Immunogenetics最新文献

Lymphomas are biologically heterogeneous malignancies with multifactorial etiologies involving genetic, environmental, and immune dysregulation. The functional variant rs1049174 SNP in the KLRK1 gene (encoding NKG2D) regulates NKG2D expression and modulates NK cells immune surveillance pathways, which may influence lymphoma susceptibility. We investigated this association through a two-stage case-control study and meta-analysis. First, we analyzed 246 diffuse large B-cell lymphoma (DLBCL) patients and 599 healthy controls (exploratory cohort), followed by a confirmatory cohort of 234 non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma (HL) patients. Genotype frequencies were assessed via chi-square tests, with odds ratios (ORs) calculated for risk associations. A systematic review and meta-analysis of 10 studies, including our cohorts (3,785 cases and 4,129 controls), testing rs1049174 and cancer risk was also conducted. In the exploratory cohort, the GG genotype showed no significant association with overall lymphoma risk (OR = 0.83; 95% CI: 0.61-1.13; *p* = 0.25). However, in NHL, the GG genotype was underrepresented (OR = 0.75; 95% CI: 0.57-0.99; *p* = 0.02). Pooled lymphoma analysis revealed a protective effect (OR = 0.78; 95% CI: 0.62-0.99; *p* = 0.03). Meta-analysis confirmed a significant protective role of the GG genotype against cancer (OR = 0.71; 95% CI: 0.63-0.79), despite heterogeneity and potential publication bias. Our findings suggest that the rs1049174 GG genotype is associated with reduced lymphoma susceptibility, particularly in NHL, underscoring the importance of immunogenetic variants in lymphomagenesis. Further functional and clinical studies are needed to elucidate the mechanistic basis of this association.

The major histocompatibility complex (MHC) plays a central role in immune responses, with strong links to both infectious disease resistance and autoimmune conditions. In typical mammals, such as humans, the MHC is large and complex, comprising many genes and exhibiting weak associations with infectious diseases, but strong associations with autoimmunity. In contrast, the chicken MHC is small and simple, with only one dominantly-expressed class I and class II gene, and strong associations with resistance to infectious pathogens; however, its role in autoimmunity is less well understood. This raises a question: Does the simplicity of the chicken MHC reduce the risk of autoimmunity? In this speculative review, we explore the question by comparing chickens and typical mammals, and by considering the spectrum of MHC alleles from promiscuous generalists to fastidious specialists. We suggest that comparing the spectrum of alleles within a single species, such as chickens, may offer a way to test the link between MHC complexity and autoimmunity. Although much work remains, this approach could provide new insights into the balance between immune protection and self-tolerance.

Non-human primates are important for preclinical vaccine evaluation. In depth characterization of the antibody response requires representative immunoglobulin (IG) germline gene databases for correct gene and allele assignments and assessment of affinity maturation of antigen-specific antibodies. Current IG-reference databases do not cover the genetic diversity observed in frequently used macaque species and it is unclear to what extent closely related animals express shared alleles at similar levels. Here, IG-germline alleles of sixteen cynomolgus macaques (CynoSet), some of which were related, were characterized and compared with previously described Mauritian and Indonesian origin cynomolgus macaque datasets. Although the CynoSet showed more overlap with the Mauritian origin dataset, compared to an Indonesian origin dataset, there were clear differences in allelic expression patterns, independent of family relationship. Calculation of somatic hypermutation levels in post-infection influenza hemagglutinin-specific B cells demonstrated the need for individualized IG-genotyping for accurate evaluation of the antigen-specific B cell response.

