Biomarkers of neural integrity and immunoglobulin genes influence neurodegeneration in Alzheimer's disease.

Compelling evidence has been presented in favor of herpes simplex virus type 1 (HSV1) being one of the causative agents of Alzheimer's disease (AD). The success of HSV1 as a pathogen relates to its sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR) that thwarts the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), a potent host immunosurveillance mechanism against virally infected cells. The decoy FcγR binds to antibodies of all IgG subclasses, except IgG3; therefore, IgG3 would be expected to play an important role in viral clearance by neutralization and ADCC, and thus contribute to protection from HSV1-spurred diseases. Previous studies have shown significant association between anti-HSV1 IgG3 antibodies and cortical thinning of the areas of the brain typically altered in AD and also targeted by HSV1. The aim of the present investigation was to determine whether GM (γ marker) 5 and GM 21 allotypes, hereditary allelic determinants expressed on IgG3, together with brain biomarkers of neural integrity, contributed to neurodegeneration-as measured by mini-mental state examination (MMSE) score-in patients with AD. Multiple regression analyses showed that the homozygous GM 5/5 genotype, preserved right hippocampus, and right insula thickness were associated with higher MMSE scores (p < 0.001), whereas the opposite pattern and GM 5/21 genotype were associated with worse clinical profiles. Influence of GM 5/21-expressing IgG3 antibodies on the ADCC of HSV1-infected neurons could, at least partially, explain these results.

Immunoglobulin genes and severity of COVID-19.

There is tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection, suggesting the involvement of host genetic factors. Here, we investigated whether IgG allotypes GM (γ marker) 3 and GM 17, genetic markers of IgG1, contributed to the severity of COVID-19. IgG1 plays a pivotal role in response against SARS-CoV-2 infection. We also investigated whether these GM alleles synergistically/epistatically with IGHG3 and FCGR2A alleles-which have been previously implicated in COVID-19-modulated the extent of COVID-19 severity. The study population consisted of 316 COVID-19 patients who needed treatment in the intensive care unit of Hospital Universitario Central de Asturias. All individuals were genotyped for GM 3/17, IGHG3 hinge length, and FCGR2A rs1801274 A/G polymorphisms. Among the 316 critical patients, there were 86 deaths. The risk of death among critical patients was significantly higher in subjects with GM 17 (IgG1) and short hinge length (IgG3). GM 17-carriers were at almost three-fold higher risk of death than non-carriers (p < 0.001; OR = 2.86, CI 1.58-5.16). Subjects with short hinge length of IgG3 had a two-fold higher risk of death than those with medium hinge length (p = 0.01; OR = 2.16, CI 1.19-3.90). GM 3/3 and IGHG3 (MM) genotypes were less frequent among death vs. survivors (9% vs 36%, p < 0.001) and associated with protective effect (OR = 0.18, 95% CI = 0.08-0.39). This is the first report implicating IgG1 allotypes in COVID-19-spurred death. It needs to be replicated in an independent study population.

Immunoglobulin γ chain allotypes and humoral immunity to HSV1 in Parkinson's disease.

The aim of this investigation was to determine if particular immunoglobulin GM (γ marker) alleles and genotypes were associated with Parkinson's disease (PD) and whether they contributed to the interindividual differences in the level of antibodies to herpes simplex virus type 1 (HSV1), which has been implicated in PD pathology. Using a case-control study design, 94 PD patients and 157 controls were characterized for anti-HSV1 IgG antibodies and genotyped for GM alleles expressed on IgG1 (3,17) and IgG2 (23 +, 23-). The homozygosity for the GM 3 and GM 23 alleles was significantly associated with susceptibility to PD (p = 0.004, 0.018, respectively). Also, GM 23 genotypes were significantly associated with anti-HSV1 IgG antibody levels in patients (p = 0.0021), but not in controls. These results suggest that GM genes may act as effect modifiers of the reported HSV1-PD association.

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.

Concerted variation of the 3' regulatory region of Ig heavy chain and Gm haplotypes across human continental populations.

