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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.

Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.

Heritable polymorphisms within the human IgG locus, collectively termed allotypes, have often been linked by statistical associations, but rarely mechanistically, to a wide range of disease states. One potential explanation for these associations is that IgG allotype alters host cell receptors’ affinity for IgG, dampening or enhancing an immune response depending on the nature of the change and the receptors. In this work, a panel of allotypic antibody variants were evaluated using multiplexed, label-free biophysical methods and cell-based functional assays to determine what effect, if any, human IgG polymorphisms have on antibody function. While we observed several differences in FcγR affinity among allotypes, there was little evidence of dramatically altered FcγR-based effector function or antigen recognition activity associated with this aspect of genetic variability.

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.

Vaccinations have had a transformative impact on public health, reducing the incidence of many infectious diseases and increasing survival. However, there remains uncertainty about the potential of vaccines to trigger autoimmune diseases such as the idiopathic inflammatory myopathies (IIM). Myositis after vaccination (MAV) is a rare clinical entity, but given immunogenetic associations with other adverse events, we explored genetic risk factors, particularly human leukocyte antigen (HLA) alleles and GM/KM immunoglobulin allotypes, that may predispose individuals to develop MAV. We examined clinical characteristics, vaccination history, autoantibodies, HLA alleles and GM/KM allotypes from 56 patients who developed MAV, 133 myositis cases with no documented vaccination within 6 months of onset (non-MAV), and 527 healthy controls from the pre-COVID-19 era. Genotyping for HLA and GM/KM allotypes was performed by standard assays. Differences in allele frequencies in race-matched groups were evaluated using chi-square tests, odds ratios (OR) and 95% confidence intervals (CI). Multivariate logistic regression adjusted for age, sex, and vaccination type. Statistical significance was defined as a Holms corrected p-value of less than 0.05. No clinical or serologic differences were found between MAV and non-MAV patients. However, the HLA-DQA1*03:03 allele was a unique risk factor for MAV in Caucasians (OR=3.87, 95% CI=1.56-9.54, p=0.002), while the known myositis risk factor, HLA-DRB1*03:01, was a protective factor for MAV (OR=0.41, 95% CI=0,18-0.94, p= 0.033). GM2, GM13, and KM1 allotypes were more frequently observed in MAV patients than healthy controls, and other HLA alleles were risk or protective factors for specific vaccines given in patients who developed MAV. Immunogenetic factors may influence the likelihood of developing MAV. Further studies of larger, deeply phenotyped populations are needed to confirm these associations and could inform personalized risk assessments and targeted interventions, thereby enhancing vaccine safety.

Mass spectrometry (MS) analysis for detection of immunoglobulins (IG) of the human IgG3 subclass is described that relies on polymorphic amino acids of the heavy gamma3 chains. IgG3 is the most polymorphic human IgG subclass with thirteen G3m allotypes located on the constant CH2 and CH3 domains of the gamma3 chain, the combination of which leads to six major G3m alleles. Amino acid changes resulting of extensive sequencing previously led to the definition of 19 IGHG3 alleles that have been correlated to the G3m alleles. As a proof of concept, MS proteotypic peptides were defined which encompass discriminatory amino acids for the identification of the G3m and IGHG3 alleles. Plasma samples originating from ten individuals either homozygous or heterozygous for different G3m alleles, and including one mother and her baby (drawn sequentially from birth to 9 months of age), were analyzed. Total IgG3 were purified using affinity chromatography and then digested by a combination of AspN and trypsin proteases, and peptides of interest were detected by mass spectrometry. The sensitivity of the method was assessed by mixing variable amounts of two plasma samples bearing distinct G3m allotypes. A label-free approach using the high-performance liquid chromatography (HPLC) retention time of peptides and their MS mass analyzer peak intensity gave semi-quantitative information. Quantification was realized by selected reaction monitoring (SRM) using synthetic peptides as internal standards. The possibility offered by this new methodology to detect and quantify neo-synthesized IgG in newborns will improve knowledge on the first acquisition of antibodies in infants and constitutes a promising diagnostic tool for vertically-transmitted diseases.

Immunoglobulin G (IgG) antibodies are a critical component of the adaptive immune system, binding to and neutralizing pathogens and other foreign substances. Recent advances in molecular antibody biology and structural protein engineering enabled the modification of IgG antibodies to enhance their therapeutic potential. This review summarizes recent progress in both natural and engineered structural modifications of IgG antibodies, including allotypic variation, glycosylation, Fc engineering, and Fc gamma receptor binding optimization. We discuss the functional consequences of these modifications to highlight their potential for therapeutical applications.

Of the five immunoglobulin isotypes, immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3, and IgG4, which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptors (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or antibody-dependent cell-mediated cytotoxicity, and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function will be the focus of the current review.

Since the outbreak of novel coronavirus pneumonia (COVID-19), numerous T-cell epitopes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteome have been reported. However, most of the identified CD8 + T-cell epitopes have been restricted primarily by HLA-A allotypes. The epitopes restricted by HLA-B and HLA-C allotypes are limited. This study focuses on the screening of T-cell epitopes restricted by 13 prevalent HLA-B and 13 prevalent HLA-C allotypes, which cover over 70% and 90% of the Chinese and Northeast Asian populations, respectively. Totally, 67 HLA-B restricted and 53 HLA-C restricted epitopes were validated as immunogenic epitopes with a herd predominance rate by peptide-PBMCs ex vivo coculture experiments using the PBMCs from convalescent Chinese cohort. In addition, 26 transfected cell lines expressing indicated HLA-B or HLA-C allotype were established, and used in the competitive peptide binding assays to define the affinities and cross-restriction of each validated epitope binding to HLA-B or HLA-C allotypes. These data will facilitate the design of T-cell-directed vaccines and SARS-CoV-2-specific T-cell detection tools tailored to the Northeast Asian population. The herd test of functionally validated T-cell epitopes, and the competitive peptide binding assay onto cell line array expressing prevalent HLA allotypes may serve as an additional criterion for selecting T-cell epitopes used in vaccine.