The Major Histocompatibility Complex (MHC) is a gene-dense genomic region essential to adaptive immunity, exhibiting both conserved features and lineage-specific rearrangements across jawed vertebrates. Amphibians, as basal tetrapods, offer critical insights into MHC evolution; however, research has largely focused on anurans (e.g., Xenopus), while urodeles remain understudied, primarily due to their exceptionally large genomes. With recent advances in sequencing technologies, chromosome-scale assemblies for urodeles are now becoming available, opening new opportunities to explore their MHC architecture. Yet, the MHC region remains notoriously challenging to annotate due to its complexity, high polymorphism, and dynamic evolutionary history. For instance, the initial annotation of the axolotl (Ambystoma mexicanum) MHC relied heavily on synteny with mammalian genomes, which led to an overestimation of its size and misinterpretation of its structure. These inaccuracies have fueled evolutionary debates regarding the ancestral genomic structure of the MHC. Here, we present a comprehensive re-annotation of the axolotl MHC, revealing a typical organization found in tetrapods other than eutherian mammals: core MHC region with several, expressed MHC class I genes, tightly linked to their antigen processing genes, and to single loci of MHC class II genes. Contrary to the previous report, class I and class II genes are not separated by class III genes, and the overall MHC region is relatively compact (by axolotl genome standards). These findings correct earlier misconceptions and emphasize the need for annotation strategies that reflect the complex and lineage-specific nature of genomic regions rich in immune genes.

The present study aimed to evaluate lymphoid defects in patients with specific IEIs (n = 28) using a 12-antibody 9-color single-tube flow cytometry assay. The lymphoid defects (lymphocyte counts below the reference range) were significantly higher in XLA patients (p-0.0002), CVID patients (p-0.00022), WAS patients (p- < 0.001), HIES patients (p- < 0.001), CHS patients (p < 0.001), and CGD patients (p < 0.0002) than age-matched controls. The lymphoid defects (lymphocyte counts above the reference range) were significantly higher in LAD-1 than age-matched controls (p < 0.001). In patients with XLA, the NK cells were reduced in 50% and naïve Tc cells in 33.3% of patients. The patients with CVID showed reduced CD4 + T cell subset in 75% and increased memory Tc cells in 50% of patients. In WAS, absolute B cell, naïve B cell, switched memory B cell, CD4 + T cell, and naïve Th cell counts were decreased in 100% of patients. In HIES, the CD4 + T cell and memory Th cell count was reduced in 100% of patients. In CGD, reduced absolute count of T cells, CD4 + T cells, CD8 + T cells, naïve Th cells, memory Th cells, naïve Tc cells and γδ T cells and increased B-cell counts were noted in 67% of cases. Both B- and T-cell defects were identified in HIGM, MHC-II deficiency, LAD-1, CHS, CARD-11, and STXBP2 defects. No significant difference was observed between routine and single-tube panel results by paired T-test.

The chicken major histocompatibility complex (MHC) represents a "minimal essential MHC" consisting of classical class I (BF) and class II (BL) molecules that present peptides to CD8⁺ cytotoxic and CD4⁺ helper T cells, respectively. Class I molecules, primarily encoded by the BF2 gene, are central to immune responses against pathogens. Moreover, these molecules show enormous genetic diversity driven by a molecular arms race with pathogens that determines peptide binding to the polymorphic α1 and α2 domains. Genotyping tools such as the 90-single nucleotide polymorphism (SNP) panel for the MHC-B region (BSNP) and the LEI0258 microsatellite marker have revealed MHC diversity in chickens but do not capture the variation within the α1 and α2 domains. In this study, six populations of Korean native chickens (KNC) were analyzed to assess BF2 gene diversity in individuals homozygous for both the BSNP panel and LEI0258 marker. Two standard BF2 alleles, B06 and B09, were identical while seven additional haplotypes showed high similarity to those found in KNC samples. A total of 30 novel SNPs were identified, with over half located in peptide-binding regions. Most variants overlapped with previously reported data from polymerase chain reaction (PCR) and next-generation sequencing (NGS), leading to the identification of four unique BF2 alleles in KNC. There was no clear relationship among BSNP, the LEI0258 marker, and the BF2 gene, but individuals homozygous for the first two markers also had a homozygous BF2 region. These findings provide insights into MHC diversity and immune potential in KNC populations, supporting conservation and breeding strategies for enhanced disease resistance. Key points • LEI0258 marker and BSNP haplotypes are good indicators of BF2 gene homozygosity. • Unique BF2 alleles from the KNC lines indicate high genetic diversity that can be used for selective breeding and conservation to enhance disease resistance.

