Viral triggers of multiple sclerosis

Abstract

Genetic and environmental factors jointly determine the susceptibility to develop Multiple Sclerosis (MS). Collaborative efforts during the past years achieved substantial progress in defining the genetic architecture, underlying susceptibility to MS. Similar to other autoimmune diseases, HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes. Less-robust susceptibility effects have been identified for MHC class I alleles and for non-MHC regions. The role of environmental risk factors and their interaction with genetic susceptibility alleles are much less well defined, despite the fact that infections have long been associated with MS development. Current data suggest that infectious triggers are most likely ubiquitous, i.e., highly prevalent in the general population, and that they require a permissive genetic trait which predisposes for MS development. In this review article, we illustrate mechanisms of infection-induced immunopathologies in experimental animal models of autoimmune CNS inflammation, discuss challenges for the translation of these experimental data into human immunology research, and provide future perspectives on how novel model systems could be utilized to better define the role of viral pathogens in MS.

Fig. 1

Molecular mechanisms of pathogen-induced autoimmunity. (A) Pathogen-activated antigen-presenting cells can display self-antigens from dying cells to autoreactive T lymphocytes in a process known as bystander activation. (B) Activation of the immune system resulting from stimulation of pattern recognition receptors by infectious agents can lead to expression of proinflammatory mediators and triggering of autoreactive lymphocytes. (C) Microbial superantigens cross-link MHC class II molecules with TCRs inducing antigen unspecific activation of autoreactive T cells. (D) Certain pathogen-derived antigens share structural similarities with self-peptides causing activation of autoreactive T cells through molecular mimicry. (E) The process of epitope spreading can enhance autoimmune responses by activating autoreactive T cells to ‘new’ self-antigens during the progression of the disease. (F) Viral agents can enhance the activation state of autoantigen presenting cells and induce the survival of autoreactive lymphocytes. As an example, persistent infection of microglial cells with Theiler's murine encephalomyelitis virus (TMEV) was shown to upregulate expression of MHC and co-stimulatory molecules and enhance the ability of these cells to function as effective APCs . Furthermore, EBV infection could assist in the survival of autoreactive B cells . APC, antigen-presenting cell; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; TCR, T-cell receptor; TLR, Toll-like receptor.