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 Allotypes and Immune Response to Meningococcal Group B Polysaccharide

Serum samples were collected from 120 healthy adult volunteers (105 Caucasians and 15 Negros) before and after immunization with meningococcal polysaccharide (MPS) group B vaccine. Antibodies to MPS group B were measured and sera were typed for several Gm and Km(l) allotypes. A significant association was found between the Km(l) allotype and immune response to MPS group B in Caucasians

Immunoglobulin G Heavy Chain (Gm) Allotypes in Multiple Sclerosis

Serum samples from 70 Caucasian patients with multiple sclerosis were typed for nine Gm markers. Significant association was found with the Gm 1,17;21 phenotype, and the relative risk for individuals with this phenotype was calculated at 3.6. The data indicate that Caucasians positive for Gm 1,17;21 are almost four times more likely to develop multiple sclerosis than those without this phenotype

Heterozygosity at Gm Loci Associated with Humoral Immunity to Osteosarcoma

Familial clustering of osteosarcoma suggests the involvement of genetic factors (1, 2), and the demonstration of a high incidence of osteosarcoma-specific antibodies (3, 4), as well as tumor-specific cell-mediated immunity (5) in patients and their relatives, indicates the involvement of immunological factors in the pathogenesis of this disease. Certain Gm allotypes (genetic markers of IgG) have been shown to be associated with a high relative risk of some forms of cancer. For instance, in Caucasians an unusual Gm haplotype--Gm 1,3;5,13,14--has been found to be associated with neuroblastoma (6), and an increased frequency of Gm (2) has been reported in patients with malignant melanoma (7, 8). A recent report has shown an association of the Gm 1,2; 13,15,16,21 phenotype with lung cancer and primary hepatoma in the Japanese (9). To our knowledge, however, the possible role of Gm allotypes in predisposition to osteosarcoma has not been examined. Immune responsiveness to a variety of antigens in both experimental animals and humans has been shown to be controlled either by major histocompatibility complex (MHC)-linked immune response (Ir) genes or by allotype-linked Ir genes (10-13). In some instances an interactive effect of these two unlinked genetic systems has been observed (12). It is possible that MHC-linked or allotype-linked Ir genes may also influence humoral immunity to tumor antigens. In this report we present evidence for complementary Ir genes controlling immune responses to osteosarcoma-associated antigens (OSAA)

Response to Immunization with Haemophilus influenzae Type b Polysaccharide-Pertussis Vaccine and Risk of Haemophilus Meningitis in Children with the Km(1) Immunoglobulin Allotype

In experimental animals, immune responses to certain antigens are regulated by immunoglobulin allotype-linked genes. In an effort to detect such genes in humans, we examined the antibody responses of 74 healthy children with different Km(l) or Gm(23) allotypes to a Haemophilus influenzae type b vaccine (type b polysaccharide capsule-pertussis vaccine). The anticapsular antibody responses of black or white children with the Km(1) allotype were 4.6- to 9.5-fold higher than those of children who lacked this determinant (P \u3c 0.004). No significant differences were found in antibody response with respect to the Gm(23) allotype. The frequencies of Km(l) and Gm(23) also were examined in 170 patients with Haemophilus meningitis, 71 patients with epiglottitis, and 173 control children. Km(1) was detected less frequently in black patients with meningitis (38%) than in those with epiglottitis (81%, P \u3c 0.002) or in controls (66%, P \u3c 0.0007). The relative risk of meningitis thus was 3.2-fold lower among black children with the Km(1) allotype than in those who lacked this allotype (odds ratio = 0.3, 95% confidence interval 0.2 to 0.6). However, the risk of meningitis was not decreased in white children with the Km(l) allotype (odds ratio = 1.0). There were no significant differences in the frequency of Gm(23) among the patient groups and controls. The Km(l) allotype but not the Gm(23) thus defines a subpopulation of children of both races who are high responders to this vaccine, and black children but not white children with the Km(l) allotype are at decreased risk of developing Haemophilus meningitis. These data indicate that in blacks, genes associated with Km(l) may affect immune response to a prototype type b Haemophilus vaccine, and perhaps interact with another factor related to race to affect susceptibility to Haemophilus meningitis

