Immunoglobulin GM and KM allotypes are associated with antibody responses to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients.

BACKGROUND: Chronic infection with Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of death in patients with cystic fibrosis (CF). Immunobiology of P. aeruginosa infection is complex and not well understood. Chronically infected CF patients generate high levels of antibodies to P. aeruginosa, but this response does not lead to clinical improvement. Therefore, additional studies aimed at identification and understanding of the host factors that influence naturally occurring immune responses to P. aeruginosa are needed. In this investigation, we evaluated the contribution of immunoglobulin GM (γ marker) and KM (κ marker) allotypes to the antibody responses to P. aeruginosa lipopolysaccharide (LPS) O1, O6, O11, and alginate antigens and the broadly-conserved surface polysaccharide expressed by many microbial pathogens, poly-N-acetyl-D-glucosamine (PNAG), in 58 chronically infected CF patients. METHODS: IgG1 markers GM 3 and 17 and IgG2 markers GM 23- and 23+ were determined by a pre-designed TaqMan® genotyping assay. The κ chain determinants KM 1 and 3 were characterized by PCR-RFLP. Antibodies to the LPS O antigens, alginate, and PNAG were measured by an ELISA. RESULTS: Several significant associations were noted with KM alleles. Particular KM 1/3 genotypes were individually and epistatically (with GM 3/17) associated with the level of IgG antibodies to O1, O11, alginate, and PNAG antigens. CONCLUSIONS: Immunoglobulin GM and KM genotypes influence the magnitude of humoral immunity to LPS O, alginate, and PNAG antigens. These results, if confirmed in a larger study population, will be helpful in devising novel immunotherapeutic approaches against P. aeruginosa.

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.

BACKGROUND: 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 gamma and kappa-type light chains, respectively--contribute to the magnitude of natural antibody responses to target antigens that are leading vaccine candidates for protection against Plasmodium vivax. METHODS: 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 P. vivax 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. RESULTS: IgG1 antibody levels to both PvMSP1-19 and PvAMA-1 antigens were significantly higher (P = 0.004, P = 0.002, respectively) in subjects with the GM 3 23 5,13,14 phenotype than in those who lacked this phenotype. CONCLUSIONS: Results presented here show that immunoglobulin GM allotypes contribute to the natural antibody responses to P. vivax 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.

Immunoglobulin allotypes influence IgG antibody responses to hepatitis C virus envelope proteins E1 and E2.

Immunoglobulin (Ig) GM and KM allotypes-genetic markers of gamma and kappa chains, respectively-are associated with the outcome of hepatitis C virus (HCV) infection, but the underlying mechanisms are not well understood. We hypothesized that GM and KM allotypes could contribute to the outcome of HCV infection by influencing the levels of IgG antibodies to the HCV glycoproteins E1E2. We serologically allotyped 100 African American individuals with persistent HCV infection for GM and KM markers and measured anti-E1E2 antibodies. Subjects with the GM 1,17 5,13 phenotype had significantly higher levels of anti-E1E2 antibodies than subjects who lacked this phenotype (p = 0.008). Likewise, subjects with the KM 1-carrying phenotypes had higher levels of anti-E1E2 antibodies than subjects who lacked these phenotypes (p = 0.041). Median titers were fourfold higher in persons expressing both GM 1,17 5,13 and KM 1-carrying phenotypes compared with those who lacked these phenotypes (p = 0.011). Interactive effects of these GM-KM phenotypes were previously found to be highly significantly associated with spontaneous HCV clearance. Results presented here show that Ig allotypes contribute to the interindividual differences in humoral immunity to the HCV epitopes, a finding that may provide a mechanistic explanation for their involvement in the outcome of HCV infection.

Immunoglobulin GM and KM genes and measles vaccine-induced humoral immunity.

Identifying genetic polymorphisms that explain variations in humoral immunity to live measles virus vaccine is of great interest. Immunoglobulin GM (heavy chain) and KM (light chain) allotypes are genetic markers known to be associated with susceptibility to several infectious diseases. We assessed associations between GM and KM genotypes and measles vaccine humoral immunity (neutralizing antibody titers) in a combined cohort (n=1796) of racially diverse healthy individuals (age 18-41years). We did not discover any significant associations between GM and/or KM genotypes and measles vaccine-induced neutralizing antibody titers. African-American subjects had higher neutralizing antibody titers than Caucasians (1260mIU/mL vs. 740mIU/mL, p=7.10×10-13), and those titers remained statistically significant (p=1.68×10-09) after adjusting for age at enrollment and time since last vaccination. There were no statistically significant sex-specific differences in measles-induced neutralizing antibody titers in our study (p=0.375). Our data indicate a surprising lack of evidence for an association between GM and KM genotypes and measles-specific neutralizing antibody titers, despite the importance of these immune response genes.