OBJECTIVES: The 3' regulatory region of the immunoglobulin heavy chain gene (IGH) includes the HS1.2 enhancer displaying length polymorphism with four known variants. The goal of the research was to provide an overview of this variability and of its evolutionary significance across human populations. MATERIALS AND METHODS: We compiled published and original data on HS1.2 polymorphism in 3,100 subjects from 26 human populations. Moreover, we imputed the haplotypic arrangement of the HS1.2 region in the 1000 Genomes Project (1KGP). In this dataset, imputation could also be obtained for the G1m-G3m allotype by virtue of the precise correspondence between serological types and amino acid (and DNA) substitutions in IGHG1 and IGHG3. RESULTS: HS1.2 variant frequencies displayed similar patterns of continental partitioning as those reported in the literature for the physically neighboring IGHG1-IGHG3 system. The 1KGP data revealed that linkage disequilibrium (LD) can explain the spread of joint HS1.2-IGHG1-IGHG3 associations across continents and within continental populations, with stronger LD out of Africa and the features of an evolutionarily stable genomic block with differential expression in lymphoblastoid cell lines. DISCUSSION: Strong population structuring involves at least the entire 70 kb genomic region here considered, due to the tight LD which maintained HS1.2, IGHG1, and IGHG3 in nonrandom arrangements. This might be key to better understand the evolutionary path of the entire genomic region driven by immune response capabilities, during the formation of continental gene pools.

The immunoglobulin γ marker 17 allotype and KIR/HLA genes prevent the development of chronic hepatitis B in humans.

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004-0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA-A-Bw4 and HLA-C2 was highly sensitive to predict the outcome of HBV infection.

Immunoglobulin Genes and Immunity to HSV1 in Alzheimer's Disease.

Although genome-wide association studies (GWAS) of late-onset Alzheimer's disease (AD) have identified numerous genes that influence the risk for disease, the majority of the genetic variance of AD remains uncharacterized. Furthermore, current GWAS, despite their name, do not evaluate all genes in the human genome. One such gene complex is immunoglobulin GM (γ marker) genes on chromosome 14. GM genes are excellent candidate genes for AD because they influence immunity to herpes simplex virus type 1 (HSV1), which has been implicated in AD pathology by an increasing number of reports. The aim of this investigation was to determine if particular GM genotypes were associated with AD and mild cognitive impairment (MCI), and whether they contributed to the interindividual differences in the level of anti-HSV1 IgG antibodies. A total of 141 HSV1 seropositive individuals-56 AD patients, 48 MCI individuals, and 37 sex- and age-matched healthy controls-were characterized for GM alleles 3, 17, and 23. The homozygosity for the GM 3 allele was significantly associated with MCI (p = 0.025). GM 3/17 heterozygous AD patients had significantly higher levels of anti-HSV1 antibodies than the healthy controls expressing the same genotype (p = 0.0004). Among MCI subjects, the GM 3/17 genotype was associated with significantly higher level of anti-HSV1 antibodies as compared to the GM 17/17 homozygous genotype (pc = 0.040). Among AD patients, the GM 23+/-genotype was significantly associated with anti-HSV1 antibody responses (pc = 0.025). These results suggest that GM genes could act as potential unifiers of the genetic and viral etiology of AD.

Unveiling the Diversity of Immunoglobulin Heavy Constant Gamma (IGHG) Gene Segments in Brazilian Populations Reveals 28 Novel Alleles and Evidence of Gene Conversion and Natural Selection.

Even though immunoglobulins are critical for immune responses and human survival, the diversity of the immunoglobulin heavy chain gene (IGH) is poorly known and mostly characterized only by serological methods. Moreover, this genomic region is not well-covered in genomic databases and genome-wide association studies due to particularities that impose technical difficulties for its analysis. Therefore, the IGH gene has never been systematically sequenced across populations. Here, we deliver an unprecedented and comprehensive characterization of the diversity of the IGHG1, IGHG2, and IGHG3 gene segments, which encode the constant region of the most abundant circulating immunoglobulins: IgG1, IgG2, and IgG3, respectively. We used Sanger sequencing to analyze 357 individuals from seven different Brazilian populations, including five Amerindian, one Japanese-descendant and one Euro-descendant population samples. We discovered 28 novel IGHG alleles and provided evidence that some of them may have been originated by gene conversion between common alleles of different gene segments. The rate of synonymous substitutions was significantly higher than the rate of the non-synonymous substitutions for IGHG1 and IGHG2 (p = 0.01 and 0.03, respectively), consistent with purifying selection. Fay and Wu's test showed significant negative values for most populations (p < 0.001), which indicates that positive selection in an adjacent position may be shaping IGHG variation by hitchhiking of variants in the vicinity, possibly the regions that encode the Ig variable regions. This study shows that the variation in the IGH gene is largely underestimated. Therefore, exploring its nucleotide diversity in populations may provide valuable information for comprehension of its evolution, its impact on diseases and vaccine research.

