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Genetics of the Human Interferon Lambda Region.

ABSTRACT: Humans are polymorphic in their ability to produce type-III interferons. Most individuals of African ancestry are genetically capable of generating all 4 type-III interferons (IFN-?1, 2, 3, and 4), whereas the majority of individuals of European and Asian ancestry lack IFN-?4 and thus can generate only IFN-?1, 2, and 3. All 4 type-III IFNs are encoded by genes located within a ?55?kb genomic region on human chromosome 19. Although IFN-?4 appears to be important in animals, genetic alterations acquired in the Hominidae lineage, and particularly in humans, resulted in the elimination of IFN-?4 or restriction of its activity, suggesting that IFN-?4 function might be detrimental to human health. Genetic variants within the IFNL region, including those controlling production and activity of IFN-?4, have been strongly associated with clearance of hepatitis C virus (HCV) infection. There is growing evidence for association of the same genetic variants with a multitude of other disease conditions. This article reviews the genetic landscape of the human IFNL genetic locus, with an emphasis on the genetic control of IFN-?4 production and activity, and its association with viral clearance.

SUBMITTER: Prokunina-Olsson L

PROVIDER: S-EPMC6767866 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetics of the Human Interferon Lambda Region.

Prokunina-Olsson Ludmila L

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20190508 10

Humans are polymorphic in their ability to produce type-III interferons. Most individuals of African ancestry are genetically capable of generating all 4 type-III interferons (IFN-λ1, 2, 3, and 4), whereas the majority of individuals of European and Asian ancestry lack IFN-λ4 and thus can generate only IFN-λ1, 2, and 3. All 4 type-III IFNs are encoded by genes located within a ∼55 kb genomic region on human chromosome 19. Although IFN-λ4 appears to be important in animals, genetic alterations ac ...[more]

PMID: 31070498

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Project description:Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered. First, the IFNLR is not ubiquitously expressed: in particular, immune cells show significant variation in the expression levels of and susceptibilities to IFN-λs. Second, the binding affinities of individual IFN-λs to the IFNLR varies greatly and are generally lower compared to the binding affinities of IFN-α to its receptor. Finally, genetic variation in the form of a series of single-nucleotide polymorphisms (SNPs) linked to genes involved in the IFN-λ signaling cascade has been described and associated with the clinical course and treatment outcomes of hepatitis B and C virus infection. The clinical impact of IFN-λ signaling and the SNP variations may, however, reach far beyond viral hepatitis. Recent publications show important roles for IFN-λs in a broad range of viral infections such as human T-cell leukemia type-1 virus, rotaviruses, and influenza virus. IFN-λ also potentially modulates the course of bacterial colonization and infections as shown for Staphylococcus aureus and Mycobacterium tuberculosis. Although the immunological processes involved in controlling viral and bacterial infections are distinct, IFN-λs may interfere at various levels: as an innate immune cytokine with direct antiviral effects; or as a modulator of IFN-α-induced signaling via the suppressor of cytokine signaling 1 and the ubiquitin-specific peptidase 18 inhibitory feedback loops. In addition, the modulation of adaptive immune functions via macrophage and dendritic cell polarization, and subsequent priming, activation, and proliferation of pathogen-specific T- and B-cells may also be important elements associated with infectious disease outcomes. This review summarizes the emerging details of the IFN-λ immunobiology in the context of the host immune response and viral and bacterial infections.

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Genetics of the Human Interferon Lambda Region.

Publications

Genetics of the Human Interferon Lambda Region.

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