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.

An Ig γ Marker Genotype Is a Strong Risk Factor for Alzheimer Disease, Independent of Apolipoprotein E ε4 Genotype.

Increasing evidence implicates HSV type 1 (HSV1) in the pathogenesis of late-onset Alzheimer disease (AD). HSV1 has evolved highly sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR), which blocks Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity. Ig γ marker (GM) allotypes, encoded by highly polymorphic IGHG genes on chromosome 14q32, modulate this immunoevasion strategy, and thus may act as effect modifiers of the HSV1-AD association. In this nested case-control human study, 365 closely matched case-control pairs-whose blood was drawn on average 9.6 y before AD diagnosis-were typed for GM alleles by a TaqMan genotyping assay. APOE genotype and a genetic risk score based on nine additional previously known AD risk genes (ABCA7, BIN1, CD33, CLU, CR1, EPHA1, MS4A4E, NECTIN2, and PICALM) were extracted from a genome-wide association study analysis. Antiviral Abs were measured by ELISA. Conditional logistic regression models were applied. The distribution of GM 3/17 genotypes differed significantly between AD cases and controls, with higher frequency of GM 17/17 homozygotes in AD cases as compared with controls (19.8 versus 10.7%, p = 0.001). The GM 17/17 genotype was associated with a 4-fold increased risk of AD (odds ratio 4.142, p < 0.001). In conclusion, the results of this study demonstrate that Ig GM 17/17 genotype contributes to the risk of later AD development, independent of apolipoprotein ε4 genotype and other AD risk genes, and explain, at least in part, why every HSV1-infected person is not equally likely to develop HSV1-associated AD.

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.

Relation between FCGRIIB rs1050501 and HSV-1 specific IgG antibodies in Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by extracellular plaques, intracellular neurofibrillary tangles and neuronal loss in the central nervous system (CNS). Pathogens are suspected to have a role in the development of AD; herpes simplex virus type 1 (HSV-1), in particular, is suggested to be a risk factor for the disease. The gamma receptor for the Fc portion of IgG molecules (FCGRs) plays a crucial role in regulating immune responses, and among FCGRs, FCGRIIB is endowed with an inhibitory function. Notably, the rs1050501 polymorphism of FCGRIIB gene associates with autoimmune diseases and with neuronal uptake and interneuronal accumulation of amyloid beta in animal AD models. METHODS: Genotype and allelic distribution of ApoE4 and FCGRIIB rs1050501 were evaluated in a case-control population of 225 AD patients, 93 MCI individuals and 201 sex and age matched healthy controls (HC). HSV-1 total IgG titers and IgG subclasses were detected and quantified in a subgroup of the main study population by ELISA. RESULTS: Genotype and allelic distribution of FCGRIIB was comparable in the study population. HSV-1-specific antibody titers were significantly higher in AD and MCI compared to HC (p < 0.01 for both); IgG3 titers, in particular, were increased in MCI compared to AD (p = 0.04). Analyses of possible correlations between the FCGRIIB rs1050501 genotype polymorphism and IgG subclasses showed that the presence of IgG3 was more frequent in MCI carrying the FCGRIIB TT (94.1%) compared to those carrying the CT genotype (63.6%) (p = 0.03). CONCLUSION: Results herein show an association between humoral immune response against HSV-1 and FCGRIIB rs1050501 genetic variation in the first stage of the disease.

Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing.

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity.

Association between γ marker, human leucocyte antigens and killer immunoglobulin-like receptors and the natural course of human cytomegalovirus infection: a pilot study performed in a Sicilian population.

Natural killer (NK) cells provide a major defence against human cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leucocyte antigen (HLA) class I molecules. Also γ marker (GM) allotypes, able to influence the NK antibody-dependent cell-mediated cytotoxicity, appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim of gaining insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK responses, and HCMV infections. In a previous study we assessed whether the KIR and HLA repertoire might influence the risk of developing symptomatic (n = 60) or asymptomatic (n = 60) disease after primary HCMV infection in the immunocompetent host. In the present study, the immunocompetent patients with primary symptomatic HCMV infection were genotyped for GM3/17 and GM23 allotypes, along with the 60 participants with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that individuals carrying the GM23 allotypes, both homozygous and heterozygous, GM17/17, HLA-C2 and Bw4T KIR-ligand groups are associated with the risk of developing symptomatic infection. Our findings on the role of both cellular and humoral immunity in the control of HCMV infection should be of value in guiding efforts to reduce HCMV-associated health complications in the elderly, including immunosenescence, and in transplantation.

Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.

BACKGROUND: VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor. METHODS AND FINDINGS: This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21-50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 µg/mL (n = 7) and 326 ± 35 µg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 µg/mL (n = 2) and 25 ± 5 µg/mL (n = 9), respectively. Over the 5-40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions. CONCLUSIONS: The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT02599896.

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.

Association of immunoglobulin GM allotypes with longevity in long-living individuals from Southern Italy.

