Immunogenetics最新文献

Immunoglobulin GM (γ marker) and KM (κ marker) allotypes have been shown to be associated with antibody responses to several viruses, but their role in immunity to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-the causative agent of Coronavirus disease 2019 (COVID-19)-has not been investigated. The aim of the present investigation was to determine the contribution of GM, KM, and FcγR genotypes to the magnitude of humoral immunity to SARS-CoV-2 and to the antibody-dependent cell-mediated cytotoxicity (ADCC) of SARS CoV-2 S-transfected cells. ADCC is a major host immunosurveillance mechanism against viruses and the leading mechanism underlying the clinical efficacy of therapeutic monoclonal antibodies. We genotyped 124 unvaccinated people for several GM, KM, and FcγR alleles, measured IgG antibodies to the receptor-binding domain of the spike protein (S-RBD) of SARS CoV-2, and quantitated the level of ADCC against SARS CoV-2 S-transfected cells. None of the associations between genotypes and antibody levels were statistically significant, potentially a reflection of relatively small sample sizes. However, we found a significant interactive effect of GM and FcγRIIIa valine (V)/phenylalanine (F) genotypes on the ADCC of SARS CoV-2 S-transfected cells. In the FcγRIIIa F/F group, the mean ADCC value was significantly (p = 0.03) lower among those with GM 17/17 (mean = 45.2) when compared to those with GM 3/3 (mean = 60.2). In the FcγRIIIa V/V group, the mean ADCC value was not significantly (p = 0.68) lower among those with GM 17/17 (mean = 52.5) when compared to those with GM 3/3 (mean = 55.4). These results may help devise potent immunotherapy against emerging SARS CoV-2 variants.

Natural killer (NK) cells, a key component of the innate immune system, play a crucial role in detecting and eliminating cancer cells, contributing to cancer immune surveillance. Increasing evidence suggests that NK cell functions are regulated by epigenetic mechanisms, including the influence of long non-coding RNAs (lncRNAs). These lncRNAs, transcripts longer than 200 nucleotides, are emerging as important regulators of gene expression. In this study, we investigated the expression of 84 lncRNAs in NK cells isolated from the peripheral blood of patients with invasive breast cancer. Using lncRNA PCR array profiling, we identified 26 differentially expressed lncRNAs in circulating NK cells isolated from peripheral blood of breast cancer patients, with 10 genes showing significant downregulation and 16 genes showing significant upregulation. Gene ontology (GO) and functional enrichment analysis revealed that among the ten downregulated lncRNAs, four lncRNAs have deposited gene ontology terms and known biological functions. These lncRNAs are PTENP1-AS (fold change 0.27, P = 0.0206), TSIX (fold change 0.05, P = 0.0037), XIST (fold change 0.42, P = 0.007), and CCAT1 (fold change 0.09, P = 0.0191). On the other hand, among the 16 upregulated lncRNAs, five lncRNAs have deposited gene ontology terms and known biological functions. These lncRNAs are GNAS-AS1 (fold change 5.10, P = 0.0104), MEG3 (fold change 46.85, P = 0.0138), CDKN2B-AS1 (fold change 81.80, P = 0.0087), HOTAIR (fold change 6.86, P = 0.0042), and AIRN (fold change 7.97, P = 0.0379). Functional enrichment analysis indicated that the downregulated lncRNAs were mainly involved in biological processes such as chromatin organization, epigenetic regulation of gene expression, and dosage compensation via X chromosome inactivation, while the upregulated lncRNAs were linked to epigenetic regulation, genomic imprinting, and chromatin remodeling. These enrichments were identified using Bonferroni correction with an adjusted P-value < 0.05. Given the biological functions of the dysregulated lncRNAs in NK cells from breast cancer patients, this has the potential to significantly impact the antitumor functionality of NK cells, possibly contributing to the impaired immune surveillance and tumor control commonly observed in breast cancer patients. Understanding the dysregulation of lncRNAs in NK cells may provide critical insights into the mechanisms underlying impaired NK cell function in breast cancer, offering promising approaches for developing immunotherapies aiming at restoring NK cell activity in cancer patients.

