Antiviral immune responses: Triggers of or triggered by autoimmunity?

Viral Immunobiology, Institute of Experimental Immunology, University Hospital Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Nature Reviews Immunology (Impact Factor: 33.84). 05/2009; 9(4):246-58. DOI: 10.1038/nri2527
Source: PubMed

ABSTRACT The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this Review, we outline the mechanisms by which viral infection can trigger autoimmune disease and describe the pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.

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    • "Molecular mimicry defines the possibility that antigens from microorganisms can activate T-lymphocytes cross-reacting with self-antigens that share similar linear or conformational structures [66]. By now mimicry mechanisms involving viral proteins are recognized to play a key role in the pathogenesis of several human autoimmune diseases [66]. In the case of anti-CYP auto-reactivity, mimicry between HCV proteins E1, NS3, NS5a and NS5b and CYP2D6 accounts for the development of LKM-1 auto-antibodies [15] [18] [67] and T-cells antigens in CYP2D6, CYP2A6 and CYP2A7 [13] [68]. "
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    ABSTRACT: Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression. Copyright © 2014. Published by Elsevier B.V.
    11/2014; 3C:72-78. DOI:10.1016/j.redox.2014.11.004
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    • "[126] The possible roles of polyreactive Abs in viral diseases, autoimmunity, and B cell malignancies are currently the subject of intense research but are still poorly understood. [86] [127] ANTIBODY HETEROSPECIFICITY "
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    ABSTRACT: The concept of antibody specificity is analyzed and shown to reside in the ability of an antibody to discriminate between two antigens. Initially, antibody specificity was attributed to sequence differences in complementarity determining regions (CDRs), but as increasing numbers of crystallographic antibody-antigen complexes were elucidated, specificity was analyzed in terms of six antigen-binding regions (ABRs) that only roughly correspond to CDRs. It was found that each ABR differs significantly in its amino acid composition and tends to bind different types of amino acids at the surface of proteins. In spite of these differences, the combined preference of the six ABRs does not allow epitopes to be distinguished from the rest of the protein surface. These findings explain the poor success of past and newly proposed methods for predicting protein epitopes. Antibody polyspecificity refers to the ability of one antibody to bind a large variety of epitopes in different antigens, and this property explains how the immune system develops an antibody repertoire that is able to recognize every antigen the system is likely to encounter. Antibody heterospecificity arises when an antibody reacts better with another antigen than with the one used to raise the antibody. As a result, an antibody may sometimes appear to have been elicited by an antigen with which it is unable to react. The implications of antibody polyspecificity and heterospecificity in vaccine development are pointed out. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Molecular Recognition 11/2014; 27(11). DOI:10.1002/jmr.2394 · 2.34 Impact Factor
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    • "As herpesvirus family has been linked to the development of fibrosis, we focused our attention on Epstein–Barr virus (EBV), a g-herpesvirus that has been a leading candidate in triggering several autoimmune diseases (Ebrahimi et al., 2001; Niller et al., 2008; Dreyfus, 2011; Stoolman et al., 2011). This virus is a biologically plausible source for endogenous innate immune activation as it is ubiquitous in nature, establishes a life-long silent infection with continuous virus production because of reactivation, and most importantly, modulates the human immune system, evolving immune evasion strategies to the host antiviral response (Young and Rickinson, 2004; Munz et al., 2009; Martorelli et al., 2012). We show that EBV is able to infect human dermal fibroblasts, and modulate the innate immune response in infected fibroblasts, inducing fibroblast–myofibroblast conversion typical of a profibrotic phenotype. "
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    ABSTRACT: Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic-γ-Herpesvirus that has co-evolved with human species infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV-non-coding-small-RNAs (EBER) and the increased expression of immediate-early-lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human-SSc-fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-TLR aberrant activation induces the expression of selected IRFs, ISGs, TGFβ1 and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the pro-fibrotic phenotype in SSc-fibroblasts.Journal of Investigative Dermatology accepted article preview online, 15 October 2013; doi:10.1038/jid.2013.423.
    Journal of Investigative Dermatology 10/2013; DOI:10.1038/jid.2013.423 · 6.37 Impact Factor
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