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  • Review Article
  • Published:

Antiviral immune responses: triggers of or triggered by autoimmunity?

Nature Reviews Immunology volume 9, pages 246–258 (2009)Cite this article

Key Points

  • Viruses can serve as triggers of autoimmune disease by acting as adjuvants, leading to the priming of autoantigen-specific lymphocytes. Autoantigen-reactive T and B cells can also be activated following recognition of viral antigens with similarity to self antigens (molecular mimicry) or following recognition of new self epitopes released from damaged tissues (epitope spreading).

  • Virus infection and immune control can also be altered, in terms of the type of immune response, the viral set point during chronic infections and the anatomical distribution of virus-specific lymphocytes, in patients with autoimmune diseases. Antiviral responses may be modified in these patients as a consequence of the same genetic variants that predispose them to autoimmune diseases.

  • Dysregulated antiviral immune responses might reflect the contribution of these responses to autoimmune disease or might result from altered immune homeostasis in patients.

  • Possible underlying mechanisms are discussed in the setting of autoimmune inflammation of the central nervous system. We focus on recent studies on the induction of immune-mediated demyelination by Theiler's murine encephalomyelitis virus infection and the association of multiple sclerosis with increased immune control of Epstein–Barr virus.

  • An understanding of the underlying mechanisms of dysregulated virus-specific immune responses in autoimmune diseases could reveal new approaches for treating or diagnosing these diseases.

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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Figure 1: Infectious agents function as adjuvants for the activation and promotion of immune responses and autoimmune diseases.
Figure 2: Mechanisms of infection-induced autoimmunity.
Figure 3: Autoimmunity can occur at a site distal to the initiating infection and/or following pathogen clearance.
Figure 4: Adjuvant activity and specific recognition of autoantigen-containing immune complexes can lead to the reactivation of lymphotropic viruses.

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Acknowledgements

The laboratory of C.M. is supported by the Dana Foundation's Neuroimmunology programme, the Arnold and Mabel Beckman Foundation, the Alexandrine and Alexander Sinsheimer Foundation, the Burroughs Wellcome Fund, the Starr Foundation, the National Cancer Institute (R01CA108609 and R01CA101741), the National Institute of Allergy and Infectious Diseases (RFP-NIH-NIAID-DAIDS-BAA-06-19), the Foundation for the National Institutes of Health (Grand Challenges in Global Health) and an Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital). J.D.L. is supported by a Dana Foundation and Irvington Institute's Human Immunology Fellowship, a Pilot Grant from the National Multiple Sclerosis Society (PP1145) and an Institutional Clinical and Translational Science Pilot and Collaborative Project Grant (to the Rockefeller University Hospital). The laboratory of S.D.M. and M.T.G. is supported by the National Institute for Neurological Diseases and Stroke (R01 NS-023349, R01 NS-040460 and R01 NS-030871), the National Multiple Sclerosis Society (RG 3793-A-7) and the Myelin Repair Foundation.

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Authors and Affiliations

  1. Viral Immunobiology, Institute of Experimental Immunology, University Hospital Zürich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland

    Christian Münz

  2. Laboratory of Viral Immunobiology, The Rockefeller University, New York, 10065, New York, USA

    Christian Münz & Jan D. Lünemann

  3. Department of Microbiology–Immunology and Interdepartmental Immunobiology Center, Northwestern University, Feinberg School of Medicine, Chicago, 60611, Illinois, USA

    Meghann Teague Getts & Stephen D. Miller

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Glossary

Pattern-recognition receptor

A host receptor (such as a Toll-like receptor) that can sense pathogen-associated molecular patterns and initiate signalling cascades (which involve activation of nuclear factor-κB) that lead to an innate immune response.

Adjuvant

A non-infectious form of immune activation used to increase immune responses to antigen.

Molecular mimicry

A term used to describe what happens when a T- or B-cell receptor recognizes a microbial peptide that is structurally similar to a self peptide. The immune response, which is initially directed at the microbial peptide, spreads to tissues that present the crossreactive self peptide, resulting in autoimmunity.

Negative selection

The intrathymic elimination of double-positive or single-positive thymocytes that express T-cell receptors with high affinity for self antigens.

Polyfunctional T cell

A T cell that has two or more functions, including, but not limited to, cytotoxicity and production of cytokines or chemokines. The development of multiparameter flow cytometry has facilitated the extensive analysis of T-cell effector functions at the single-cell level.

Clonal exhaustion

A state of non-reactivity in which all precursor lymphocytes are induced by a persistent antigen (or antigens) to become effector cells, purging the immune-response repertoire of this specificity (or specificities).

Activation-induced cell death

A process by which fully activated T cells undergo programmed cell death through engagement of cell-surface-expressed death receptors, such as CD95 (also known as FAS) or the tumour-necrosis-factor receptor.

Bystander activation

Activation and/or expansion of an immune response at a site of direct inflammation-induced tissue damage.

Epitope spreading

A process by which autoreactive T-cell or B-cell responses induced by a single peptide (or epitope) can spread to include other peptides (or epitopes) in the same autoantigen (intramolecular spreading) or in other self antigens (intermolecular spreading) that are released after T- or B-cell-mediated bystander tissue damage.

Immunodominant epitope

A portion of an antigen that is targeted preferentially or to a greater level during an immune response.

Superantigen

A microbial protein that activates all T cells which express a particular set of T-cell receptor (TCR) Vβ chains by cross-linking the TCR to a particular MHC molecule regardless of the peptide presented.

Altered peptide ligand

(APL). A peptide analogue of the original antigenic peptide. APLs commonly have amino acid substitutions at T-cell receptor (TCR) contact residues. TCR engagement by these APLs usually leads to partial or incomplete T-cell activation. Antagonistic APLs can specifically antagonize and inhibit T-cell activation induced by the wild-type antigenic peptide.

Rheumatoid factor

An antibody (usually IgM) that binds to the Fc region of IgG, thereby forming immune complexes. Rheumatoid factors are sometimes found in patients with rheumatoid arthritis or other autoimmune diseases, such as systemic lupus erythematosus.

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Münz, C., Lünemann, J., Getts, M. et al. Antiviral immune responses: triggers of or triggered by autoimmunity?. Nat Rev Immunol 9, 246–258 (2009). https://doi.org/10.1038/nri2527

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