(b,f,n) group produced G3m(b) (as IgG3), G1m(f) (as IgG1) and G2m(n) (as IgG2). This group was also found to have increased serum IgE levels, specific IgE antibodies, increased peripheral blood eosinophils and decreased CD8 peripheral lymphocytes, representing the atopic phenotype. These patients were significantly different from the Gm(g,a,-n) group producing G3m(g) (as IgG3), G1m(a) (as IgG1) and G2m(-n) (as IgG2) together with low serum IgE and negative skin prick tests, representing the nonatopic phenotype [4]. The influence of Gm allotypes and HLA antigens on immune regulation has also been reported by Legrand and co-workers [5], who showed that the degradation rate of endocytosed sheep red blood cells by macrophages was very low in Gm(b,f,n) individuals. Genetic variation of B cells can be concluded and designated according to the four Gm haplotypes: the Bb,f,n cell or B1 cell expressing the Gm(b,f,n) molecules found is in 44.8% and the Bb,f,-n cell or B2 cell expressing the Gm(b,f,-n) molecules in 22.9%, the Bg,a,n cell or B3 cell expressing the Gm(g,a,n) molecules is found in only 0.9%, and the Bg,a,-n cell or B4 cell expressing the Gm(g,a,-n) molecules in 31.4%, of the Caucasian population (Table 1). B cells in Caucasian individuals can be assigned in the following way according to figures for different combinations of Gm haplotypes: B1/B1 22.3%, B1/B2 20.4% and B2/B2 in 7%; B3/B3 in 1.3%; B3/B4 extremely rare (none of 157); B4/B4 14.0%; B1/B3 in 3.8%; B2/B3 extremely rare; B1/B4 19.1%; and B2/B4 12.1% of a Caucasian population [3]. Different B cells are related to different clinical conditions. Individuals with B1/B1 cells express atopic bronchial asthma with increased IgE and specific IgE antibodies, while B4/B4 cells are found in nonatopic bronchial asthma [4]. B2/B2 cells dominate in IgG2 deficiency and in common variable immunodeficiency [6,7]. B4/B4 cells are found in IgG3 deficiency [6]. The relationship of B cells to different cytokine patterns of T cells, as B1/B1 cells to the type 2 cytokine pattern of T helper (Th)2 cells linked to atopy, should be investigated further. IgG molecules are found in serum and tissue fluids, and some are carried on the surface of B cells. The membrane-bound immunoglobulin is the same on the precursor B cell and the antibody-forming cell, mainly studied for the variable part of the molecule. The structure of the constant heavy chains, different amino acid epitopes of which relate to Gm allotypes, is responsible for the function of IgG molecules. We have recently shown that different Gm allotypes within the same IgG subclass have different metabolic rates and immunochemical properties and different rates of development during childhood [8–10]. There is a need for better understanding of different antibody responses. The hypothesis of a B-cell variation based on different IGHG genes has not been sufficiently discussed. Variant B cells associated with different pathways of immune response in clinical conditions such as allergy and primary immunodeficiencies are examples of its importance. Scand. J. Immunol. 49, 345–346, 1999