Immunoglobulin κ Chain Allotypes (KM) in Onchocerciasis

GM and KM allotypes, powerful tools for genetic characterization of human populations, have been shown to play an important role in genetic predisposition to some infectious diseases. Two diverse racial groups-Afro-Ecuadorians and Amerindians-living in a single restricted geographical area of Ecuador, appear to have different risk factors for acquisition and clinical expression of onchocerciasis, a disease caused by the filarial parasite Onchocerca volvulus. In this study, GM and KM allotypes were determined in 25 Afro-Ecuadorians and 24 Amerindians infected with Onchocerca volvulus (INF) and in putative immune individuals (PI). In Afro-Ecuadorians, the frequency of the homozygous KM 3 phenotype was significantly decreased in INF as compared with the PI group (20 vs. 68%; P = 0.0012), while the frequency of the heterozygous KM 1,3 phenotype was increased in INF as compared with the PI subjects (48 vs 9%; P = 0.0044). These results suggest that in Afro- Ecuadorians KM 3 is associated with a lower relative risk (resistance), whereas KM 1,3 is associated with an increased risk (susceptibility) of onchocerciasis

Genetic Markers of IgG Influence The Outcome of Infection with Hepatitis C Virus

We examined the role that immunoglobulin GM and KM allotypes—genetic markers of γ and κ chains, respectively—play in the outcome of hepatitis C virus (HCV) infection in white Americans. A total of 119 persons who had cleared HCV and 111 with persistent HCV infection were genotyped for the presence of several GM and KM determinants. Persistent HCV infection was more than three times as likely (odds ratio, 3.50; P = .01) in subjects who were carriers of the GM3 allele than in those who were noncarriers. These results show that particular GM alleles may be important determinants of the outcome of HCV infection

GM Allotypes and COVID-19. A Pilot Study Performed on Sicilian Patients

Several studies suggest that genetic variants that influence the onset, maintenance and resolution of the immune response might be fundamental in predicting the evolution of COVID-19. In the present paper, we analysed the distribution of GM allotypes (the genetic markers of immunoglobulin γ chains) in symptomatic and asymptomatic COVID-19 patients and in healthy controls, all born and residing in Sicily. Indeed, the role played by GM allotypes in immune responses and infection control is well known. Our findings show that the GM23 allotype is significantly reduced in healthy controls. Interestingly, in a previous study, Sicilians carrying the GM23 allotype were associated with the risk of developing a symptomatic Human Cytomegalovirus infection. However, a note of caution should be considered, due to the small sample size of patients and controls

Immunoglobulin GM 3 23 5,13,14 phenotype is strongly associated with IgG1 antibody responses to Plasmodium vivax vaccine candidate antigens PvMSP1-19 and PvAMA-1

<p>Abstract</p> <p>Background</p> <p>Humoral immune responses play a key role in the development of immunity to malaria, but the host genetic factors that contribute to the naturally occurring immune responses to malarial antigens are not completely understood. The aim of the present investigation was to determine whether, in subjects exposed to malaria, GM and KM allotypes--genetic markers of immunoglobulin γ and κ-type light chains, respectively--contribute to the magnitude of natural antibody responses to target antigens that are leading vaccine candidates for protection against <it>Plasmodium vivax</it>.</p> <p>Methods</p> <p>Sera from 210 adults, who had been exposed to malaria transmission in the Brazilian Amazon endemic area, were allotyped for several GM and KM determinants by a standard hemagglutination-inhibition method. IgG subclass antibodies to <it>P. vivax </it>apical membrane antigen 1 (PvAMA-1) and merozoite surface protein 1 (PvMSP1-19) were determined by an enzyme-linked immunosorbent assay. Multiple linear regression models and the non-parametric Mann-Whitney test were used for data analyses.</p> <p>Results</p> <p>IgG1 antibody levels to both PvMSP1-19 and PvAMA-1 antigens were significantly higher (<it>P </it>= 0.004, <it>P </it>= 0.002, respectively) in subjects with the GM 3 23 5,13,14 phenotype than in those who lacked this phenotype.</p> <p>Conclusions</p> <p>Results presented here show that immunoglobulin GM allotypes contribute to the natural antibody responses to <it>P. vivax </it>malaria antigens. These findings have important implications for the effectiveness of vaccines containing PvAMA-1 or PvMSP1-19 antigens. They also shed light on the possible role of malaria as one of the evolutionary selective forces that may have contributed to the maintenance of the extensive polymorphism at the GM loci.</p

Antigen-specific influence of GM/KM allotypes on IgG isotypes and association of GM allotypes with susceptibility to Plasmodium falciparum malaria

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control.</p> <p>Methods</p> <p>In this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined.</p> <p>Results</p> <p>The GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent.</p> <p>Discussion</p> <p>The results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptible</p> <p>Conclusions</p> <p>The GM allotypes have significant influence on susceptibility to uncomplicated <it>P. falciparum </it>malaria and antigen-dependent influence on total IgG and IgG subclasses.</p