Infection as an Environmental Trigger of Multiple Sclerosis Disease Exacerbation

Abstract

Over the past several decades, significant advances have been made in identifying factors that contribute to the pathogenesis of multiple sclerosis (MS) and have culminated in the approval of some effective therapeutic strategies for disease intervention. However, the mechanisms by which environmental factors, such as infection, contribute to the pathogenesis and/or symptom exacerbation remain to be fully elucidated. Relapse frequency in MS patients contributes to neurological impairment and, in the initial phases of disease, serves as a predictor of poor disease prognosis. The purpose of this review is to examine the evidence that supports a role for peripheral infection in modulating the natural history of this disease. Evidence supporting a role for infection in promoting exacerbation in animal models of MS is also reviewed. Finally, a few mechanisms by which infection may exacerbate symptoms of MS and other neurological diseases are discussed. Those who comprise the majority of MS patients acquire approximately two upper-respiratory infections per year; furthermore, this type of infection doubles the risk for MS relapse, underscoring the contribution of this relationship as being potentially important and particularly detrimental.

Keywords: multiple sclerosis; natural history; neuroinflammation; relapse; viral infection.

Figures

Figure 1

Potential mechanisms underlying infection induced T-cell activation. (A) Molecular mimicry occurs when there are sufficient overlapping structural similarities between a pathogen-specific peptide and self-peptide such that it triggers T-cell activation. (B) Autoimmunity can be triggered by T-cells possessing both pathogen-specific and autoreactive T-cell receptors (TCR). (C) Bacterial superantigens can crosslink MHC class II and TCR leading to autoreactive T-cell activation and autoimmune disease onset and/or exacerbation. (D) Bystander activation of T-cells by infection could promote exacerbation. Here, infection promotes APC activation leading to the activation of CD44hi polyclonal T-cells via cytokine production. (E) Infection via activation of APCs could drive the process of epitope spreading wherein on constitutively released self-peptides resulting from chronic inflammation are presented to polyclonal autoreactive T-cells.

Figure 2

Model describing how peripheral infection induces neuroinflammation and T-cell-mediated relapse in MS. During peripheral infection, serum acute phase proteins enter the parenchyma at the choroid plexus, cross the BBB via cytokine transporters, or activate afferent nerves causing glial activation (1). Glial activation induces chemokine (2) and cytokine expression that upregulates endothelial adhesion molecules that promote the extravasation of encephalitogenic T-cell and monocyte/dendritic cell trafficking across the BBB (3). T-cells initially encounter resident perivascular meningeal microglia/macrophages, which have been “primed” for optimal antigen presentation (i.e., upregulation of CD86/CD80 and MHCII). T-cell activation stimulates the recruitment of professional APCs (including CCR4+ dendritic cells) and the production of cytotoxic factors, culminating in demyelination and neurodegeneration (4). Abbreviations: APC, antigen-presenting cell; AST, astrocyte; DC, dendritic cell; OL, oligodendrocyte.