TYPE I Interferons (alpha/beta) in immunity and autoimmunity

Immunology Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/2005; 23(1):307-36. DOI: 10.1146/annurev.immunol.23.021704.115843
Source: PubMed


The significance of type I interferons (IFN-alpha/beta) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-alpha/beta, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.

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Available from: Bruce Beutler, Mar 10, 2014
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    • "maturation as well releasing the cytokines involved in T cell activation (Theofilopoulos et al. 2005). It is important to note that type I IFNs are transcriptionally regulated and are induced after recognition of typical PAMPs during infection (Taniguchi and Takaoka 2002). "
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    ABSTRACT: Interferons (IFNs) are cytokines released by host cells in response to the presence of pathogens or tumor cells. The aim of this review was to present the previously known and new findings about the role of interferons type I and II, and recently discovered type III in Mycobacterium tuberculosis (M. tuberculosis) infection control. Infection of various cell types with M. tuberculosis induce both IFN-α and IFN-β synthesis. The majority of the studies support the findings that IFN type I actually promotes infection with M. tuberculosis. It has been well establish that IFN-γ has protective function against M. tuberculosis and the other mycobacteria and that the primary source of this cytokine are CD4(+) and CD8(+) T cells. Recently, it has been shown that also the innate lymphocytes, γδ T cells, natural killer (NK) T cells, and NK cells can also be the source of IFN-γ in response to mycobacterial infection. Several studies have shown that CD4(+) T cells protect mice against M. tuberculosis independently of IFN-γ. The balance between IFN-γ and different cytokines such as IL-10 and other Th2 cell cytokines is likely to influence disease outcome. Type I IFN appears to be detrimental through at least three separate, but overlapping, type I IFN-mediated mechanisms: induction of excessive apoptosis, specific suppression of Th1 and IFN-γ responses, and dampening of the immune response by strong IL-10 induction. Recently it has been found that M. tuberculosis infection in A549 lung epithelial cells stimulate up-regulation of IFN-λ genes in vitro. IFN-λs also have a role in modulation of Th1/Th2 response. IFN-λs are not essential for M. tuberculosis infection control, but can give some contribution in immune response to this pathogen.
    Full-text · Article · Sep 2015 · Archivum Immunologiae et Therapiae Experimentalis
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    • "These observations are critical for understanding the innate immune function of pluripotent stem as well as progenitor cells and tissue rejection during cell therapy application. Interferons are a diverse family of cytokines which possess antiviral and immunomodulatory properties (Isaacs and Lindenmann, 1957; Stark et al., 1998; Theofilopoulos et al., 2005). These specialized proteins are produced by cells in response to viral infection. "
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    ABSTRACT: Pluripotent stem cells are being actively studied as a cell source for regenerating damaged liver. For long-term survival of engrafting cells in the body, not only do the cells have to execute liver-specific function but also withstand the physical strains and invading pathogens. The cellular innate immune system orchestrated by the interferon (IFN) pathway provides the first line of defense against pathogens. The objective of this study is to assess the innate immune function as well as to systematically profile the IFN-induced genes during hepatic differentiation of pluripotent stem cells. To address this objective, we derived endodermal cells (day 5 post-differentiation), hepatoblast (day 15) and hepatocyte-like cells (day 21) from human embryonic stem cells (hESCs). Day 5, 15 and 21 cells were stimulated with IFN-α and subjected to IFN pathway analysis. Transcriptome analysis was carried out by RNA sequencing. The results showed that the IFN-α treatment activated STAT-JAK pathway in differentiating cells. Transcriptome analysis indicated stage specific expression of classical and non-classical IFN-stimulated genes (ISGs). Subsequent validation confirmed the expression of novel ISGs including RASGRP3, CLMP and TRANK1 by differentiated hepatic cells upon IFN treatment. Hepatitis C virus replication in hESC-derived hepatic cells induced the expression of ISGs - LAMP3, ETV7, RASGRP3, and TRANK1. The hESC-derived hepatic cells contain intact innate system and can recognize invading pathogens. Besides assessing the tissue-specific functions for cell therapy applications, it may also be important to test the innate immune function of engrafting cells to ensure adequate defense against infections and improve graft survival. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Stem Cell Research
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    • "The evolutionarily conserved Jak-Stat pathway controls important developmental and homeostatic processes, including hematopoiesis and immunity[9,10]. Deficiencies in Jak-Stat pathway genes cause serious immune disorders and increase susceptibility to infections[11– 13], whereas hyperactivated Jak-Stat responses are associated with autoimmune diseases and carcinogenesis in humans[13,14]. Also in insects, the Jak-Stat pathway needs to be tightly controlled . "
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    ABSTRACT: Author Summary Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune response. The molecular mechanisms underlying this novel concept remain largely uncharacterized. Here, we demonstrate that the epigenetic regulator G9a mediates tolerance to virus infection in Drosophila. We found that G9a-deficient flies succumb faster than control flies to infection with RNA viruses, but that the viral burden did not significantly differ. Unexpectedly, mutant flies express higher levels of genes that are regulated by the Jak-Stat signaling pathway, which in other studies was found to be important for antiviral defense. Exploiting the genetic toolbox in Drosophila, we demonstrate that Jak-Stat hyperactivation induces early mortality after virus infection. Precise control of immune pathways is essential to ensure efficient immunity, while preventing damage due to excessive immune responses. Our results indicate that G9a, an epigenetic modifier, dampens Jak-Stat responses to prevent immunopathology. Therefore, we propose epigenetic regulation of immunity as a new paradigm for disease tolerance.
    Full-text · Article · Apr 2015 · PLoS Pathogens
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