Interaction between immunoglobulin allotypes and NK receptor genes in diabetes post-hepatitis C virus infection.
Ontology highlight
ABSTRACT:
SUBMITTER: Granados-Montiel J
PROVIDER: S-EPMC3089690 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
Publications
Interaction between immunoglobulin allotypes and NK receptor genes in diabetes post-hepatitis C virus infection.
Granados-Montiel Julio J Zúñiga Joaquin J Azocar Jose J Feris Edmond J EJ Terreros Daniel D Larsen Charles E CE Clavijo Olga P OP Cruz-Lagunas Alfredo A Middleton Derek D Alper Chester A CA Pandey Janardan P JP Yunis Edmond J EJ
Immunobiology 20101105 6
Genetic interactions between natural killer (NK) cells immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes have been previously reported in type 2 diabetes mellitus (DM) patients. Puerto Rican Americans with a history of intravenous drug use who developed DM following HCV infection (n=32) were compared to individuals infected with HCV without diabetes (n=121) and to DM non-infected individuals (n=95). Subjects were genotyped for KIRs and immunoglobulin allotypes. We found inter ...[more]
Similar Datasets
Project description:Background & aimsEndoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection.MethodsWe performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury.ResultsTwo hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV.ConclusionsERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV.Lay summaryEndoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.
| S-EPMC6527866 | biostudies-literature
Project description:Persistent hepatitis B virus (HBV) infection is a significant public health problem because it is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Roughly one-third of the world population has been infected with HBV and there are about 350 million (5%-6%) persistent carriers. HBV causes 80% of all liver cancer cases and is the second most important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a persistent carrier following perinatal infection in infants born to e antigen positive carrier mothers and a 30% risk in pre-school children. Only 5%-10% of adults become persistent carriers following infection. Of individuals persistently infected with HBV, 10%-30% will develop liver cirrhosis and HCC. These highly variable outcomes in both clearance rates and disease outcomes in persistently infected individuals cannot be fully explained by differences in immunological, viral or environmental factors. Thus, differences in host genetic factors may affect the natural history of hepatitis B.
| S-EPMC4069298 | biostudies-literature
Project description:Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
| S-EPMC6523734 | biostudies-literature
Project description:Hepatitis C virus (HCV) is one of the leading causes of chronic liver diseases and B-lymphocyte proliferative disorders, including mixed cryoglobulinemia and B-cell lymphoma. It has been suggested that HCV infects human cells through the interaction of its envelope glycoprotein E2 with a tetraspanin molecule CD81, the putative viral receptor. Here, we show that the engagement of B cells by purified E2 induced double-strand DNA breaks specifically in the variable region of immunoglobulin (V(H)) gene locus, leading to hypermutation in the V(H) genes of B cells. Other gene loci were not affected. Preincubation with the anti-CD81 monoclonal antibody blocked this effect. E2-CD81 interaction on B cells triggered the enhanced expression of activation-induced cytidine deaminase (AID) and also stimulated the production of tumor necrosis factor alpha. Knockdown of AID by the specific small interfering RNA blocked the E2-induced double-strand DNA breaks and hypermutation of the V(H) gene. These findings suggest that HCV infection, through E2-CD81 interaction, may modulate host's innate or adaptive immune response by activation of AID and hypermutation of immunoglobulin gene in B cells, leading to HCV-associated B-cell lymphoproliferative diseases.
| S-EPMC1143751 | biostudies-literature
Project description:The role of hepatitis virus infection in glucose homeostasis is uncertain. We examined the associations between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and the development of diabetes in a cohort (N?=?439,708) of asymptomatic participants in health screening examinations. In cross-sectional analyses, the multivariable-adjusted odds ratio for prevalent diabetes comparing hepatitis B surface antigen (HBsAg) (+) to HBsAg (-) participants was 1.17 (95% CI 1.06-1.31; P?=?0.003). The corresponding odds ratio comparing hepatitis C antibodies (HCV Ab) (+) to HCV Ab (-) participants was 1.43 (95% CI 1.01-2.02, P?=?0.043). In prospective analyses, the multivariable-adjusted hazard ratio for incident diabetes comparing HBsAg (+) to HbsAg (-) participants was 1.23 (95% CI 1.08-1.41; P?=?0.007). The number of incident cases of diabetes among HCV Ab (+) participants (10 cases) was too small to reliably estimate the prospective association between HCV infection and diabetes. In this large population at low risk of diabetes, HBV and HCV infections were associated with diabetes prevalence and HBV infection with the risk of incident diabetes. Our studies add evidence suggesting that diabetes is an additional metabolic complication of HBV and HCV infection.
| S-EPMC5496892 | biostudies-other
Project description:NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-? in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-? production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright) NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-?. Blockade of IL-10 +/- TGF-? restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-?, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-? persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-? blockade.
