Human immunoglobulin constant heavy G chain (IGHG) (Fcγ) (GM) genes, defining innate variants of IgG molecules and B cells, have impact on disease and therapy.

The distinguished alternative GM allotypes localized in immunoglobulin constant heavy G chain IGHG (Fcγ) (GM) genes on chromosome 14q32.3 define two unique variants of respectively IgG3, IgG1 and IgG2 subclasses, with different structures and functions. The IGHG allele (allotypes), expressed in homozygous or heterozygous forms, are assessed by new serological methods. Fixed combinations of γ3, γ1 and γ2 allotypes constitute the haplotypes, which are indirect markers of B cells. We highlight the role of homozygous IGHG genes with restricted qualities of IgG subclass molecules and B cells. These common Mendelian IGHG genes respond differently to allergens and infections, both bacterial and viral, and to active and passive immunotherapies. IGHG genes have an impact on diseases such as allergy, immunodeficiency, autoimmunity and malignancy. Association/linkage of different IGHG genes gives information about risk/protection, good or bad prognosis, for improvement of clinical care. The IGHG gene map of healthy Caucasians is registered

Immunoglobulin constant heavy G subclass chain genes in asthma and allergy.

The IGHG (ImmunoGlobulin constant Heavy G chain) genes are situated close to the IGHE gene on chromosome 14q32, 5'mu, delta, gamma3, gamma1, alpha1, gamma2, gamma4, epsilon, alpha2, 3', in linkage disequilibrium. The polymorphism of gamma3, gamma1 and gamma2 genes, is investigated as alternative allotypes. They are inherited in a Mendelian fashion and are expressed randomly in allelic exclusion. The alternative and functionally different gamma3, gamma1 and gamma2 gene variants, are found in four IGHG haplotypes, coding 4 B-cell variants: IGHG*bfn (=B1-cells), IGHG*bf-n (=B2-cells), IGHG*gan (=B3-cells) and IGHG*ga-n (=B4-cells). The dominance of the IGHG2*n allele from the IGHG*bfn haplotype (=B1-cells) has been shown in repeated investigations, namely in patients with asthma and allergy with increased serum levels of IgE > 600 ku/l and more often so in those with IgE > 1,000 ku/l or IgG4>1 g/l, in childhood asthma patients with mean level of IgE = 1,762 ku/l and in allergen exposed individuals developing laboratory animal allergy. In children with non-atopy and mean IgE level = 9.5 ku/l there is instead a dominance of the alternative allotypes from the IGHG*ga-n (=B4-cells) with IGHG2*-n alleles. In a case-control study allergic children with a family history of allergy, clinically manifest allergy and/or positive SPT, the IGHG*bfn haplotype (=B1-cells) with the IGHG2*n allele dominates, with increased risk of atopy and the IGHG*bf-n haplotype (=B2-cells) with the IGHG2*-n allele is infrequent with low risk, probably protective against atopy. The phenotypic expressions of the IGHG*bfn haplotype (=B1 cells) and IGHG*bfn/*bfn diplotypes (B1/B1-cells) are increased IgG2*n allotype together with increased IgE serum levels and IgE sensitisation in agreement with atopy. The alternative IGHG*ga-n/*ga-n diplotype (B4/B4-cells) express low IgG1*a- and IgG2*-n allotypes, together with low IgE and non-IgE sensitisation, in agreement with non-atopy. Together these studies have given us a greater understanding of the involvement of IGHG genes, IGHG coded B-cells and immunochemical and functional variants of IgG molecules describing different forms of asthma and allergy, which will improve diagnoses and treatment

From Genotypes of Immunoglobulin Constant Heavy G Chains (Fcγ) (GM) Genes (IGHG) to Phenotypes in Childhood Asthma.