Positive regulatory domain member (PRDM) family proteins play important roles in nervous system development, neural stem cell proliferation and differentiation, and central nervous system inflammation. The unique evolutionary position of the lamprey (Lethenteron reissneri) as one of the oldest jawless vertebrates makes it an ideal animal model for understanding vertebrate evolution. Nevertheless, the evolutionary characteristics of PRDM genes have not yet been demonstrated in lampreys. In this study, we identified PRDM1, 4, 5, 8, 12, 14, and 15 genes in the lamprey genomes and also investigated their evolutionary relationships through phylogenetic analysis. The characterization of PRDM genes appears to be conserved among vertebrates, as indicated by protein structural domain, motif, and 3D structure analysis. Genomic synteny analysis revealed that lamprey PRDM neighbor genes are significantly different from those of jawed vertebrates. Real-time quantitative results demonstrate that the PRDM gene family may be involved in immune defense and spinal cord injury (SCI) repair. This study not only enriches the understanding of PRDM gene evolution but also provides new clues for the Lr-PRDMs' roles in immune defense and SCI.

Estonia is a small country in the Baltic region of Northern Europe with 1.3 million inhabitants. As a coastal area, the population of Estonia was subjected to migration influences. Due to this admixture of populations, HLA gene diversity in Estonia is interesting to study with regard to allele frequencies, haplotypes, and polymorphism. In this study, we focused on HLA-E polymorphism within the Estonian population and compared these with the polymorphism identified in other populations. Full-length HLA-E sequencing of 143 individuals originating from Estonia show dimorphism frequencies at amino acid position 107 (0.55 R vs 0.45 G) comparable to other populations. Within the study population, 16 different HLA-E alleles were identified, including four novel alleles. These 16 alleles encode four different protein variants. Despite a strong differentiation between the South-East and the rest of the Estonian country, no allele frequency differences for HLA-E between these regions were identified. Comparing the allele and SNP frequencies to frequencies found in the different neighboring countries revealed no major differences, except for the SNP encoding for HLA-E*01:06. Association analysis between classical HLA class I genes and polymorphism at amino acid position 107 of HLA-E revealed higher frequencies of HLA-A*01 with R107 and HLA-A*03 and HLA-C*04 with G107. In summary, our study provides new insights into HLA-E variation within the Estonian population and demonstrates that its level of polymorphism is comparable to those observed in other global populations.

The Maniq, a small and isolated nomadic hunter-gatherer population from the rainforests of Southern Thailand, offer a unique context for investigating how demographic history, genetic drift, and pathogen-driven selection shape human leucocyte antigen (HLA) diversity. Using high-coverage whole-genome data from 21 individuals (12 unrelated), we genotyped HLA alleles with HLA-HD and T1K, identifying 32 alleles in classical and 14 in non-classical HLA genes. Although overall HLA diversity was comparatively low, a few alleles at each locus occurred at high frequency, mirroring patterns observed in other small, isolated populations. Principal-component analysis clustered the Maniq with other Austroasiatic-speaking Semang hunter-gatherers (Jehai, Kintaq) on the Malay Peninsula and, intriguingly, with the Austronesian-speaking Tao of Taiwan, indicating shared immunogenetic features across linguistic boundaries. Despite reduced diversity, multiple loci bore signatures of both long-term balancing and recent positive selection. Several SNPs under selection were in complete linkage disequilibrium with eQTLs known to influence responses to hepatitis B virus (HBV) and other pathogens, suggesting that pathogen-driven pressure-in particular HBV-may have contributed to recent HLA evolution in the Maniq. These findings provide critical insights into how demographic constraints and pathogen landscapes converge to shape HLA diversity and evolution. In light of increasing infectious disease burdens in indigenous communities, our results underscore the importance of studying small, isolated populations to better understand the adaptive significance of HLA genes.

The basal chordate, Botryllus schlosseri, undergoes a natural transplantation reaction that is controlled by a single, highly polymorphic locus called the fuhc. The fuhc is one of the most polymorphic loci ever described, with most populations having hundreds of alleles, and up to a thousand found worldwide. Two individuals are compatible if they share one or both alleles, while those with no shared alleles are incompatible; thus, Botryllus uses a missing-self recognition strategy to discriminate between up to a thousand histocompatibility ligands. Remarkably, this discriminatory capability, which rivals that of vertebrate adaptive immunity, is carried out by germline-encoded receptors; thus, the mechanisms that establish and maintain this remarkable specificity are not understood. Multiple complete haplotypes of the fuhc locus have recently been sequenced, and at least seven genes with characteristics that suggest a role in allorecognition have been identified, including ligands, receptors, and intracellular proteins that likely organize and tune signal transduction complexes. This includes a new receptor family called the fester co-receptors (FcoRs) that encode ITIM and hemITAM domains, linking allorecognition in Botryllus to canonical immune transduction pathways. This review will summarize our current understanding and working hypotheses on the cellular and molecular mechanisms that control this innate, highly polymorphic allorecognition response, and how those may have been co-opted during the evolution of adaptive immunity.

