Screening of key immune genes and pathways related to the ineffectiveness of interferon alpha treatment in patients with chronic hepatitis B based on GEO database / 西安交通大学学报(医学版)

【Objective】 To screen the differentially expressed immune genes between responders （Rs） and non-responders （NRs） in chronic hepatitis B patients receiving interferon alpha （IFN-α） treatment and to explore the molecular basis of IFN-α treatment failure. 【Methods】 The gene expression profile GSE27555 which contained 6 Rs and 7 NRs was obtained from the Gene Expression Omnibus （GEO） database； then differentially expressed genes between liver tissues of Rs and NRs were selected by the R software. The iconic immune gene set consisting of 1793 genes was downloaded from the immunology database and analysis portal （ImmPort）. The immune genes were extracted from the differentially expressed genes to obtain the differentially expressed immune genes. Subsequently， Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses of the differentially expressed immune genes were performed by the R software. Protein-protein interaction （PPI） network of the differentially expressed immune genes was constructed using the STRING online tool. The plugin CytoHubba of the Cytoscape software was applied to identify the top 10 genes by using Degree， MCC， MNC， and Closeness algorithms； then the intersection was taken to obtain the hub genes. 【Results】 A total of 88 differentially expressed immune genes， consisting of 13 upregulated and 75 downregulated genes， were identified between Rs and NRs. GO analysis showed that the differentially expressed immune genes were significantly enriched in T cell activation， cell chemotaxis， regulation of cell-cell adhesion， antigen processing and presentation. KEGG pathway analysis suggested that the differentially expressed immune genes were significantly enriched in cytokine-cytokine receptor interactions， Th cell differentiation， antigen processing and presentation， interactions between viral proteins and cytokines and cytokine receptors， chemokine signaling pathways， T cell receptor signaling pathway， IL-17 signaling pathway， natural killer cell-mediated cytotoxicity， Toll-like receptor signaling pathway， and other immune response signaling pathways. The top 7 hub genes， identified by the plugin cytoHubba of the Cytoscape software by using Degree， MCC， MNC and Closeness algorithms， were CD8A， IFNG， CCL2， CCL5， CXCL10， CCL4， and FCGR3A. 【Conclusion】 This study made a comprehensive analysis of the differentially expressed immune genes and signal pathways between Rs and NRs by bioinformatics， and identified 7 Hub genes related to the ineffectiveness of IFN-α treatment in CHB patients. These hub genes may serve as potential biomarkers for predicting the response of IFN-α treatment in CHB patients.

Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans

Abstract Hominin evolution is characterized by adaptive solutions often rooted in behavioral and cognitive changes. If balancing selection had an important and long-lasting impact on the evolution of these traits, it can be hypothesized that genes associated with them should carry an excess of shared polymorphisms (trans- SNPs) across recent Homo species. In this study, we investigate the role of balancing selection in human evolution using available exomes from modern (Homo sapiens) and archaic humans (H. neanderthalensis and Denisovan) for an excess of trans-SNP in two gene sets: one associated with the immune system (IMMS) and another one with behavioral system (BEHS). We identified a significant excess of trans-SNPs in IMMS (N=547), of which six of these located within genes previously associated with schizophrenia. No excess of trans-SNPs was found in BEHS, but five genes in this system harbor potential signals for balancing selection and are associated with psychiatric or neurodevelopmental disorders. Our approach evidenced recent Homo trans-SNPs that have been previously implicated in psychiatric diseases such as schizophrenia, suggesting that a genetic repertoire common to the immune and behavioral systems could have been maintained by balancing selection starting before the split between archaic and modern humans.

Human diversity of killer cell immunoglobulin-like receptors and disease

Natural Killer (NK) cells are the third population of lymphocyte in the mononuclear cell compartment that triggers first-line of defense against viral infection and tumor transformation. Historically, NK cells were thought of as components of innate immunity based on their intrinsic ability to spontaneously kill target cells independent of HLA antigen restriction. However, it is now clear that NK cells are quite sophisticated and use a highly specific and complex target cell recognition receptor system arbitrated via a multitude of inhibitory and activating receptors. Killer cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells development and function. To date, fourteen distinct KIRs have been identified: eight are inhibitory types, and six are activating types. The number and type of KIR genes present varies substantially between individuals. Inhibitory KIRs recognize distinct motifs of polymorphic HLA class I molecules. Upon engagement of their specific HLA class I ligands, inhibitory KIR dampen NK cell reactivity. In contrast, activating KIRs are believed to stimulate NK cell reactivity when they sense their ligands (unknown). KIR and HLA gene families map to different human chromosomes (19 and 6, respectively), and their independent segregation produces a wide diversity in the number and type of inherited KIR-HLA combinations, likely contributing to overall immune competency. Consistent with this hypothesis, certain combinations of KIR-HLA variants have been correlated with susceptibility to diseases as diverse as autoimmunity, viral infections, and cancer. This review summarizes our emerging understanding of KIR-HLA diversity in human health and disease.