Background: IgE-mediated allergy is associated with immunoglobulin heavy constant G chain (Fcγ) (GM) genes (IGHG) on chromosome 14q32.3. Investigation of the alternative GM allotypes of γ3, γ1 and γ2 chains has disclosed new structural and functional IgG subclasses and B-cell variants, with possible effects on childhood asthma. Objective: To investigate different IGHG (GM) gene complexes in a childhood asthma population for allergy parameters. Methods: IGHG alleles and correlated allotypic (allelic) IgG subclass levels were analyzed with a sensitive indirect competitive ELISA in 10-year-old children with bronchial asthma. Individual IGHG diplotype-, genotype- and haplotype-related B cells were compared for allelic IgG subclass levels, IgE sensitization, IgE, IgA and IgM levels, and numbers of peripheral blood eosinophils and lymphocytes. Results: The group with homozygous IGHG*bfn/*bfn (B1/B1 cells) demonstrated low IgG1*f levels (p < 0.001) but increased IgG2*n levels (p < 0.001) together with increasd IgE and IGHG2*n gene dose-dependent IgE sensitization (atopic phenotype). The IGHG*bf-n/*bf-n (B2/B2 cells) demonstrated low IgG1*f (p < 0.05) and IgG2*-n (p < 0.001) and the IGHG*ga-n/*ga-n (B4/B4 cells) low IgG1*a (p < 0.001) and IgG2*-n (p < 0.02) together with low IgE sensitization (non-atopic phenotype). B*(bfn) (B1) and B*(bf-n) (B2) demonstrated increased numbers of peripheral blood eosinophils, compared to B*(gan) (B4) cells, which demonstrated increased peripheral blood CD8 lymphocytes instead. Conclusion: IGHG diplotypes present different phenotypes in childhood asthma. The IGHG2*n dose relationship to IgE sensitization and increased IgG2*n levels in IgE sensitized are risk markers for IgE-mediated asthma. The opposite IGHG2*-n presents non-IgE-mediated asthma and IgG subclass deficiencies

Imbalanced serum IgG subclass pattern in toxic shock syndrome patients: deficiency of specific IgG1 and IgG4 subclass antibodies to toxic shock syndrome toxin 1

An imbalanced serum IgG subclass pattern was identified in 10 patients with toxic shock syndrome (TSS) showing remarkably low subclass levels of various combinations. IgG2 levels were significantly reduced as compared to normal controls. The IgG subclass-specificity of antibodies to toxic shock syndrome toxin (TSST-1) was investigated by a solid-phase radioimmunoassay. TSS-patients lacked pre-immunity to TSST-1 in all four IgG subclasses. Normally acquired immunity to the toxin as well as the serological response developing in two patients with TSS was generally restricted to IgG1 and IgG4. A strong booster response of all four IgG subclasses was seen in three patients with S. aureus septicaemia due to TSST-1 producing strains. The lack of specific IgG1 and IgG4 antibodies to TSST-1 and the low serum IgG subclass levels found in the TSS-patients could be of pathogenetic significance and help to explain the susceptibility to TSS in certain individuals

Immunoglobulin heavy G2 chain (IGHG2) gene restriction in the development of severe respiratory syncytial virus infection

Aim: Respiratory syncytial virus (RSV) is a prominent cause of airway morbidity in children under 1 y of age. It is assumed that host factors influence the severity of disease presentation, and thus the need for hospitalization. The variation of IGHG genes from chromosome 14q32 are linked to serum IgG subclass levels but also to the variations in IgG responses to pneumococcal, meningococcal and Haemophilus influenzae antigens. The aim of this investigation was to clarify whether IGHG genes are involved in the development of severe RSV lower respiratory tract infection (LRTI). Methods: The alternative expressions of IGHG3(b) and (g), IGHG I(f) and (a), and IGHG2(n) and (-n) genes were studied in a cohort of 49 previously healthy children hospitalized for RSV LRTI. The gene frequencies were compared to a population of healthy individuals. Results: The homozygous IGHG2(-n/-n) genotypes dominated in hospitalized children with severe RSV infection: 55.1%, compared with 34.2% in the healthy population (OR 2.3; p = 0.004). The IGHG2 genotypes containing (n/n) and (n/-n) were significantly decreased. The IGHG(bf-n) alleles were significantly increased (OR 1.7; p=0.025) and the IGHG(bfn) alleles significantly decreased (OR 0.5; p=0.005). Conclusion: The IGHG(bf-n) allele and homozygous IGHG2(-n/-n) genotypes are associated with the development of severe RSV LRTI

Restricted immunoglobulin constant heavy G chain genes in primary immunodeficiencies.

