The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?

Abstract

Multiple sclerosis (MS) is a T cell driven autoimmune disease of the central nervous system (CNS). Despite its association with Epstein-Barr Virus (EBV), how viral infections promote MS remains unclear. However, there is increasing evidence that the CNS is continuously surveyed by virus-specific T cells, which protect against reactivating neurotropic viruses. Here, we discuss how viral infections could lead to the breakdown of self-tolerance in genetically predisposed individuals, and how the reactivations of viruses in the CNS could induce the recruitment of both autoaggressive and virus-specific T cell subsets, causing relapses and progressive disability. A disturbed immune surveillance in MS would explain several experimental findings, and has important implications for prognosis and therapy.

Figure 1

Viral Infections Could Induce Bystander Generation of Pathogenic T Helper (Th)-1/17Cells. Local reactivations of neurotropic viruses in the central nervous system (CNS) parenchyma (A) leads to tissue damage and the uptake of both viral and myelin-derived antigens by dendritic cells (DCs). Virus-activated DCs then migrate via the cerebrospinal fluid (CSF) to draining deep cervical lymph nodes (B), present both viral and myelin-derived antigens to naïve and central memory T cells, and produce antiviral and proinflammatory cytokines, such as IL-12 and IL-1β. This not only leads to the priming of virus-specific Th1 cells, but could also result in the inappropriate stimulation of autoreactive CCR6⁺ T cells that are present in healthy individuals. Under the influence of IL-1β and/or IL-12, T cell receptor (TCR)-activated autoreactive CCR6⁺ central memory T cells (T_CM) could acquire CXCR3 expression and IFN-γ-producing capacities, and downregulate IL-10 production, thus differentiating into potentially encephalitogenic Th1/17_CM cells that are specifically expanded in patients with relapsing–remitting multiple sclerosis (RR-MS).

Figure 2

Hypothetical Mechanism of Competition between Protective Central Memory T Helper Type 1 (Th1_CM) and Pathogenic Th1/17_CM Cells. (A) Th1_CM and Th1/17_CM cells express increased levels of the transcription factor T-bet, which induces the expression of the IL-2/15Rβ-chain that renders T cells responsive to the homeostatic cytokine IL-15, which is required to maintain antiviral CD4 memory in the absence of antigen. (B) In healthy individuals (i) Th1_CM and Th1/17_CM cells are in equilibrium, and both compete successfully for IL-15, which is most abundant in peripheral tissues, but is also produced by stromal and epithelial cells in lymph nodes. In addition, they occasionally interact with dendritic cells (DCs) in lymph nodes and sense self-major histocompatibility complexes (MHCs). In patients with multiple sclerosis (MS) (ii) autoreactive Th1/17_CM cells could expand at the cost of virus-specific Th1_CM cells, because they proliferate with self-MHC-presenting DCs in lymph nodes during the remission phase. In addition, natalizumab could limit the access to IL-15 in peripheral tissues and, thus, intensify competition. However, while Th1/17_CM cells might have preferential access to IL-15 that is trans-presented on IL-15Rα by DCs (iii), Th1_CM cells might be less fit under these conditions and die by neglect.

Figure 3

Key Figure: Viral Reactivation Could Lead to Bystander Recruitment of Autoreactive Central Memory T Helper Type 1/17 (Th1/17_CM) Cells (A) In healthy individuals, the central nervous system (CNS) is surveyed by antiviral T cells. Upon viral reactivation (i), IP-10 is induced via IFNs and leads to the recruitment of antiviral CXCR3⁺ T cells, likely both Th1/17- and Th1 cells, to the CNS parenchyma from the blood stream (ii). Antiviral T cells rapidly control the virus, and tissue repair mechanisms ensure that damage to the CNS is limited. Relapses could be triggered when the same immune surveillance mechanism leads to the erroneous bystander recruitment of autoreactive Th1/17_CM cells to the CNS in patients with multiple sclerosis (MS). In addition, infected CXCR3⁺ B cells could be recruited that transport viruses, such as Epstein-Barr virus (EBV) and John Cunningham virus (JCV) to the CNS. Th1/17_CM cells in patients with MS, but not in healthy individuals, react with myelin-derived self-antigens and, thus, could attack healthy, uninfected tissues, inducing extensive tissue damage and relapses (iii). (B) Alternatively, autoreactive Th1/17_CM cells could home spontaneously to the CNS parenchyma via CCR6 during the remission phase of patients with MS (i), and induce de novo viral reactivations and, consequently, the recruitment of CXCR3⁺ lymphocytes (ii). Reactivation of viruses in the CNS induced by autoreactive Th1/17_CM cells could either trigger relapses or represent an amplification loop of virus-induced relapses. Notably, autoreactive Th17 cells in healthy individuals could also induce viral reactivation in the CNS by this mechanism, but they are less pathogenic.