IGHG, IGKC, and FCGR genes and endogenous antibody responses to GARP in patients with breast cancer and matched controls.

Glycoprotein-A repetitions predominant (GARP) is a transmembrane protein that is highly expressed in breast cancer. Its overexpression correlates with worse survival, and antibodies to GARP appear to play a protective role in a mouse model. No large-scale studies of immunity to GARP in humans have yet been undertaken. In this investigation, using a large multiethnic cohort (1738 subjects), we aimed to determine whether the magnitude of anti-GARP antibody responsiveness was significantly different in patients with breast cancer from that in matched healthy controls. We also investigated whether the allelic variation at the immunoglobulin GM (γ marker), KM (κ marker), and Fcγ receptor (FcγR) loci contributed to the interindividual variability in anti-GARP IgG antibody levels. A combined analysis of all subjects showed that levels of anti-GARP antibodies were significantly higher in patients with breast cancer than in healthy controls (mean ±â€¯SD: 7.4 ±â€¯3.5 vs. 6.9 ±â€¯3.5 absorbance units per mL (AU/µL), p < 0.0001). In the two populations with the largest sample size, the probability of breast cancer generally increases as anti-GARP antibody levels increase. Several significant individual and epistatic effects of GM, KM, and FcγR genotypes on anti-GARP antibody responsiveness were noted in both patients and controls. These results, if confirmed by independent investigations, will aid in devising personalized GARP-based immunotherapeutic strategies against breast cancer and other GARP-overexpressing malignancies.

Immunoglobulin genotypes and cognitive functions in schizophrenia.

Exposure to neurotropic viruses, such as herpes simplex virus type 1 and human cytomegalovirus, has been reported to be associated with cognitive impairment in schizophrenia. These viruses have evolved highly sophisticated strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. Particular immunoglobulin GM (γ marker) genotypes modulate these viral immunoevasion strategies, influence antibody responsiveness to viral proteins, and are also associated with susceptibility to schizophrenia, providing an excellent rationale for determining their possible involvement in the cognitive functions in this highly heritable neurodevelopmental disorder. In this investigation, we assessed the cognitive functions (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive function) in 145 patients with schizophrenia and characterized their DNA for several GM and KM (κ marker) alleles. Particular KM and GM genotypes were significantly associated with verbal memory and attention and processing speed scores, respectively (P = 0.01 and 0.001). Epistatic effects of GM and KM genotypes on attention and processing speed, verbal fluency, and motor speed were also noted (P = 0.031, 0.047, 0.003). These results, for the first time, show that hitherto understudied immunoglobulin GM and KM genotypes-individually and epistatically-contribute to the magnitude of interindividual variability in the cognitive functions in patients with schizophrenia. Additional studies involving these highly polymorphic genes of the immune system are needed.

Human Immunoglobulin Heavy Gamma Chain Polymorphisms: Molecular Confirmation Of Proteomic Assessment.

Immunoglobulin G (IgG) proteins are known for the huge diversity of the variable domains of their heavy and light chains, aimed at protecting each individual against foreign antigens. The IgG also harbor specific polymorphism concentrated in the CH2 and CH3-CHS constant regions located on the Fc fragment of their heavy chains. But this individual particularity relies only on a few amino acids among which some could make accurate sequence determination a challenge for mass spectrometry-based techniques.The purpose of the study was to bring a molecular validation of proteomic results by the sequencing of encoding DNA fragments. It was performed using ten individual samples (DNA and sera) selected on the basis of their Gm (gamma marker) allotype polymorphism in order to cover the main immunoglobulin heavy gamma (IGHG) gene diversity. Gm allotypes, reflecting part of this diversity, were determined by a serological method. On its side, the IGH locus comprises four functional IGHG genes totalizing 34 alleles and encoding the four IgG subclasses. The genomic study focused on the nucleotide polymorphism of the CH2 and CH3-CHS exons and of the intron. Despite strong sequence identity, four pairs of specific gene amplification primers could be designed. Additional primers were identified to perform the subsequent sequencing. The nucleotide sequences obtained were first assigned to a specific IGHG gene, and then IGHG alleles were deduced using a home-made decision tree reading of the nucleotide sequences. IGHG amino acid (AA) alleles were determined by mass spectrometry. Identical results were found at 95% between alleles identified by proteomics and those deduced from genomics. These results validate the proteomic approach which could be used for diagnostic purposes, namely for a mother-and-child differential IGHG detection in a context of suspicion of congenital 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.

