Urbanization processes drive divergence at the major histocompatibility complex in a common waterbird

Urban sprawl is one of the most common landscape alterations occurring worldwide, and there is a growing list of species that are recognised to have adapted to urban life. To be successful, processes of urban colonization by wildlife require a broad spectrum of phenotypic (e.g., behavioural or physiological) adjustments, but evidence for genetic adaptations is much scarcer. One hypothesis proposes that different pathogen-driven selective pressures between urban and non-urban landscapes leads to adaptations in host immune genes. Here, we examined urbanization-related differentiation at the key pathogen-recognition genes of vertebrate adaptive immunity-the major histocompatibility complex (MHC)-in a common waterbird, the Eurasian coot (Fulica atra). Samples were collected from an old urban population (established before the 1950s), a new urban population (established in the 2000s), and two rural populations from central Poland. We found strong significant divergence (as measured with Jost’s D) at the MHC class II between the old urban population and the remaining (new urban and rural) populations. Also, there was a moderate, but significant divergence at the MHC between the new urban population and two rural populations, while no divergence was found between the two rural populations. The total number of MHC alleles and the number of private (population-specific) MHC alleles was lower in old urban populations, as compared to the rural ones. These patterns of differentiation at the MHC were not consistent with patterns found for neutral genetic markers (microsatellites), which showed few differences between the populations. Our results indicate that MHC allele composition depended on the level of anthropogenic disturbance and the time which passed since urban colonization, possibly due to the processes of genotype sorting and local adaptation. As such, our study contributes to the understanding of genetic mechanisms associated with urbanization processes in wildlife.

No evidence that HLA genotype influences the driver mutations that occur in cancer patients

The major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumor. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

Diversity of MHC IIB genes and parasitism in hybrids of evolutionarily divergent cyprinoid species indicate heterosis advantage

The genes of the major histocompatibility complex (MHC) are an essential component of the vertebrate immune system and MHC genotypes may determine individual susceptibility to parasite infection. In the wild, selection that favors MHC variability can create situations in which interspecies hybrids experience a survival advantage. In a wild system of two naturally hybridizing leuciscid fish, we assessed MHC IIB genetic variability and its potential relationships to hosts’ ectoparasite communities. High proportions of MHC alleles and parasites were species-specific. Strong positive selection at specific MHC codons was detected in both species and hybrids. MHC allele expression in hybrids was slightly biased towards the maternal species. Controlling for a strong seasonal effect on parasite communities, we found no clear associations between host-specific parasites and MHC alleles or MHC supertypes. Hybrids shared more MHC alleles with the more MHC-diverse parental species, but expressed intermediate numbers of MHC alleles and positively selected sites. Hybrids carried significantly fewer ectoparasites than either parent species, suggesting a hybrid advantage via potential heterosis.

Immunopathogenesis and Immunotherapeutic Strategies in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a systemic autoimmune disease which results from failure of immune tolerance. Autoantibodies like Rheumatoid factor, Anti-Carbamylated Antibodies, Anti-Acetylated and Anti- Citrullinated Protein Antibodies keep on circulating in blood which target self-tissues. The major symptoms of RA are polyarticular inflammation of the synovial membrane, wrists and feet along with the joint tenderness and formation of nodules in the joints. There are many MHC alleles as well as non-MHC immunoregulatory genes which confer the genetic risk in Rheumatoid Arthritis. Immunotherapeutic strategies involved are dendritic cell targeted therapeutics, cell-based therapy and autoantibody-mediated refractoriness. The increase in the mortality rate of RA is recognized widely but different aspects of immunopathogenesis are not explained fully. The aim of the review article is to discuss all the factors that can contribute towards the immunopathogenesis of this disease and to screen out the most prominent immunotherapeutic strategies.

O-118 New insight into the genetic contribution of common variants to the development of extreme phenotypes of unexplained male infertility: a multicenter genome-wide association study

Study question What is the contribution of the common genetic variation to the development of unexplained male infertility due to severe spermatogenic failure (SPGF)? Summary answer Genetic polymorphisms of key immune and spermatogenesis loci are involved in the etiology of the most severe SPGF cases, defined by Sertoli cell-only (SCO) phenotype. What is known already Male infertility is a rising worldwide concern that affects millions of couples. Non-obstructive azoospermia (NOA) and severe oligospermia (SO) are two extreme manifestations characterized by SPGF. A genetic cause can be established in only around 20% of affected men, with the remaining cases being classified as otherwise unexplained. To date, the genome-wide association study (GWAS) strategy, although already successfully applied in several other complex traits and diseases, was less fruitful in studies that attempted to decipher the genetic component of unexplained SPGF, mainly due to both a lack of well-powered samples in different ancestries and limitations in study design. Study design, size, duration We designed a GWAS for unexplained male infertility due to SPGF including a total of 1,274 affected cases and 1,951 fertile controls from the Iberian Peninsula (Spain and Portugal) and Germany. Different biostatistics and bioinformatics approaches were used to evaluate the possible effect of single-nucleotide polymorphisms (SNPs) across the whole genome in the susceptibility to specific subtypes of unexplained SPGF. Participants/materials, setting, methods The case cohort comprised 502 SO and 772 NOA patients, who were subdivided according to histological phenotypes (SCO, maturation arrest, and hypospermatogenesis) and the outcome of testicular sperm extraction techniques (TESE) from testis biopsies. Genotyping was performed with the GSA platform (Illumina). After quality-control and genotype imputation, 6,539,982 SNPs remained for the analysis, which was performed by logistic regression models. The datasets went through a meta-analysis by the inverse variance weighted method under fixed effects. Main results and the role of chance Genetic associations with SCO at the genome-wide-level of significance were identified in the major histocompatibility (MHC) class II region (rs1136759, OR = 1.80, P = 1.32E-08) and in a regulatory region of chromosome 14 nearby the vaccinia-related kinase 1 (VRK1) gene (rs115054029, OR = 3.14, P = 4.37-08). VRK1 is a relevant proliferative factor for spermatogenesis that causes progressive loss of spermatogonia when disrupted in mouse models. The role of the MHC system in SCO susceptibility was comprehensively evaluated through a validated imputation method that infers classical MHC alleles and polymorphic amino acid positions. A serine at position 13 of the HLA-DRβ1 protein (defined by the risk allele of the lead variant rs1136759) explained most of the SCO association signals within the MHC class II region. This residue is located in the binding pocket of the HLA-DR molecule and interacts directly with the presented antigen. Interestingly, position 13 of HLA-DRβ1 is the most relevant risk amino acid position for a wide spectrum of immune-mediated disorders. The HLA-DRB1*13 haplotype (which includes the serine at position 13 and represents the strongest NOA-associated marker in Asians to date) was the strongest signal amongst the classical MHC alleles in our study cohort (OR = 1.93, P = 9.90E-07). Limitations, reasons for caution Although the statistical power for the overall analysis was appropriate, the subphenotype analyses performed had considerably lower counts, which may influence the identification of genetic variants conferring low to moderate risk effects. Independent studies in larger SCO study cohorts should be performed to confirm our findings. Wider implications of the findings The molecular mechanisms underlying unexplained SPGF are largely unknown. Our data suggest a relevant role of common genetic variation in the development of SCO, the most extreme histological phenotype of NOA. SCO is characterized by the loss of germ cells and, therefore, implies a considerably higher probability of unsuccessful TESE. Trial registration number N/A

