Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects about 0.1% of the worldwide population. This deleterious disease is marked by infiltration of myelin-specific T cells that attack the protective myelin sheath that surrounds CNS nerve axons. Upon demyelination, saltatory nerve conduction is disrupted, and patients experience neurologic deficiencies. The exact cause for MS remains unknown, although most evidence supports the hypothesis that both genetic and environmental factors contribute to disease development. Epidemiologic evidence supports a role for environmental pathogens, such as viruses, as potentially key contributors to MS induction. Pathogens can induce autoimmunity via several well-studied mechanisms with the most postulated being molecular mimicry. Molecular mimicry occurs when T cells specific for peptide epitopes derived from pathogens cross-react with self-epitopes, leading to autoimmune tissue destruction. In this review, we discuss an in vivo virus-induced mouse model of MS developed in our laboratory, which has contributed greatly to our understanding of the mechanisms underlying molecular mimicry-induced CNS autoimmunity.

Figure 1

 Mechanisms of viral induced autoimmunity. (A). Bystander activation. Chronic viral infection leads to activated lymphocytes that secrete inflammatory mediators mediating tissue damage. Once tissue is damaged, self‐epitopes are released into the milieu, presented by APCs to autoreactive T cells which can mediate further tissue damage. (B). Epitope spreading. T‐cell responses ‘spread’ from virus‐specific to self‐specific after continuous inflammation in a chronic virus setting. As tissue is destroyed, self‐epitopes are released and present to T cells by APCs, which can mediate further damage to the tissue. Upon further tissue destruction, increasing self‐epitopes are released and can be presented and activate naive autoreactive T cells. (C). Molecular mimicry. Tissue damage is mediated by autoreactive T cells that become activated after cross‐reacting with viral epitopes presented by APCs.

Figure 2

 Summary of induction of CNS autoimmunity in SJL/J mice by virus infection‐induced molecular mimicry. (A). Amino acid sequence of PLP_139–151 and molecular mimics. The amino acid sequence of PLP_139–151 and natural molecular mimics of this dominant encephalitogenic self‐epitope encoded by H. influenza (HI_574–586) and mouse hepatitis virus (MHV_3821–3832). The primary and secondary TCR and MHC class II residues are indicated. (B). Pictorial representation of the ability of engineered TMEV encoding PLP_139–151 and varying molecular mimics to induce early onset demyelinating disease. Induction of early onset demyelinating disease in SJL/J mice following i.c. infection with the various viruses is indicated.