Pathogenesis of Multiple Sclerosis

Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the CNS. MS is classified into several categories according to its clinical course: benign, RR (relapsing-remitting, the most common variant), PR (progressive-relapsing), PP (primary-progressive) and SP (secondary-progressive). MS first manifests itself as a series of attacks followed by complete or partial remissions as symptoms mysteriously lessen, only to return later after a period of stability. Rarely, patients may have a PR course in which the disease takes a progressive path punctuated by acute attacks. PP, SP, and PR are sometimes lumped together and called chronic progressive MS.Pathologically, MS is characterized by the presence of areas of demyelination and T cell predominant perivascular inflammation in the brain white matter. Disease begins most commonly with acute or subacute onset of neurological abnormalities. During an MS attack, inflammation occurs in areas of the white matter of the CNS in random patches called plaques. Once immune cells have spread to the white matter of the CNS, the immune response is targeted to the entire supramolecular complex of myelin and is followed by destruction of myelin. The name 'multiple sclerosis' signifies both the number (multiple) and condition (sclerosis, from the Greek term for scarring or hardening) of the demyelinated areas in the CNS. Another effect of the inflammation is to kill the maintenance glial cells. The most vulnerable of these are the oligodendrocytes which are lost in great numbers.T cells play a particularly important role in MS which is an autoimmune disease. The immune system wrongly identifies myelin as 'non-self' and produces anti-myelin T cells. Chemokine receptors are centrally involved in the pathogenesis of MS. The neuronal damage that leads to paralysis in MS patients is initiated by an inflammatory phase in which T cells and monocytes are recruited across the blood-brain barrier. Activated T cells produce CXCR3 which is responsible for the recruitment of auto-aggressive T cells. The ligands for CXCR3 include CXCL10, CXCL9 and CXCL11. Two other chemokine receptors, CCR1 and CCR5 and their ligands CCL5, CCL3, CCL7 and CCL4 have also been observed in the pathogenesis of MS. These receptors are produced on T cells and monocytes/macrophages and the accumulation of these cells is directly correlated with lesions in which demyelination occurs, followed by axonal loss, which ultimately leads to paralysis.