Squamate reptiles are a diverse group of terrestrial vertebrates that includes over 10,000 species. Despite their broad distribution, they are relatively understudied immunologically. Fortunately, recent advances in comparative genomics have facilitated studies of squamate immune systems, revealing their unique features. For example, squamates lack of γδ T cells entirely due to genomic deletions. Here we annotated and analyzed the loci encoding the Tiliqua rugosa immunoglobulin heavy and lambda light chains, revealing a remarkably large and complex number of variable region genes in both. Tiliqua rugosa lacks genes encoding a kappa light chain, which can be found in some but not all squamates. We also identified common reptile IgH isotypes including IgM, IgD, and IgY, but no IgA. Overall, T. rugosa, has the germline capability of generating a highly diverse antibody repertoire.

COVID-19, caused by the SARS-CoV-2 virus, has had a global impact, leading to high incidence and mortality rates worldwide. Host genetics significantly influence individual susceptibility to severe COVID-19. The C-type lectin domain family 4 member M (CLEC4M) gene plays an important role in SARS-CoV-2 infection and coagulation pathways. In this study, we genotyped and investigated the functional variant rs868875 of the CLEC4M gene in COVID-19 patients receiving anticoagulant therapy. This cross-sectional study included 485 patients, divided into moderate (n = 139) and critical/severe (n = 346) groups. Significant disparities in D-dimer levels were observed between patient groups (p < 0.0001), thus serving as a critical marker for stratification. Genetic analysis revealed significant associations between allele (p = 0.0170) and genotype (p = 0.0096) frequencies across the groups. Regarding genotypic models, an association was found in dominant (p = 0.0035) and overdominant (p = 0.004) models. Logistic regression confirmed that the presence of G allele (AG/GG) significantly impacts COVID-19 severity, independent of confounding variables (p = 0.017). Moreover, expression quantitative trait loci (eQTLs) analysis indicated that the GG genotype of rs868875 is associated with lower CLEC4M gene expression in lung and liver tissue, and STRING analysis revealed relevant biological interactions between CLEC4M and other genes in the inflammatory process, innate immunity, and vascular response. Overall, our findings suggest an association between the rs868875 polymorphism and severe clinical outcomes of COVID-19 in patients receiving anticoagulants. However, further validation studies are essential to corroborate these findings and elucidate the functional implications of this polymorphism. These efforts will contribute to a comprehensive understanding of the pathogenesis of COVID-19.

Genetic diversity of the bovine leukocyte antigen BoLA-DRB3 gene has been reported in cattle breeds due to its central role in immune response. However, the gene has been characterized in only a few Latin American native cattle breeds. In this study, we aimed to investigate the genetic diversity of this gene in other native bovine breeds from Argentina, Bolivia, Cuba, and Paraguay, thereby contributing to the global knowledge regarding BoLA-DRB3 diversity. The gene was genotyped using PCR-sequence-based typing; 60 reported alleles and one novel variant were identified. The observed and expected heterozygosity values were higher than 0.81, and only two populations showed deviation from the Hardy-Weinberg equilibrium. The Slatkin neutrality test indicated even allele distribution in one population. Nucleotide diversity and the number of pairwise differences ranged from 0.073 to 0.081 and 17.88 to 20.19, respectively. The mean number of non-synonymous and synonymous nucleotide substitutions was estimated for the entire sequence and the antigen-binding site (ABS), with higher values observed in the latter. Amino acid motifs varied in their frequencies, and the diversifying selection index (ω) at each amino acid was high in more than 25 sites, with the most prominent peaks located in the ABS. A distribution of native cattle according to their historical and geographical origin and degree of Zebu gene introgression demonstrated that the Latin American native populations exhibit high variability in the BoLA-DRB3 gene, including private alleles, and a distinct genetic profile, making them a valuable genetic resource and emphasizing the importance of their conservation.