No evidence that HLA genotype influences the driver mutations that occur in cancer patients

The major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumour. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

Identification of MHC Alleles Associated With Disease Resistance/Susceptibility In Smallholder Cattle In Zambia

Background: The occurrence of Major Histocompatibility complex (MHC) alleles associated with resistance to Mastitis, Bovine Leukaemia Virus (BLV), Theileriosis, Foot and Mouth Disease (FMD) and susceptibility Dermatophilosis in African cattle is ill defined. Methods: Here, we used manual annotation to screen for five MHC alleles previously known to be associated with resistance/susceptibility to these diseases from a database of alleles sequenced from 846 cattle in Zambia. Results: Overall, we found 28 (3.3%), 21 (2.6%), 55 (6.5%), and 15 (1.8%) animals with resistance alleles to Mastitis, BLV, Theileriosis, FMD and 39 (4.6%) animals with susceptibility alleles to Dermatophilosis, respectively. Conclusion: This study provides the first evidence of resistance/susceptibility alleles in smallholder cattle in Zambia and the data could aid strategies for breeding cattle with enhanced resistance to disease in endemic countries.

Computational identification of significant immunogenic epitopes of the putative outer membrane proteins from Mycobacterium tuberculosis

Novel vaccines are required to effectively combat the epidemic spread of tuberculosis. Using in silico approaches, this study focuses on prediction of potential B cell and T cell binding immunogenic epitopes for 30 putative outer membrane proteins of Mtb. Among these, certain immunodominant epitopes of Rv0172, Rv0295c, Rv1006, Rv2264c, and Rv2525c were found, which are capable of binding B-cell and a maximum number of MHC alleles. The selected immunodominant epitopes were screened for their allergenic and antigenic properties, their percentage identity against the human proteome and their structural properties. Further, the binding efficacy of the immunodominant epitopes of Rv0295c and Rv1006 with HLA-DRB1*04:01 was analyzed using molecular docking and molecular dynamics studies. Hence, the in silico-derived immunogenic peptides (epitopes) could potentially be used for the design of subunit vaccines against tuberculosis.

epitopepredict: a tool for integrated MHC binding prediction

A key step in the cellular adaptive immune response is the presentation of antigens to T cells. Computational prediction of T cell epitopes has many applications in vaccine design and immuno-diagnostics. This is the basis of immunoinformatics, which allows in silico screening of peptides before experiments are performed. With the availability of whole genomes for many microbial species it is now feasible to computationally screen whole proteomes for candidate peptides. epitopepredict is a programmatic framework and command line tool designed to aid this process. It provides access to multiple binding prediction algorithms under a single interface and scales for whole genomes using multiple target MHC alleles. A web interface is provided to assist visualization and filtering of the results. The software is freely available under an open-source license from https://github.com/dmnfarrell/epitopepredict

Corona Viruses and Human Leukocyte Antigen (HLA) alleles

Major histocompatibility complex (MHC) is consisted of cluster of genes known as human leukocyte antigen HLA, these genes are committed to process and present antigens to T lymphocyte. Corona viruses, belonging to a genus of the corona viridae family, are enveloped viruses containing single stranded RNA 27-32 kb. This study was conducted to highlight some observations that may help other researcher for rapid research advances; the new corona virus genome sequence was obtained from Virus pathogen database, the spike protein (surface glycoprotein) was aligned with SPIKE_CVHSA Spike glycoprotein OS=Human SARS coronavirus OX=694009 GN=S PE=1 SV=1 which was retrieved from Uniprot data base Distribution of HLA alleles was obtained from allele frequencies database, IEDB server was used for MHC 1 prediction. The distribution of HLA-A alleles among population revealed that, the most common wasHLA-A*11:01. The affinity prediction of HLA-A*03:01(AAAYFVGYLK) and HLA-A*11:01(AAYFVGYLK) alleles to the spike peptide were positive. The two positive predicted peptides for both 2 alleles showed mutation of K245Q, This mutation may affect the binding affinity of the protein peptides to HLA-A alleles. Keywords: HLA. MHC, alleles, Corona viruses, SARS, APS