Immunogenetics最新文献

We previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 ("Abd3") and a mutated Pkhd1 gene (Pkhd1^del36-67) upstream from Abd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a scid background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the Abd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated Pkhd1^del36-67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the Pkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous Pkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD Pkhd1 homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant Pkhd1 can cause such an autoimmune response.

The involvement of small nucleolar RNA host gene 3 (SNHG3) in cancer regulation has been reported. This study attempted to deeply investigate the molecular regulatory mechanism of SNHG3 on malignant progression of hepatocellular carcinoma (HCC). According to TCGA analysis, high SNHG3 expression was a risk factor for poor prognosis of HCC patients. Therefore, we further detected the mRNA level of SNHG3 in HCC tissue and cells. It was found that SNHG3 was upregulated in HCC tissue and cells. Afterwards, CCK-8 and flow cytometry assays further proved that silencing SNHG3 inhibited HCC cell proliferation while inducing cell apoptosis and G0/G1 phase arrest. It was also attested in vivo experiments that silencing SNHG3 could reduce the volume and weight of tumors and downregulate the Ki-67 expression to suppress HCC tumor growth. Next, it was discovered that SNHG3 increased the binding of E2F1 and NEIL3 promoter region, thereby activating the transcription feature of NEIL3. Lastly, rescue assays indicated that NEIL3 participated in SNHG3-mediated HCC cell cycle, apoptosis and proliferation. All in all, this study revealed the specific regulatory mechanism of SNHG3 in HCC to enable SNHG3 a hopeful marker for HCC diagnosis and treatment.

Multiple novel immunoglobulin-like transcripts (NILTs) have been identified from salmon, trout, and carp. NILTs typically encode activating or inhibitory transmembrane receptors with extracellular immunoglobulin (Ig) domains. Although predicted to provide immune recognition in ray-finned fish, we currently lack a definitive framework of NILT diversity, thereby limiting our predictions for their evolutionary origin and function. In order to better understand the diversity of NILTs and their possible roles in immune function, we identified five NILT loci in the Atlantic salmon (Salmo salar) genome, defined 86 NILT Ig domains within a 3-Mbp region of zebrafish (Danio rerio) chromosome 1, and described 41 NILT Ig domains as part of an alternative haplotype for this same genomic region. We then identified transcripts encoded by 43 different NILT genes which reflect an unprecedented diversity of Ig domain sequences and combinations for a family of non-recombining receptors within a single species. Zebrafish NILTs include a sole putative activating receptor but extensive inhibitory and secreted forms as well as membrane-bound forms with no known signaling motifs. These results reveal a higher level of genetic complexity, interindividual variation, and sequence diversity for NILTs than previously described, suggesting that this gene family likely plays multiple roles in host immunity.

The genetics of allorecognition has been studied extensively in inbred lines of Hydractinia symbiolongicarpus, in which genetic control is attributed mainly to the highly polymorphic loci allorecognition 1 (Alr1) and allorecognition 2 (Alr2), located within the Allorecognition Complex (ARC). While allelic variation at Alr1 and Alr2 can predict the phenotypes in inbred lines, these two loci do not entirely predict the allorecognition phenotypes in wild-type colonies and their progeny, suggesting the presence of additional uncharacterized genes that are involved in the regulation of allorecognition in this species. Comparative genomics analyses were used to identify coding sequence differences from assembled chromosomal intervals of the ARC and from genomic scaffold sequences between two incompatible H. symbiolongicarpus siblings from a backcross population. New immunoglobulin superfamily (Igsf) genes are reported for the ARC, where five of these genes are closely related to the Alr1 and Alr2 genes, suggesting the presence of multiple Alr-like genes within this complex. Complementary DNA sequence evidence revealed that the allelic polymorphism of eight Igsf genes is associated with allorecognition phenotypes in a backcross population of H. symbiolongicarpus, yet that association was not found between parental colonies and their offspring. Alternative splicing was found as a mechanism that contributes to the variability of these genes by changing putative activating receptors to inhibitory receptors or generating secreted isoforms of allorecognition proteins. Our findings demonstrate that allorecognition in H. symbiolongicarpus is a multigenic phenomenon controlled by genetic variation in at least eight genes in the ARC complex.

Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), has increasing prevalence in the world. Due to the lack of cure strategy, most patients with CD develop progressive disease companying with a series of serious complications. Therefore, exploring molecular mechanism differences between active and inactive CD will help in the screening of predict markers and therapeutic targets. In this study, we analyzed differentially expressed genes (DEGs) and molecular pathways through between active and inactive CD patients. In addition, the abundance of 22 immune cell types were assessed by using the CIBERSORT. The hub DEGs were screened out by the CytoHubba in Cytoscape, followed by the least absolute shrinkage and selection operator (LASSO) regression. Finally, the clinical predictive model was constructed by binary logistic regression model. The diagnostic efficacy was tested by receiver operating characteristic (ROC) curve and verified in independent datasets. The results showed that there were 137 DEGs between the active and inactive CD. Most of them were involved in regulating the immunity process. In addition, the decreased abundance of CD8 T cells and the increased abundance of M0, M1 macrophages, and neutrophils were closely related to CD activation. CXCL9, C3AR1, IL1B, and TLR4 were the hub gene and can be applied to the prediction of CD activation. Our results provided important targets for the prediction of CD activation and the selection of therapeutic targets.

The Notch pathway is a highly conserved signaling pathway involved in the regulation of cell proliferation and differentiation. However, the relationships between Notch pathway-related genes (NPRGs), immunosuppression, and immunotherapy resistance of hepatocellular carcinoma (HCC) remain unclear. Gene expression data and clinical information were extracted from GSE14520, GSE36376, GSE76427, LIRI-JP, TCGA-LIHC, GSE20140, GSE27150, and IMvigor210 datasets. A consensus clustering analysis based on 10 NPRGs was performed to determine the molecular subtypes, and then a notchScore was constructed based on differentially expressed and prognostic genes between molecular subtypes. Two molecular subgroups with significantly distinct survival and immune cell infiltration were identified. Then, a notchScore was constructed to quantify the Notch index of each patient with HCC. Next, we investigated the correlations between the clinical characteristics and the notchScore using logistic regression. Furthermore, multivariate Cox analysis showed that a high notchScore was an independent predictor of poor overall survival (OS) in the TCGA and LIRI-JP datasets and was associated with higher pathological stages. Additionally, a high notchScore was associated with higher immune cells, higher ESTIMATE score, higher immune score, higher stromal score, higher immune checkpoint, and lower tumor purity, which was consistent with the "immunity tidal model theory." Importantly, a high notchScore was sensitive to immunotherapy. Additionally, GSEA indicated that several GO and KEGG items associated with apoptosis, immune-related pathways, and cell cycle signal pathways were significantly enriched in the high notchScore phenotype pathway. Our findings propose that a high notchScore is a prognostic biomarker and correlates with immune infiltration and sensitivity to immunotherapy in HCC.

Polymorphism of the major histocompatibility complex (MHC), DAB1 gene was characterized for the first time in the European bitterling (Rhodeus amarus), a freshwater fish employed in studies of host-parasite coevolution and mate choice, taking advantage of newly designed primers coupled with high-throughput amplicon sequencing. Across 221 genotyped individuals, we detected 1-4 variants per fish, with 28% individuals possessing 3-4 variants. We identified 36 DAB1 variants, and they showed high sequence diversity mostly located within predicted antigen-binding sites, and both global and codon-specific excess of non-synonymous mutations. Despite deep divergence between two major allelic lineages, functional diversity was surprisingly low (3 supertypes). Overall, these findings suggest the role of positive and balancing selection in promotion and long-time maintenance of DAB1 polymorphism. Further investigations will clarify the role of pathogen-mediated selection to drive the evolution of DAB1 variation.

Males and females often exhibit differences in behaviour, life histories, and ecology, many of which are typically reflected in their brains. Neuronal protection and maintenance include complex processes led by the microglia, which also interacts with metabolites such as hormones or immune components. Despite increasing interest in sex-specific brain function in laboratory animals, the significance of sex-specific immune activation in the brain of wild animals along with the variables that could affect it is widely lacking. Here, we use the Kentish plover (Charadrius alexandrinus) to study sex differences in expression of immune genes in the brain of adult males and females, in two wild populations breeding in contrasting habitats: a coastal sea-level population and a high-altitude inland population in China. Our analysis yielded 379 genes associated with immune function. We show a significant male-biased immune gene upregulation. Immune gene expression in the brain did not differ in upregulation between the coastal and inland populations. We discuss the role of dosage compensation in our findings and their evolutionary significance mediated by sex-specific survival and neuronal deterioration. Similar expression profiles in the coastal and inland populations suggest comparable genetic control by the microglia and possible similarities in pathogen pressures between habitats. We call for further studies on gene expression of males and females in wild population to understand the implications of immune function for life-histories and demography in natural systems.