Human Allergen-Specific IgG Subclass Antibodies Measured Using ImmunoCAP Technology.

BACKGROUND: Knowledge of human IgG subclass antibody responses to various allergens has been hampered by a lack of reliable standardized assays. The aim here was to develop quantitative immunoassays for human IgG1, IgG2, and IgG3 antibodies using ImmunoCAP® technology and to evaluate their application. METHODS: Enzyme conjugates with isotype-specific monoclonal antibodies and calibrators composed of purified myeloma paraproteins were developed for each assay and used together with other standardized assay reagents for the Phadia® 100 instrument. The calibrators were adjusted to the international reference preparation IRP 67/86. The assays were characterized and used together with other standard ImmunoCAP assays to measure antibodies to various allergens in preliminary studies. RESULTS: The new assays had limits of quantitation of 1.0 (IgG1), 4.6 (IgG2), and 0.04 mgA/L (IgG3), and coefficients of variation of <20%. Only some minor cross-reactivity with IgG2 was observed for the specific IgG1 assay. The specific IgG2 assay showed a bias for the allotype G2m(23) and compensation factors were used to adjust the measured concentrations accordingly. Preliminary studies indicated a strong and stable IgG4 antibody response to ß-lactoglobulin in healthy individuals, a high IgG1 and even higher IgG2 antibody response to house dust mite in sensitized and nonsensitized subjects, and a mixed IgG subclass response to venom allergens in allergic patients with increasing IgG4 antibody levels during venom immunotherapy. CONCLUSIONS: The new research assays are valuable tools for immunological studies, enabling the characterization of antibody profiles using a standardized approach, and facilitating data interpretation and the comparison of results across studies.

Genetic markers of immunoglobulin G and immunity to cytomegalovirus in patients with breast cancer.

Human cytomegalovirus (CMV), a ubiquitous herpesvirus, has been implicated in the etiology of breast cancer. It is clear that not all people exposed to CMV are equally likely to develop this malignancy, implying the presence of host genetic factors that might modulate the cancer-spurring properties of the virus. CMV has evolved sophisticated strategies for evading host immunosurveillance. One strategy involves encoding decoy Fcγ receptors (FcγR) that thwart the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity. In this investigation, using an enzyme-linked immunosorbent assay (ELISA), we aimed to determine whether the decoy FcγR encoded by the CMV gene RL13 binds differentially to anti-CMV antibodies expressing different immunoglobulin GM (γ marker) allotypes, genetic markers of immunoglobulin G (IgG). Results of our ELISA binding studies showed that the absorbance values for the binding of the viral FcγR to the GM 17-expressing IgG antibodies were significantly higher than for the GM 3-expressing antibodies (0.60 vs. 0.36; p=0.0019). These findings provide mechanistic insights into the modulating role played by the genetic variants of IgG in the generation of immunity to CMV in patients with breast cancer.

Immunoglobulin G genotypes and the risk of schizophrenia.

Genes of the immune system are relevant to the etiology of schizophrenia. However, to our knowledge, no large-scale studies, using molecular methods, have been undertaken to investigate the role of highly polymorphic immunoglobulin GM (γ marker) genes in this disorder. In this investigation, we aimed to determine whether particular GM genotypes were associated with susceptibility to schizophrenia. Using a matched case-control study design, we analyzed DNA samples from 798 subjects-398 patients with schizophrenia and 400 controls-obtained from the U.S. National Institute of Mental Health Repository. GM alleles were determined by the TaqMan(®) genotyping assay. The GM 3/3; 23-/23- genotype was highly significantly associated with susceptibility to schizophrenia (p = 0.0002). Subjects with this genotype were over three times (OR 3.4; 95 % CI 1.7-6.7) as likely to develop schizophrenia as those without this genotype. Our results show that immunoglobulin GM genes are risk factors for the development of schizophrenia. Since GM alleles have been implicated in gluten sensitivity and in immunity to neurotropic viruses associated with cognitive impairment, the results presented here may help unify these two disparate areas of pathology affected in this disorder.