BACKGROUND: The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity. The role played by immunoglobulin allotypes in the control of immune responses is well known as well as the role of an efficient immune response in longevity achievement. So, it is conceivable that particular GM allotypes may contribute to the generation of an efficient immune response that supports successful ageing, hence longevity. METHODS: In order to show if GM allotypes play a role in the achievement of longevity, we typed the DNA of 95 Long-living individuals (LLIs) and 96 young control individuals (YCs) from South Italy for GM3/17 and GM23+/- alleles. RESULTS: To demonstrate the role of GM allotypes in the attainment of longevity we compared genotype and allele frequencies of GM allotypes between LLIs and YCs. A global chi-square test (3 × 2) shows that the distribution of genotypes at the GM 3/17 locus is highly significantly different in LLIs from that observed in YCs (p < 0.0001). The 2 × 2 chi-square test shows that the carriers of the GM3 allele contribute to this highly significant difference. Accordingly, GM3 allele is significantly overrepresented in LLIs. No significant differences were instead observed regarding GM23 allele. CONCLUSION: These preliminary results show that GM3 allotype is significantly overrepresented in LLIs. To best of our knowledge, this is the first study performed to assess the role of GM allotypes in longevity. So, it should be necessary to verify the data in a larger sample of individuals to confirm GM role in the attainment of longevity.

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.

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation.

HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A-C (encoded by FCGR3A and FCGR2A-C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell-mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1-infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1-infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2C(bright)NKG2A(-)CD57(+)FcRγ(-)), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell-Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.

Humoral Immunity to Cytomegalovirus Glycoprotein B in Patients With Breast Cancer and Matched Controls: Contribution of Immunoglobulin γ, κ, and Fcγ Receptor Genes.

Increasing evidence implicates human cytomegalovirus (HCMV) in the etiopathogenesis of breast cancer. Antibodies to this virus in patients with breast cancer have been reported, but no large-scale studies have been conducted to determine whether the antibody levels differ between patients and matched controls. Using specimens from a large (1712 subjects) multiethnic case-control study, we aimed to determine whether the levels of antibodies to the HCMV glycoprotein B (gB) differed between patients and controls and whether they were associated with particular immunoglobulin γ marker (GM), κ marker (KM), and Fcγ receptor (FcγR) genotypes. A combined analysis showed that anti-gB immunoglobulin G antibody levels were higher in healthy controls than in patients (P < .0001). Stratified analyses showed population-specific differences in the magnitude of anti-gB antibody responsiveness and in the contribution of particular GM, KM, and FcγR genotypes to these responses. These findings may have implications for HCMV-based immunotherapy against breast cancer and other HCMV-associated diseases.

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.

Kynurenine and Tryptophan Levels in Patients With Schizophrenia and Elevated Antigliadin Immunoglobulin G Antibodies.

OBJECTIVE: Several studies have reported an association between nonceliac gluten sensitivity and schizophrenia. Immune and kynurenine (KYN) pathways have also been implicated in the pathophysiology of schizophrenia, and certain proinflammatory immune mediators may increase KYN and reduce tryptophan (TRP) levels. METHODS: We measured serum antigliadin immunoglobulin G (IgG), KYN, and TRP in 950 patients with schizophrenia. Patients with antibody level at the 90th percentile or higher of control participants (21.9% of all patients) were classified as having elevated antigliadin IgG. Independent t tests and linear regression models were used to compare TRP, KYN, and KYN-TRP ratio (indicator of TRP metabolism) between patients with and those without elevated antigliadin IgG. The correlation between antigliadin IgG and TRP, KYN, and the ratio was also evaluated in the patients. RESULTS: KYN and KYN-TRP ratio were higher in patients with elevated antigliadin IgG (geometric mean [standard deviation {SD}] = 2.65 [0.25] µmol/L versus 2.25 [0.23] µmol/L [p < .001] and 0.05 [0.26] versus 0.04 [0.25; p = .001] respectively), findings robust to adjustment for potential demographic and clinical confounders. Antigliadin IgG positively correlated with KYN and KYN-TRP ratio (r = 0.12, p < .001; r = 0.11, p = .002). TRP did not differ between the two groups and did not correlate with antigliadin IgG. CONCLUSIONS: Our results connect nonceliac gluten sensitivity with the KYN pathway of TRP metabolism in psychotic illness and hint toward potential individualized treatment targets.

Immunoglobulin genes influence the magnitude of humoral immunity to cytomegalovirus glycoprotein B.

Human cytomegalovirus (HCMV) is a risk factor for many human diseases, but among exposed individuals, not everyone is equally likely to develop HCMV-spurred diseases, implying the presence of host genetic factors that might modulate immunity to this virus. Here, we show that antibody responsiveness to HCMV glycoprotein B (gB) is significantly associated with particular immunoglobulin GM (γ marker) genotypes. Anti-HCMV gB antibody levels were highest in GM 17/17 homozygotes, intermediate in GM 3/17 heterozygotes, and lowest in GM 3/3 homozygotes (28.2, 19.0, and 8.1 µg/mL, respectively; P=.014). These findings provide mechanistic insights in the etiopathogenesis of HCMV-spurred diseases.