Initial immunopathogenesis of multiple sclerosis: innate immune response

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The hallmark to MS is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, the formation of astrocytic scars, and the mononuclear cell infiltrates concentrated in perivascular spaces composed of T cells, B lymphocytes, plasma cells, and macrophages. Activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurological deficit. The immunological phenomena that lead to the activation of autoreactive T cells to myelin sheath components are the result of multiple and complex interactions between environment and genetic background conferring individual susceptibility. Within the CNS, an increase of TLR expression during MS is observed, even in the absence of any apparent microbial involvement. In the present review, we focus on the role of the innate immune system, the first line of defense of the organism, as promoter and mediator of cross reactions that generate molecular mimicry triggering the inflammatory response through an adaptive cytotoxic response in MS.

Figure 1

Role of innate immunity in multiple sclerosis. Glial cells, astrocytes, and microglia express a wide variety of TLRs. Stimulation with TLR ligands, dsRNA (TLR3), LPS (TLR4), peptidoglycans (PGN; TLR2 with TLR1/6), and viral CpG DNA (TLR9), promotes an array of immune functions in glial cells, including the secretion of proinflammatory cytokines, chemokines, type I interferons (IFN-α/β), and an increase in MHC classes I and II expression. TLRs activate macrophages, microglia, and dendritic cells (DCs) resulting in the production of cytokines of the innate immune system such as IL-6, IL-1β, and TNFα. These cytokines participate in blood brain barrier disruption and lymphocyte attraction to sites of inflammation, promote inflammation, and modulate adaptive immunity. For instance, IL-6 promotes Th17 and B cell differentiation. Th17 and Th1 cells and inflammation will contribute to tissue damage. Finally, MG, microglia, and DC also secrete IFNβ which, among other immunomodulatory functions, prevents leukocyte adhesion and extravasation across the blood brain barrier. Modified by Carpentier et al. [34].

Figure 2

Multiple sclerosis pathophysiology. Contact in early childhood with a pathogen plus other susceptibility factors as racial and demographic background can elicit their reactivation, triggering innate mechanism of defense as toll-like receptors (TLRs), that signalizes downstream through MyD88 (myeloid differentiation primary response 88), and phosphorylated IκB which permits translocation of NF-κB and the transcription of IL-6, TNF, IL-1, IL-12, E-selectin, MCP-1, and IL-8. TLR through IRF7 (Interferon regulatory factor 7) gives the signal to the transcription of IFN α/β. Another important signal is given by NOD receptors (nucleotide-binding oligomerization domain) activated also by potassium efflux-inducing agents such as ATP and TLR stimulation; PAMS, toxins, danger or stress triggers induce the inflammasome via NLRP that form a complex with ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1, activating IL-1B, a major factor inducing inflammation, autophagy and cell death, particularly necrosis. All these proinflammatory soluble factors activate microglia and endothelial cells, upregulating expression of adhesion molecules as E-selectin, facilitating the migration of T cells into the SNC. Matrix metalloproteinases (MMP) degrades BBB (blood brain barrier) enhancing further migration of autoreactive T cells and macrophages via chemokines (CX3CL-1). The Th1 response evocated via IL-12 and IFN-γ further activates macrophages that in turn do so to T cells CD8+. Th2 response via IL-6 mainly stimulates maturation of B cells and production of autoantibodies. Cytotoxic damage to the oligodendrocyte mediated myelin loss and exposure of the axon to reactive oxygen species, slowing or blocking action potentials and the production of neurological spectrum. There are intents to remyelinate these lesions via OPCs (oligodendrocyte precursor cells), but neuronal factors such as LINGO-1 or TLR2 inhibit their migration.