The role of antigen presenting cells in multiple sclerosis

Abstract

Multiple Sclerosis (MS) is a debilitating T cell-mediated autoimmune disease of the central nervous system (CNS). Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-Induced demyelinating disease (TMEV-IDD) have given light to cellular mechanisms involved in the initiation and progression of this organ-specific autoimmune disease. Within the CNS, antigen presenting cells (APC) such as microglia and astrocytes participate as first line defenders against infections or inflammation. However, during chronic inflammation they can participate in perpetuating the self-destructive environment by secretion of inflammatory factors and/or presentation of myelin epitopes to autoreactive T cells. Dendritic cells (DC) are also participants in the presentation of antigen to T cells, even within the CNS. While the APCs alone are not solely responsible for mediating the destruction to the myelin sheath, they are critical players in perpetuating the inflammatory milieu. This review will highlight relevant studies which have provided insight to the roles played by microglia, DCs and astrocytes in the context of CNS autoimmunity.

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…Dendritic cells play a critical role in instructing the development of these pathogenic T cells. In the steady state, immature DCs lack the capacity to initiate a strong T cell response due to low expression of MHC class II, CD80, and CD86 (3,4). Activation of DCs through Toll-like receptor signaling or encounter with antigen leads to maturation and increased expression of MHC class II, CD80, and CD86.…”

“…Cytokine production is also initiated during the maturation of DCs. This is important as unique cytokine microenvironments influence naive T cell differentiation (3,4). IL-12 instructs T cells toward IFN-␥-producing CD4 ϩ cells (Th1), whereas IL-6 in the absence of IL-12 favors IL-17-producing cell (Th17) differentiation (2).…”

Role of autophagy in the pathogenesis of multiple sclerosis

“…Impairment of autophagy in microglia may hinder debris clearance, leading to damaged remyelination and augmentation of persistent neuroinflammation. The rapid activation of microglia produces pro-infl ammatory cytokines and free radicals, and acts as the major antigen-presenting cell [73,74] . Pro-inflammatory factors such as IL-1β can trigger microglial autophagy, suggesting links between autophagy and inflammation activation [75] .…”

NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

“…Further phagocytosis of myelin debris by APCs (particularly macrophages) increases the presentation of myelin-derived Ags to effector T cells, creating a positive feedback loop that amplifies the inflammatory process to a level that is clinically apparent. Hence, the local and recruited macrophages act as the central "gatekeepers" of T cell reactivation and ultimately the initiation and propagation of clinical EAE (11,(13)(14)(15). Thus, EAE presents a good model for studying the generation of MHC-II-restricted autoepitopes, from both exogenous and endogenous sources, by different APCs in different tissues.…”