Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus

Paladino, Natalia; Flores, Ana Claudia; Marcos, C. Y.; Fainboim, Hugo; Theiler, G.; Arruvito, Lourdes; Williams, Fionnuala; Middleton, D.; Fainboim, Leonardo

doi:10.1111/j.1399-0039.2006.762_7.x

Cited by 43 publications

(33 citation statements)

References 9 publications

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“…Indeed, our analysis led to identification of a specific KIR haplotype in the centromeric haplotype block that is associated with chronic HCV infection in patients. This haplotype also included KIR2DL2, KIR3DL3, KIR2DS2, and KIR2DL1 genes, some of which have been found to be associated with chronic HCV infection in other studies (16,18). Indeed, because KIR2DL1 and KIR2DL2 both encode receptors that bind to HLA-C2 (32,44), these are possible candidate genes for explaining the increased risk of chronic infection associated with KIR2DS3 and HLA-C2.…”

Section: Discussionmentioning

confidence: 99%

“…NK cells detect virally infected cells through KIR interactions with HLA class I. Several studies have investigated the role of KIR and HLA in HCV infection, but low sample numbers and heterogeneity of patient cohorts in terms of sex, age, ethnicity, route of infection, and HCV genotype have resulted in conflicting results (15)(16)(17). One larger study identified an inhibitory KIR gene, KIR2DL3, associated with resolution of HCV infection, and this was dependent on a homozygous HLA class I ligand background (11,18,19).…”

Section: −7mentioning

confidence: 99%

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Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Dring

Morrison

McSharry

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

114

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Hepatitis C is a common infection with significant morbidity and mortality, and only a minority of patients successfully clear the infection. Identification of factors that influence disease progression in HCV infection is difficult owing to the lack of well-defined patient cohorts. However, recent evidence supports a role for the innate immune system in virus clearance. In this study, we investigated innate immune genes for their contribution to disease progression in a unique cohort of well-controlled HCV-infected patients. The Irish cohort of HCV patients is uniquely homogenous; patients were infected with a single genotype of HCV from contaminated anti-D Ig. We genotyped 543 infected patients, including 247 patients who spontaneously resolved infection, for natural killer (NK) cellassociated killer cell Ig-like receptors (KIR) genes and the recently reported IL28B (IFNλ3) SNP. The NK cell gene KIR2DS3 was significantly increased in patients with chronic infection [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.25-2.90, P < 0.002]. The IL28B "T" allele was also significantly increased in chronically infected patients (OR 7.38, 95% CI 4.93-11.07, P < 10). The presence of both markers synergized to significantly increase the risk of chronic infection over either factor alone (OR 20.11, 95% CI 9.05-44.68, P < 10 −7). In functional experiments, we found that IL28A significantly inhibited IFN-γ production by NK cells. Thus, we demonstrate a functional link between NK cells and type 3 IFN. Our findings may contribute to the development of a prognostic test for HCV and identify therapeutic strategies for the clinical management of HCV-infected patients.

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Section: Discussionmentioning

confidence: 99%

Section: −7mentioning

confidence: 99%

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Dring

Morrison

McSharry

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

114

View full text Add to dashboard Cite

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“…Interestingly, the homozygous expression of the inhibitory NK cell receptor gene KIR2DL3 and its ligands, the HLA-C group 1 alleles, correlate with clearance of HCV (40). In turn, the activating receptor gene KIR2DS3 is associated with elevated transaminases and seropositive HCV infection (41). Both studies suggest that reduced NK cell activity might have a beneficial impact on HCV clearance.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity

Lang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

286

330

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Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3 −/− , E4BP4 −/− ) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.

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“…[15][16][17][18] While data on HCV sequelae in other indigenous peoples of the Americas are lacking, the possibility that inherited KIR gene profiles could contribute to these disease patterns is strengthened by the observation that similarities exist between the KIR gene profiles of this Aboriginal cohort and those reported in association with spontaneous clearance of HCV. 1,39,40 …”

Section: Current Kir Genetic Profiles May Reflect Historical Immune Smentioning

confidence: 99%

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

et al. 2011

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Genetic differences in immune regulators influence disease resistance and susceptibility patterns. There are major health discrepancies in immune-mediated diseases between Caucasians and Canadian Aboriginal people, as well as with other indigenous people of the Americas. Environmental factors offer a limited explanation as Aboriginal people also demonstrate a rare resistance to chronic hepatitis C virus infection. Killer immunoglobulin-like receptors (KIRs) are known modulators of viral responses and autoimmune diseases. The possibility that variation in KIR cluster profiles contribute to the health outcomes of Aboriginal people was evaluated with Canadian Caucasian (n¼93, population controls) and Aboriginal (n¼86) individuals. Relative to Caucasians, the Aboriginal KIR cluster displayed a greater immune activating phenotype associated with genes of the B haplotype situated within the telomeric region. In conjunction, there was a decrease in the genes of the B haplotype from the centromeric region. Caucasian and Aboriginal cohorts further demonstrated distinct genotype and haplotype relationships enforcing the disconnect between the B haplotype centromeric and telomeric regions within the Aboriginal population. Moreover, Caucasian KIR cluster patterns reflected studies of Caucasians globally, as well as Asians. In contrast, the unique pattern of the Canadian Aboriginal cohort mirrored the phenotype of other indigenous peoples of the Americas, but not that of Caucasians or Asians. Taken together, these data suggest that historically indigenous peoples of the Americas were subject to immune selection processes that could be influencing the current disease resistance and susceptibility patterns of their descendents.

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Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus

Cited by 43 publications

References 9 publications

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

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Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus

Cited by 43 publications

References 9 publications

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

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Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 ⁺ T-cell immunity