Excluded GM-specific IgG Subclass Genes in Health and Disease - Inborn Errors of Immunity

IgG subclass genes from chromosome 14q32.3 are assessed serologically by GM allotypes, genetic markers of the Fc part of the immunoglobulin constant heavy G chains, (IGHG(Fcγ)(GM) genes. Alternative GM allotypes of IgG3, IgG1 and IgG2, respectively, define 6 unique, precise GM-specific IgG subclass genes, inherited the Mendelian way with allelic exclusion, and linkage disequilibrium of IgG3-IgG1. Increased number of homozygous GM-specific IgG subclass genotypes with total loss of alternative IgG subclass molecules, inborn errors of immunity (IEI), are found in severe immunological diseases. A novel ELISA using GM-specific myeloma proteins and GM-specific monoclonals, identifies 6 alternative GM-specific IgG subclass genes and molecules IgG3*b & IgG3*g, IgG1*f & IgG1*a and IgG2*n & IgG2*-n, with different structures and functions. 4 different IgG3-IgG1-IgG2 haplotypes encode 10 individual IGHG diplotypes from 10 innate lymphoid combined B cells in 587 healthy. The alternative GM-specific IgG subclass genes have different structures and functions and respond differently in immunotherapy to antigen stimulation with virus, bacteria and allergens. In this report we focus on excluded GM-IgG subclass genes, inborn errors of immunity (IEI) dominating in severe immunological diseases, severe infections, primary immunodeficiencies (PIDs), JCA, asthma, diabetes type 1 and malignancy. By intravenous immunoglobulins (IVIG) the excluded IgG subclass molecules are supplied and may prevent primary virus attacks and exacerbations in autoimmune disorders. IgG subclass genes orchestrate additional immune factors of inflammation. Excluded GM-specific IgG subclass genes, IEI explore diagnosis, pathogenesis, prognosis and different phenotypes in immunological diseases, with IVIG as treatment.