Small, isolated populations are often vulnerable to increased inbreeding and genetic drift, both of which elevate the risk of extinction. The Bellinger River turtle (Myuchelys georgesi) is a critically endangered species endemic to a single river catchment in New South Wales, Australia. The only extant wild population, along with the breeding program, face significant threats from viral outbreaks, most notably a nidovirus outbreak in 2015 that led to a 90% population decline. To enhance our understanding of genomic characteristics in the species, including genome-wide and functional gene diversity, we re-sequenced, assembled, and analysed 31 re-sequenced genomes for pure M. georgesi (N = 31). We manually annotated the major histocompatibility complex (MHC), identifying five MHC class I and ten MHC class II genes and investigated genetic diversity across both classes in M. georgesi. Our results showed that genome-wide diversity is critically low in pure M. georgesi, contexualised through comparison with opportunistically sampled backcross animals-offspring of F1 hybrids (M. georgesi × Emydura macquarii) backcrossed to pure M. georgesi (N = 4). However, the variation observed within the core MHC region of pure M. georgesi, extending across scaffold 10, exceeded that of all other macrochromosomes. Additionally, no significant short-term changes in either genome-wide or immunogenetic diversity were detected following the 2015 nidovirus outbreak (before; N = 19, after; N = 12). Demographic history reconstructions indicated a sustained, long-term decline in effective population size since the last interglacial period, accompanied by more recent steep declines. These patterns suggested that prolonged isolation and reduced population size have significantly influenced the dynamics of genome-wide diversity. It is likely that contemporary stressors, including the recent nidovirus outbreak, are acting on an already genetically depleted population. This study offers new insights into genome-wide and immune gene diversity, including immune gene annotation data with broader implications for testudines. These findings provide crucial information to support future management strategies for the species.

The major histocompatibility complex (MHC) constitutes a functionally relevant multigene family playing an essential role in the adaptive immune responses of jawed vertebrates, being directly involved in pathogen recognition. MHC diversity, driven by pathogen-mediated selection, is vital for species survival and is characterized by high genetic diversity in many taxa, namely at the sequence, allelic and haplotype levels. Chondrichthyans, the most basal jawed vertebrates with an adaptive immune system, exhibit a high diversity of MHC gene lineages conservatively organized in a compact region of the genome. Such genomic architecture suggests linkage among MHC genes, where alleles from different genes possibly co-segregate together. Such condition may have major implications on immune response, individual fitness and evolution. In this study, we examine MHC IIβ haplotype diversity in a model shark species, the small spotted catshark, Scyliorhinus canicula. Making use of pedigree data, we reconstructed MHC IIβ haplotypes to understand allele transmission from parent to offspring. Results indicate allele co-segregation consistent with tight linkage among MHC IIβ genes, suggesting the presence of functional stable haplotypes inherited from parents to offspring. The reconstructed haplotypes suggested extensive haplotype diversity characterized by variable allele numbers and allelic lineage composition, as well as marked allelic divergence, consistent with previous population-level data on this species. These findings underscore the complexity of MHC genetics (and of MHC evolution) in chondrichthyans. Accurate reconstruction of MHC haplotypes and assessment of its functional significance are crucial for better understanding adaptive immune responses and MHC evolutionary dynamics in chondrichthyans.

Our bodies are continuously exposed to injurious insults by infection and tissue damage, which are primarily sensed by innate immune receptors to maintain homeostasis. Among such receptors is macrophage-inducible C-type lectin (Mincle, gene symbol CLEC4E), a member of the C-type lectin receptor (CLR) family, which functions as an immune sensor for both pathogens and damaged self. To monitor these injurious stimuli, Mincle recognizes disaccharide-based pathogen-derived glycolipids and monosaccharide-based intracellular metabolites, such as β-glucosylceramide. Mincle is well-conserved among mammals; however, there are questions that remain unclear, such as from which lower vertebrate did it arise and whether the original ligand was self or non-self. Here, we found homologues of Mincle and its signaling subunit Fc receptor γ chain (FcRγ) in lower vertebrates, such as reptiles, amphibians, and fishes. The crystal structure of a Mincle homologue revealed that fish Mincle possesses a narrower sugar-binding pocket than that of mammalian Mincle, and accommodates only monosaccharide moieties. These results suggest that Mincle may have evolved from a self-recognizing receptor, and its sugar-binding pocket widened during evolution, presumably to adapt to disaccharide-based glycolipids derived from life-threatening pathogens.