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

Falsely low IgG4 in routine analysis - How not to miss IgG4 disease

Background IgG4 disease can have apparently “normal” levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK NEQAS data and other reports have suggested this problem occurred despite pre-existing antigen excess detection steps. Methods We examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts, to determine the clinical relevance of the problem. Results We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (<1%) using one of the 2 routine methods in use in the UK. We show that subsequent assay modification appears to have reduced the likelihood of misleading readings. However, the original version of the assay prozoned to low levels (below 0.64g/L) in 41% of high IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone-resistant protocols. Conclusions All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning

Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

Haplotypes of the bovine IgG2 heavy gamma chain in tick-resistant and tick-susceptible breeds of cattle

Bovines present contrasting, heritable phenotypes of infestations with the cattle tick, Rhipicephalus (Boophilus) microplus. Tick salivary glands produce IgG-binding proteins (IGBPs) as a mechanism for escaping from host antibodies that these ectoparasites ingest during blood meals. Allotypes that occur in the constant region of IgG may differ in their capacity to bind with tick IGBPs; this may be reflected by the distribution of distinct allotypes according to phenotypes of tick infestations. In order to test this hypothesis, we investigated the frequency of haplotypes of bovine IgG2 among tick-resistant and tick-susceptible breeds of bovines. Sequencing of the gene coding for the heavy chain of IgG2 from 114 tick-resistant (Bos taurus indicus, Nelore breed) and tick-susceptible (B. t. taurus, Holstein breed) bovines revealed SNPs that generated 13 different haplotypes, of which 11 were novel and 5 were exclusive of Holstein and 3 of Nelore breeds. Alignment and modeling of coded haplotypes for hinge regions of the bovine IgG2 showed that they differ in the distribution of polar and hydrophobic amino acids and in shape according to the distribution of these amino acids. We also found that there was an association between genotypes of the constant region of the IgG2 heavy chain with phenotypes of tick infestations. These findings open the possibility of investigating if certain IgG allotypes hinder the function of tick IGBPs. If so, they may be markers for breeding for resistance against tick infestations