Some primary immunodeficiencies (PIDs) express low serum levels of antibodies. The constant heavy G chain (IGHG) genes, also representing Fc domains of gamma3, gamma1 and gamma2 on chromosome 14q32.3, genotyped by the alternative IgG subclass allotypes, found in four fixed IGHG haplotypes, designating four B cell variants, were identified by a competitive ELISA and double immunodiffusion. IGHG genes were hypothesized to contribute to the development of PIDs. From 235 Caucasian patients, the homozygous IGHGbf-n/bf-n diplotype (B(bf-n)/B(bf-n) cells) dominated significantly in 43 IgG2 deficiency (OR 6.0), 32 common variable immunodeficiency (OR 4.6) and 22 Ataxia telangiectasia (OR 3.0) and the IGHGga-n/ga-n diplotype (B(ga-n)/B(ga-n) cells) dominated in 53 IgG3 deficiency (OR 10.6) and 21 Wiscott-Aldrich syndrome (OR 4.1). 62 IgA deficiency patients were dominated by both diplotypes (OR 2.3 and OR 2.8 respectively). Restricted IGHG genes, restricted IgG allotypes (Fc domains) and restricted B cells are significant in PIDs for diagnosis, treatment and pathogenetic mechanisms

Development of allergy to laboratory animals is associated with particular Gm and HLA genes

To find out whether IgG genes are involved in atopy we studied 26 of 101 laboratory technicians who had developed laboratory animal allergy (LAA). The genes for the constant region of the heavy chains of IgG subclasses were analyzed by serum Gm allotypes, representing products on allelic level of the IGHCG1, IGHCG2 and IGHCG3 on chromosome 14q32. There was a significantly increased frequency of the GM(f,f;n,n;b,b) genotype (57.7 instead of 22.3%, p < 0.001) representing IgG1, IgG2 and IgG3 molecules and in particular increased frequency of Gm genotypes with the homozygous expression of G2m (n,n) (69.2 instead of 27.4%, p < 0.001) and of the Gm(f,n,b) haplotype (75 instead of 44.8%, p < 0.001) compared to a normal Caucasian population. An increased HLA-DR4 content of the LAA group (61.5 instead of 33.7%, p < 0.01) was further investigated for Gm allotypes. Among 16 HLA-DR4 LAA individuals, the Gm(f,f;n,n;b,b) genotype (56.3 instead of 22.3%, p < 0.01) and the Gm genotypes with the homozygous expression G2m(n,n) (62.6 instead of 27.4%, p < 0.01) dominated. However, the HLA-DR4 frequency among Gm(f,f;n,n;b,b) of LAA patients did not deviate from the frequency of healthy individuals of the same Gm genotype. The increased frequency of HLA-DR4 antigen in LAA patients might be due to its association to the Gm(f,f;n,n;b,b) genotype. This study supports the following concept: the susceptibility of developing LAA is associated with Gm allotypes Glm(f) expressed from IGHCG1, G2m(n) from IGHCG2 and G3m(b) from IGHCG3 on both alleles situated close to IGHCE on chromosome 14q32. The association of LAA to Gm allotypes [Gm(f,f;n,n;b,b)] expressed from chromosome 14q32 and of HLA class II antigens (HLA-DR4) expressed from chromosome 6p21.3 further confirms the polygenic inheritance of the immune response in atopy