A comparison of the ability of the human IgG1 allotypes G1m3 and G1m1,17 to stimulate T-cell responses from allotype matched and mismatched donors.

The immunogenicity of clinically administered antibodies has clinical implications for the patients receiving them, ranging from mild consequences, such as increased clearance of the drug from the circulation, to life-threatening effects. The emergence of methods to engineer variable regions resulting in the generation of humanised and fully human antibodies as therapeutics has reduced the potential for adverse immunogenicity. However, due to differences in sequence referred to as allotypic variation, antibody constant regions are not homogeneous within the human population, even within sub-classes of the same immunoglobulin isotype. For therapeutically administered antibodies, the potential exists for an immune response from the patient to the antibody if the allotype of patient and antibody do not match. Allotypic distribution in the human population varies within and across ethnic groups making the choice of allotype for a therapeutic antibody difficult. This study investigated the potential of human IgG1 allotypes to stimulate responses in human CD4(+) T cells from donors matched for homologous and heterologous IgG1 allotypes. Allotypic variants of the therapeutic monoclonal antibody trastuzumab were administered to genetically defined allotypic matched and mismatched donor T cells. No significant responses were observed in the mismatched T cells. To investigate the lack of T-cell responses in relation to mismatched allotypes, HLA-DR agretopes were identified via MHC associated peptide proteomics (MAPPs). As expected, many HLA-DR restricted peptides were presented. However, there were no peptides presented from the sequence regions containing the allotypic variations. Taken together, the results from the T-cell assay and MAPPs assay indicate that the allotypic differences in human IgG1 do not represent a significant risk for induction of immunogenicity.

The decoy Fcγ receptor encoded by the cytomegalovirus UL119-UL118 gene has differential affinity to IgG proteins expressing different GM allotypes.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in many diseases. However, there is significant divergence between HCMV seroprevalence and the prevalence of HCMV-associated diseases, implying the presence of host genetic factors that might modulate immunity to this virus. HCMV deploys many sophisticated strategies to evade host immunosurveillance. One strategy involves encoding for proteins that have functional properties of the Fcγ receptor (FcγR). The aim of the present investigation was to determine whether the UL119-UL118-encoded recombinant FcγR ectodomain binds differentially to genetically disparate IgG1 proteins. Results show that mean absorbance values for binding of HCMV UL119-UL118-encoded Fcγ receptor to the immunoglobulin GM (γ marker) 1,17-expressing IgG1 were significantly higher than to the IgG1 expressing the allelic GM 3 allotype (0.225 vs. 0.151; p=0.039). These findings suggest possible mechanisms underlying the maintenance of immunoglobulin GM gene polymorphism and its putative role in the etiology of HCMV-associated diseases.

Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics.

PURPOSE OF REVIEW: This article will review the genetic evidence implicating ERAP1, which encodes the endoplasmic reticulum-associated amino-peptidase 1, in susceptibility to rheumatic disease. RECENT FINDINGS: Genetic variants and haplotypes of ERAP1 are associated with AS, psoriasis, and Behçet's disease in people of varying ancestries. In each of these diseases, disease-associated variants of ERAP1 have been shown to interact with disease-associated class I human leukocyte antigen alleles to influence disease risk. Functionally, disease-associated missense variants of ERAP1 concertedly alter ERAP1 enzymatic function, both quantitatively and qualitatively, whereas other disease-associated variants influence ERAP1 expression. Therefore, ERAP1 haplotypes (or allotypes) should be examined as functional units. Biologically, this amounts to an examination of the gene regulation and function of the protein encoded by each allotype. Genetically, the relationship between disease risk and ERAP1 allotypes should be examined to determine whether allotypes or individual variants produce the most parsimonious risk models. SUMMARY: Future investigations of ERAP1 should focus on comprehensively characterizing naturally occurring ERAP1 allotypes, examining the enzymatic function and gene expression of each allotype, and identifying specific allotypes that influence disease susceptibility.

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.