IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis

Eslam, Mohammed; McLeod, Duncan; Kelaeng, Kebitsaone Simon; Mangia, Alessandra; Berg, Thomas; Thabet, Khaled; Irving, William L.; Dore, Gregory J.; Sheridan, David; Grønbæk, Henning; Abate, Maria Lorena; Hartmann, Rune; Bugianesi, Elisabetta; Spengler, Ulrich; Rojas, Ángela; Booth, David R.; Weltman, Martin; Mollison, Lindsay; Cheng, Wendy; Riordan, Stephen M.; Mahajan, Hema; Fischer, Janett; Nattermann, Jacob; Douglas, Mark W.; Liddle, Christopher; Powell, Elizabeth E.; Romero–Gómez, Manuel; George, Jacob

doi:10.1038/ng.3836

Cited by 88 publications

(94 citation statements)

References 43 publications

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“…Further, considering both genotypes together (rs12979860 CC and rs8099917 TT), we also found this association to be significant, suggesting and additive effect on liver inflammation in patients harboring both genotypes. As these polymorphisms are close to IFN-λ3, which has been involved in the modulation of antiviral responses [13] [26] [27] [28], our results, in agreement with a recent report concluding that IFN-λ3 rather than IFN-λ4 likely mediates haplotype-dependent hepatic inflammation and fibrosis [29], support the hypothesis that this interferon is contributing to a stronger immune response to HCV during the acute infection phase, favoring the spontaneous clearance. Moreover, they also suggest a role for this cytokine in the chronic infection inducing a favorable outcome to the antiviral therapy.…”

Section: Discussionsupporting

confidence: 91%

IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients

Machicote¹,

Flichmann²,

Arana³

et al. 2018

IJCM

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Background: Hepatitis C virus (HCV) is a major cause of chronic liver disease, including cirrhosis and liver cancer. The aim of our study was to determine whether IL28B single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 can be considered a prognostic host factor in untreated chronic HCV patients. Methods: We set up a real-time Allele Specific PCR amplification to determine the allele present in each polymorphic site, and statistically grouped and compared this result with clinical data. Results: We determined rs12979860 and rs8099917 genotype and allele frequencies in a single cohort of untreated chronically HCV-infected patients. We found significant associations between higher inflammatory activity, measured as ALT levels or METAVIR scores and rs12979860 CC (P = 0.0013 and P = 0.0033, respectively) and rs8099917 TT (P = 0.0005 and P = 0.0264, respectively) genotypes. Interestingly, considering both genotypes together, we also found association with ALT levels (P = 0.0003; OR = 5.125) or METAVIR scores (P = 0.0038; OR = 5.179), suggesting and additive effect on liver inflammation in these patients. Conclusion: we show association between hepatic inflammatory activity in a single Argentinean untreated chronically HCV cohort and SNPs located in the interferon lambda gene region. The studied polymorphisms, together with further innate and adaptive immune responses, clearly play a role in modulating the HCV infected patients outcome, contributing to hepatic inflammation and possible fibrosis/cirrhosis.

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Section: Discussionsupporting

confidence: 91%

IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients

Machicote¹,

Flichmann²,

Arana³

et al. 2018

IJCM

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“…Growing literature demonstrates genetic associations between rs368234815 or its linked variants with other clinical phenotypes, such as relapse on DAA treatment of HCV (12), liver fibrosis (13, 14), hepatic metallothionein expression (15), post-partum immune activation (16, 17), risk of mucinous ovarian cancer (18), etc. Although other, invariantly expressed type-III IFNs might be also important for these phenotypes, only IFN-λ4 is directly and most dramatically affected by the associated variant, rs368234815, that either creates or eliminates IFN-λ4.…”

Section: Introductionmentioning

confidence: 99%

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

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Type-III interferons (IFNs) are important mediators of antiviral immunity. IFN-λ4 is a unique type-III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear HCV infection. Here, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on HCV clearance. We used fresh primary human hepatocytes (PHH) treated with recombinant type-III IFNs or infected with Sendai virus (SeV) to model acute viral infection, and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in SeV-infected PHH from individuals with the dG allele, where it was poorly secreted but highly functional even at concentrations below 50 pg/ml. IFN-λ4 acted faster than other type-III IFNs in inducing antiviral genes as well as negative regulators of IFN response, such as USP18 and SOCS1. Transient treatment of PHH with IFN-λ4 but not IFN-λ3 caused a strong and sustained induction of SOCS1, and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.

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“…After the adjustment of all the co-variates, the association persisted, indicating that there was no recruitment bias and that resistant genotype frequencies between groups were not influenced by ancestry. The rs12979860 has been the most important polymorphism in the region (Eslam et al, 2017). When, we arranged the haplotypes, including this SNP, our analysis showed that C-C combination at rs8109886 and rs12979860 demonstrated that the likelihood of abnormal CZS was reduced 14.3 times (OR = 0.07).…”

Section: Discussionmentioning

confidence: 86%

Congenital Zika Syndrome is associated with interferon alfa receptor 1

Azamor

Cunha²,

Silva³

et al. 2019

Preprint

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Graphical abstract SummaryMaternal and/or fetal factors that influence Congenital Zika Syndrome (CZS) development remain elusive. Interferon lambda has been reported as an antiviral factor in Zika infections. Using functional analysis, we conducted a case-control study to demonstrate that maternal interferon lambda single nucleotide polymorphisms (SNPs) contribute to newborn protection. Mothers carrying CA/CC genotypes of rs8109886 SNP have 4.5 times reduced risk of having children with CZS. When we combined the genotypes CC from rs12979860 and CA/CC from rs8109886, 93% of the mothers delivered healthy newborns.Placenta coming from CZS cases displayed diminished level of IFNL2 along with higher tissue-specific type-I IFN genes, tagged by of IFIT5, indicating that lower IFNL levels upon ZIKV infection can lead to uncontrolled damage to overexpression of type-I IFN pathway.In summary, genetically regulated IFNL levels contribute to immune homeostasis and CZS prevention.

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IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis

Cited by 88 publications

References 43 publications

IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients

IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Congenital Zika Syndrome is associated with interferon alfa receptor 1

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