Is multiple sclerosis an autoimmune disease?

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.

Figure 1

CD4⁺ T Cells differentiated into subsets. CD4⁺ T cells can differentiate into different subtypes based on the factors within the inflammatory milieu with which T cells come into contact. TH1⁺ cells secrete IFN-γ and tumor necrosis factor (TNF) and mediate the pathology in experimental autoimmune encephalomyelitis (EAE). Many of the results previously attributed to TH1 cells are actually mediated by Th17⁺ cells. Th17⁺ cells secrete IL17, IL21, and IL22. These cells have been identified in MS lesions, where they may serve as important effectors. As a result of  TGF-β stimulation, CD4⁺ T cells develop into T-regulatory cells. These cells downregulate the immune response and express FOXP3, CD25, and IL10. The mechanism of suppression is by the secretion of factors such as IL10. TH-helper cells provide help to other T cells, such as CD8⁺ T cells or B cells. Th-helper cells secrete IL2, IL10, and IL21. Th2⁺ cells downregulate the immune response and are associated with recovery from acute attacks in EAE and, possibly, MS. The cytokines that mediate the downregulation of the immune response are IL4 and IL10, in addition to IL13 and IL5.

Figure 2

Perforin is the primary mediator of  injury by CD8⁺ T cells. Perforin is the primary molecule known to mediate injury by CD8⁺ T cells. Perforin mediates axonal transection in multiple sclerosis (MS) and correlates with neurological disability. Cytotoxic T cells secrete perforin in the form of granules along with granzymes. This release activates calcium, which results in “poly-perforin” channels on the target cells. This results in holes in the membrane of the target cells, causing leakage of intracellular material, which results in cell death.

Figure 3

The in vitro effects of 1,25(OH)₂D on the immune system. The effects of 1,25(OH)₂D either directly or indirectly are depicted by arrows. While a green arrow represents positive influence, a red arrow represents the negative influence. The negative influence on inflammation indicates dampening of the inflammatory response. DC: dendritic cell; Th1: T helper type 1 lymphocyte; Th2: T helper type 2 lymphocyte; Tr: regulatory T lymphocyte [94].