| S-EPMC3003000 | biostudies-literature
Project description:Background & objectives:Multiple transfusions in ?-thalassaemia patients undergoing regular transfusion regimen are at a risk of developing transfusion transmitted infections, including hepatitis C virus (HCV). The present study was conducted to investigate the association of HCV viraemia and genotype with clinical parameters in HCV seroreactive ?-thalassaemic individuals. Methods:A total of 172 HCV seroreactive ?-thalassaemic individuals aged between 2-35 yr with at least 25 units of blood transfusion were catagorized into four groups (2-12 yr, group 1; 13-19 yr, group 2; 20-29 yr, group 3; 30-35 yr, group 4). Aged matched control samples (n=87; ?-thalassaemics without HCV infection) were also included. HCV RNA was detected by nested reverse transcriptase polymerase chain reaction (RT-PCR) based on 5' UTR of HCV genome, viral load was determined by real-time RT-PCR. Nested RT-PCR amplified partial core region was used for DNA sequencing. Liver function parameters [serum total bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] were also determined. Results:Of the 172 HCV seroreactive individuals, 59.30 per cent (n=102) were HCV RNA positive. HCV viral load ranged from 173 to 32.04×10[5] IU/ml; 87.65 per cent were infected with HCV genotype 3. Liver enzymes, such as ALT, AST and serum total bilirubin were significantly elevated in all age groups compared to control groups. Serum ferritin levels were found to be high in all individuals, but 16.27 per cent of HCV-infected individuals with >10,000 IU/ml viral load also showed high ferritin levels (>1500 ?g/l) where the majority of them were infected with HCV genotype 3. Interpretation & conclusions:HCV genotype 3 was the major circulating genotype among ?-thalassaemia patients in this region. Our findings indicated an association between HCV replication and hepatic iron load and also highlighted the need for sensitive quantitative RT-PCR-based detection of HCV RNA in the high risk population.
| S-EPMC6118143 | biostudies-literature
Project description:Neurotropic recombinant strain of Mouse Hepatitis Virus, RSA59, induces meningo-encephalitis, myelitis and demyelination following intracranial inoculation. RSA59 induced neuropathology is partially caused by activation of CNS resident microglia, as demonstrated by changes in cellular morphology and increased expression of a microglia/macrophage specific calcium ion binding factor, Iba1. Affymetrix Microarray analysis for mRNA expression data reveals expression of inflammatory mediators that are known to be released by activated microglia. Microglia-specific cell surface molecules, including CD11b, CD74, CD52 and CD68, are significantly upregulated in contrast to CD4, CD8 and CD19. Protein analysis of spinal cord extracts taken from mice 6 days post-inoculation, the time of peak inflammation, reveals robust expression of IFN-γ, IL-12 and mKC. Data suggest that activated microglia and inflammatory mediators contribute to a local CNS microenvironment that regulates viral replication and IFN-γ production during the acute phase of infection, which in turn can cause phagolysosome maturation and phagocytosis of the myelin sheath, leading to demyelination.
| S-EPMC4216085 | biostudies-literature
Project description:UNLABELLED:An association of hepatitis C virus (HCV) infection with diabetes has been reported in many studies, but few have been population based and applied standard criteria for diabetes diagnosis. We examined this relationship using recent population-based data from the U.S. National Health and Nutrition Examination Survey. Adult participants (15,128) in the 1999-2010 surveys had data on diabetes status and serum HCV antibody (anti-HCV) or HCV RNA. Using American Diabetes Association criteria, diabetes was defined as a health care provider diagnosis, serum hemoglobin A1C (A1C) ?6.5%, or fasting plasma glucose (FPG) ?126 mg/dL, prediabetes as A1C 5.7%-<6.5% or FPG 100-<126 mg/dL, and normal glucose as A1C <5.7% and FPG <100 mg/dL. Odds ratios (ORs) for diabetes and prediabetes, comparing persons with HCV infection to those without, were adjusted for demographics, BMI, C-reactive protein, smoking, drinking, and blood transfusion before 1992. Among participants without diabetes, we compared mean insulin resistance (IR), estimated using homeostasis model assessment (HOMA-IR), by HCV status. The overall prevalence of anti-HCV+ was 1.7%, of HCV RNA(+) 1.1%, of diabetes 10.5%, and of prediabetes 32.8%. The prevalence of diabetes and prediabetes did not differ by HCV status. In multivariate-adjusted analysis, diabetes remained unassociated with anti-HCV (OR, 1.0; 95% confidence interval [CI]: 0.6-1.7) or with HCV RNA (OR, 1.1; 95% CI: 0.6-1.9). In contrast, elevated alanine aminotransferase and gamma glutamyltransferase activities were associated with diabetes regardless of HCV status. HOMA-IR was not associated with HCV markers in unadjusted or multivariate-adjusted analyses (P > 0.05). CONCLUSION:In the U.S. population, HCV was not associated with diabetes or with IR among persons with normal glucose. Previously reported relationships of HCV with diabetes were possibly attributable to the effect of elevated liver enzymes.
| S-EPMC4122643 | biostudies-literature
Project description:Hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection can be encountered in either virus endemic countries. Co-infection can also be found in populations at risk of parenteral transmission. Previous studies demonstrated a high risk of liver disease progression in patients with HCV/HBV co-infection; thus, they should be treated aggressively. Previous evidence recommended therapy combining peginterferon (pegIFN) alfa and ribavirin for co-infected patients with positive HCV RNA. Recent trials further advise using direct-acting antivirals (DAAs) for the clearance of HCV in the co-infected patients. Reactivation of HBV has been observed in patients post-intervention, with higher risks and earlier onset in those having had HCV cured by DAA- versus pegIFN-based therapy. The mechanism of HBV reactivation is an interesting but unsolved puzzle. Our recent study revealed that in vitro HBV replication was suppressed by HCV co-infection; HBV suppression was attenuated when interferon signaling was blocked. In vivo, the HBV viremia, initially suppressed by the presence of HCV super-infection, rebounded following HCV clearance by DAA treatment and was accompanied by a reduced hepatic interferon response. In summary, major achievements in the treatment of HCV/HBV co-infection have been accomplished over the past 20 years. Future clinical trials should address measures to reduce or prevent HBV reactivation post HCV cure.
| S-EPMC7412310 | biostudies-literature