Antiviral immune responses: triggers of or triggered by autoimmunity?

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.

Figure 1. Infectious agents act as adjuvants for the activation and potentiation of immune responses, fostering induction of autoimmune diseases

Detection of pathogen-associated molecular patterns (PAMP) occurs via pattern recognition receptors (PRR). These include Toll-like receptors (TLRs), a set of receptors that sense a variety of molecules associated with bacteria and viruses outside or within endosomes or phagosomes of cells; nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), which detect similar molecules found within the cytoplasm; retinoic acid-inducible gene-I (RIG-I)-like helicases (RLH), which detect viral RNA within the cytoplasm; and a subset of C-type lectin receptors (CLR), which detect microbial DNA, RNA, or cell wall components. Activation of these PRRs results in a cascade of events culminating in the activation of interferon response factors (IRF) and NFκB, which trigger release of Type I Interferons and inflammatory cytokines, respectively. PRR ligation also results in cellular maturation and activation, including the upregulation of costimulatory molecules to allow efficient T-cell activation. Autoreactive T cells, activated in this fashion, could then cause autoimmune tissue damage. In addition, PRR stimulation can result in class switching and upregulation of antibody production in B cells . Thus for autoreactive B cells, PRR triggers can directly augment autoimmune responses. Finally, the presence of a microbial infection provides antigen for activation of microbe-specific T and B cells that potentiate the inflammatory response, or for activation of T and B cells specific for antigens that are cross-reactive with self antigens.

Figure 2. Mechanisms of infection-induced autoimmunity

A) Molecular mimicry occurs through cross-reactive recognition between a microbial antigen/MHC and a self antigen/MHC complex. B) i, Microbial infection stimulates TLRs, NLRs, etc., leading to tissue destruction via inflammatory mediators originating from cells of the innate immune system. ii, During bystander activation, engulfment of self antigen by activated APC is followed by presentation to autoreactive T cells (concomitant with presentation of virus antigen to virus-specific T cells). Alternatively an infection can lead to microbial superantigen-induced activation of a subset of T cells, some of which are specific for self antigen. iii, T cell-mediated tissue destruction along with inflammatory molecule-mediated destruction releases more self antigen from tissues. iv, During epitope spreading, the response spreads to T cells specific for other self antigens.

Figure 3. Mechanisms by which infection-induced autoimmune disease can occur in an organ distant from that of the initial infection, and/or subsequent to pathogen clearance

Autoreactive T cells can be activated via molecular mimicry or bystander activation in a tissue undergoing infection, without eliciting overt autoimmune disease before the infection is resolved. A) After migrating to a distant site, if sufficient antigen is available at this site, these previously activated T cells can trigger autoimmune disease. If sufficient self-antigen is not present, the induction of overt autoimmune disease may require a secondary infection or trauma. B) Similarly, T cells that were activated during infection in a particular tissue can become re-activated at a later date by a secondary infection with the same or a new microbe, or by a trauma. Presumably, autoimmune disease subsequent to microbial clearance can occur in the initial tissue or in a secondary site, if enough self-antigen is available for presentation.

Figure 4. Adjuvant activity and cognate autoantigen recognition in autoantigen complexes can lead to the reactivation of lymphotropic viruses like EBV

B cell receptor cross-linking triggers lytic infection in EBV positive B cells, increasing viral load and lytic EBV antigen presentation to specific T cells. This might lead to elevated EBV specific immune control in patients with autoimmune disease. The adjuvant activity of autoantigen complexes might sustain or reactivate latent EBV antigen expression, resulting in the expansion of latent EBV specific T cell responses.

Figure 5. Primed T and B cells might accumulate in autoimmune lesions due to their migratory behaviour to inflamed tissues

The chemokine CXCL10/IP-10 binding to CXCR3 has been implicated in effector T cell recruitment to inflamed tissues, and the chemokine CXCL13 has been implicated in CXCR5-dependent attraction of B cells to multiple sclerosis lesions.