Endogenous antibody responsiveness to epidermal growth factor receptor is associated with immunoglobulin allotypes and overall survival of patients with glioblastoma.

BACKGROUND: Immunoglobulin γ marker (GM) and κ marker (KM) allotypes, hereditary antigenic determinants of γ and κ chains, respectively, have been shown to be associated with immunity to a variety of self and nonself antigens, but their possible contribution to immunity to the tumor-associated antigens epidermal growth factor receptor (EGFR) and EGFR variant (v)III has not been evaluated. The aim of the present investigation was to determine whether the interindividual variation in endogenous antibody responsiveness to EGFR and EGFRvIII is associated with particular GM, KM, and Fcγ receptor (FcγR) genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma. METHODS: A total of 126 Caucasian participants with glioblastoma were genotyped for several GM, KM, and FcγR alleles and characterized for IgG antibodies to EGFR and EGFRvIII antigens. RESULTS: The anti-EGFR antibody levels associated with GM 3/3 homozygotes and GM 3/17 heterozygotes were similar (15.9 vs 16.4 arbitrary units [AU]/µL) and significantly lower than those associated with GM 17/17 homozygotes (19.6 AU/µL; nominal P = .007). Participants homozygous for the GM 21 allele also had significantly higher levels of anti-EGFR antibodies than GM 5/5 homozygotes and GM 5/21 heterozygotes (20.1 vs 16.0 and 16.3 AU/µL; nominal P = .005). Similar associations were found with immune responsiveness to EGFRvIII. Higher anti-EGFR and anti-EGFRvIII antibody levels were associated with enhanced overall survival (16 vs 11 mo, nominal P = .038 and 20 vs 11 mo, nominal P = .004, respectively). CONCLUSIONS: GM allotypes contribute to humoral immunity to EGFR in glioblastoma.

Combined effects of Gm or Km immunoglobulin allotypes and age on antibody responses to Plasmodium falciparum VarO rosetting variant in Benin.

Clinical protection of Beninese children against Plasmodium falciparum malaria was shown to be influenced by immunoglobulin (IG) Gm and Km allotypes, and related to seroreactivity with the rosette-forming VarO-antigenic variant. IgG to the VarO-infected erythrocyte surface, IgG1 and IgG3 to PfEMP1-NTS-DBL1α(1)-VarO were higher in the under 4-year-old children carrying the Gm 5,6,13,14;1,17 phenotype. In contrast, surface-reactive IgG, total IgG, IgG1 and IgG3 to NTS-DBL1α(1)- and DBL2ßC2-VarO domains were lower in the above 4-year-old children harbouring the Km1 allotype. These data outline an age-related association of antibodies against malaria antigens and IG allotype distribution.

Immunoglobulin KM allotypes are associated with the prevalence of autoantibodies to GD1a ganglioside, but not with susceptibility to the disease, in Japanese patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS), an autoimmune disease of the peripheral nervous system, is associated with antecedent Campylobacter jejuni infection. GM and KM allotypes--genetic markers of immunoglobulin gamma and kappa chains, respectively--are implicated in the etiopathogenesis of several autoimmune diseases. To determine if GM/KM phenotypes are associated with GBS and influence antibody responses to C. jejuni and to GM1 and GD1a gangliosides, 72 Japanese GBS patients and 73 controls were allotyped for several GM and KM markers. Sera from patients were characterized for antibodies to C. jejuni, GM1, and GD1a. The distribution of KM phenotypes was significantly different in patients with anti-GD1a ganglioside antibodies from those who lacked these antibodies (P=0.029). No other significant associations were found. These results suggest that KM allotypes are not risk factors for developing GBS, but contribute significantly to the generation of autoimmune responses to GD1a ganglioside in patients with this disease.

Immunoglobulin GM and KM allotypes and vaccine immunity.

Immunoglobulin (Ig) GM and KM allotypes are genetic markers of gamma and kappa-type light chains, respectively. The striking qualitative and quantitative differences in the distribution of these determinants among different races raise questions concerning the nature of the evolutionary selective mechanism that maintains this variation. Associations between Ig allotypes and specific antibody responses could be a selective force for the maintenance of various haplotypes and their frequencies. Data from several studies reporting significant associations between certain GM and KM allotypes and immune responsiveness to polysaccharide vaccines and to particular infectious pathogens support this hypothesis. Possible ways in which constant (C)-region allotypes could contribute to the antibody specificity include the following: (i) certain alleles coding for allotypes may be in linkage disequilibrium with particular variable (V)-region determinants associated with immune responsiveness; (ii) they could directly contribute to the formation of specific idiotypes, as shown for the T15 system in mice; and (iii) allotype-associated structural variability in the C-region could modulate the kinetic competence of the antigen binding sites.