Genetic variants of innate immune receptors and infections after liver transplantation.
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ABSTRACT:
SUBMITTER: Sanclemente G
PROVIDER: S-EPMC4145753 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
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Project description:Liver transplantation (LT) has become the standard of care for patients with end-stage liver disease and those with hepatic malignancies, while adaptive immune-dominated graft rejection remains a major challenge. Despite potent anti-inflammatory and cytoprotective functions of heme oxygenase-1 (HO-1) overexpression upon innate immune-driven hepatic ischemia reperfusion injury, its role in adaptive immune cell-driven responses remains to be elucidated. We analyzed human biopsies from LT recipients (n = 55) to determine putative association between HO-1 levels and adaptive/co-stimulatory gene expression programs in LT. HO-1 expression negatively correlated with innate (CD68, Cathepsin G, TLR4, CXCL10), adaptive (CD4, CD8, IL17) and co-stimulatory (CD28, CD80, CD86) molecules at the graft site. LT recipients with high HO-1 expression showed a trend towards improved overall survival. By demonstrating the association between graft HO-1 levels and adaptive/co-stimulatory gene programs, our study provides important insights to the role of HO-1 signaling in LT patients.
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Project description:Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed "trained immunity." Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.
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Project description:Plant genomes contain large numbers of cell surface leucine-rich repeat (LRR) and intracellular nucleotide binding (NB)-LRR immune receptors encoded by resistance (R) genes that recognize specific pathogen effectors and trigger resistance responses. The unregulated expression of NB-LRR genes can trigger autoimmunity in the absence of pathogen infection and inhibit plant growth. Despite the potential serious consequence on agricultural production, the mechanisms regulating R-gene expression are not well understood. We identified microRNA (miRNA) progenitor genes precursor transcripts, and two miRNAs [nta-miR6019 (22-nt) and nta-miR6020 (21-nt)] that guide cleavage of transcripts of the Toll and Interleukin-1 receptor-NB-LRR immune receptor N from tobacco that confers resistance to tobacco mosaic virus (TMV). We further showed that cleavage by nta-miR6019 triggers RNA-dependent RNA polymerase 6- and ribonuclease Dicer-like 4-dependent biogenesis of 21-nt secondary siRNAs "in phase" with the 22-nt miR6019 cleavage site. Furthermore, we found that processing of the 22-nt nta-miR6019 depended on an asymmetric bulge caused by mismatch in the nta-miR6019 precursor. Interestingly, coexpression of N with nta-miR6019 and nta-miR6020 resulted in attenuation of N-mediated resistance to TMV, indicating that these miRNAs have functional roles in NB-LRR regulation. Using a bioinformatics approach, we identified six additional 22-nt miRNA and two 21-nt miRNA families from three Solanaceae species-tobacco, tomato, and potato. We show that members of these miRNA families cleave transcripts of predicted functional R genes and trigger production of phased secondary 21-nt siRNAs. Our results demonstrate a conserved role for miRNAs and secondary siRNAs in NB-LRR/LRR immune receptor gene regulation and pathogen resistance in Solanaceae.
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Project description:Biofilm has been recognized as a well-protected form of living for bacteria, contributing to bacterial pathogenicity, particularly for opportunistic species. Biofilm-associated infections are marked by their persistence. Extensive research has been devoted to the formation and composition of biofilms. The immune response against biofilms remains rather unexplored, but there is the notion that bacteria within a biofilm are protected from host defences. Here we glance at the mechanisms by which neutrophils recognize and face biofilms in implant infections and discuss the implications of this interplay, as well as speculate on its significance.
| S-EPMC5503022 | biostudies-other
Project description:Background & aimsAcute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF.MethodsTwenty-one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow-up in relation to the innate immunity genetic variants were analysed.ResultsThe NOD2-G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular.ConclusionsInnate immune system-specific NOD2-G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short-term mortality in AD/ACLF patients with bacterial infection.
| S-EPMC7079071 | biostudies-literature
Project description:BackgroundRecurrence of hepatitis C, the main indication for liver transplantation in the United States, leads to rapid fibrosis progression and worse outcomes compared to other indications. While clinical variables play a role, they are insufficient to explain all inter-patient variability in posttransplant fibrosis progression. Genetic factors associated with hepatitis C virus (HCV) outcomes have been identified, but limited studies have been conducted in the context of HCV-related liver transplantation. Therefore, the purpose of this study was to examine candidate genes related to the immune response and rate of fibrosis in subjects undergoing liver transplantation for HCV.MethodsOne hundred twelve recipients with detailed posttransplant fibrosis and clinical information were genotyped using 25 single nucleotide variants (SNVs), including five SNVs within the IL28B gene region. Associations between SNVs and rapid fibrosis progression were performed controlling for pertinent clinical variables and haplotype analyses for the IL28B gene were completed.ResultsSignificant multivariable associations were found for rs8099917 (IL28B), rs1991401 (DDX5), rs4969168 (SOC3), and rs7976497 (MLEC). The minor allele was protective against rapid fibrosis progression for the IL28B SNV (G allele), MLEC SNV (T allele), and DDX5 SNV (G allele). For the SOC3 SNV, the minor allele (A) increased the risk for rapid fibrosis progression. Additionally, two recipient haplotype structures for IL28B were significantly associated with rapid fibrosis progression.ConclusionsThese findings indicate that recipient genetic factors play a role in posttransplant HCV-related fibrosis progression. Molecular studies of these pathways may elucidate the pathogenesis of posttransplant fibrosis progression and provide risk prediction markers.
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Project description:The resolution of the gar genome affords an opportunity to examine the diversification and functional specialization of immune effector molecules at a distant and potentially informative point in phylogenetic development. Although innate immunity is effected by a particularly large number of different families of molecules, the focus here is to provide detailed characterization of several families of innate receptors that are encoded in large multigene families, for which orthologous forms can be identified in other species of bony fish but not in other vertebrate groups as well as those for which orthologs are present in other vertebrate species. The results indicate that although teleost fish and the gar, as a holostean reference species, share gene families thought previously to be restricted to the teleost fish, the manner in which the members of the multigene families of innate immune receptors have undergone diversification is different in these two major phylogenetic radiations. It appears that both the total genome duplication and different patterns of genetic selection have influenced the derivation and stabilization of innate immune genes in a substantial manner during the course of vertebrate evolution.
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Project description:Dendritic cells (DCs) are the most powerful antigen presenting cells (APCs), they are considered one of the key regulatory factors in the liver immune system. There is currently much interest in modulating DC function to improve transplant immune response. In liver transplantation, DCs participate in both the promotion and inhibition of the alloreponse by adopting different phenotypes and function. Thus, in this review, we discussed the origin, maturation, migration and pathological effects of several DC subsets, including the conventional DC (cDC), plasmacytoid DC (pDC) and monocyte-derived DC (Mo-DC) in liver transplantation, and we summarized the roles of these DC subsets in liver transplant rejection and tolerance. In addition, we also outlined the latest progress in DC-based related treatment regimens. Overall, our discussion provides a beneficial resource for better understanding the biology of DCs and their manipulation to improve the immune adaptability of patients in transplant status.
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Project description:Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10-05 ) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10-05 ) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.
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