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.


Available from: Bruce Beutler, Mar 10, 2014
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Archivum Immunologiae et Therapiae Experimentalis 09/2015; DOI:10.1007/s00005-015-0365-7 · 3.18 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Stem Cell Research 08/2015; 15(2):354-364. DOI:10.1016/j.scr.2015.08.003 · 3.69 Impact Factor
  • Source
    • "Although SLE is a multifactorial disease, increasing evidence indicates that type I interferon (IFN-I) plays a pivotal role in the disease pathogenesis (Crow, 2010); (Elkon & Wiedeman, 2012). IFN-I constitutes a family of cytokines (IFN-a, IFN-b IFN-e, IFN-j, IFN-x, IFN-d and IFN-s) that are important for clearance of viral infections but whose uncontrolled production contributes to autoimmune and inflammatory conditions (Theofilopoulos et al, 2005). While most cells can produce IFN-I in response to nucleic acids, plasmacytoid dendritic cells (pDCs) are considered the major producers of IFN-I (Liu, 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes bind to the CD32a (FcγRIIa) receptor on the surface of plasmacytoid dendritic cells (pDCs) and stimulate the secretion of IFN-I from pDCs. BDCA2 is a pDC-specific receptor that, when engaged, inhibits the production of IFN-I in human pDCs. BDCA2 engagement, therefore, represents an attractive therapeutic target for inhibiting pDC-derived IFN-I and may be an effective therapy for the treatment of SLE. In this study, we show that 24F4A, a humanized monoclonal antibody (mAb) against BDCA2, engages BDCA2 and leads to its internalization and the consequent inhibition of TLR-induced IFN-I by pDCs in vitro using blood from both healthy and SLE donors. These effects were confirmed in vivo using a single injection of 24F4A in cynomolgus monkeys. 24F4A also inhibited pDC activation by SLE-associated immune complexes (IC). In addition to the inhibitory effect of 24F4A through engagement of BDCA2, the Fc region of 24F4A was critical for potent inhibition of IC-induced IFN-I production through internalization of CD32a. This study highlights the novel therapeutic potential of an effector-competent anti-BDCA2 mAb that demonstrates a dual mechanism to dampen pDC responses for enhanced clinical efficacy in SLE. © 2015 Biogen Idec. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 03/2015; 7(4). DOI:10.15252/emmm.201404719 · 8.67 Impact Factor
Show more