Pathophysiology

Pathophysiology of Multiple Sclerosis

The pathophysiology of multiple sclerosis (MS) is believed to be immune-mediated, with the adaptive immune system (both T and B cells) responsible for the formation of lesions (also known as focal plaques) in the white and gray matter of the CNS (both brain and spinal cord). The lesions are areas of demyelination that are usually adjacent to postcapillary venules, forming where an immune-mediated breakdown of the blood-brain barrier (BBB) has occurred. Plaques can be characterized as active (containing immune cells throughout the lesion) or chronic active (containing phagocytes at the edge of demyelination) and chronic inactive (which are hypocellular, with pronounced gliosis – the “sclerosis” of “multiple sclerosis”).

Actively demyelinating lesions are associated with abnormal macrophage, antibody, or complement activation and immune-mediated oligodendrocyte apoptosis. During a relapse (whether in Relapsing-Remitting MS (RRMS) or Secondary Progressive MS (SPMS), autoreactive lymphocytes cross the BBB and initiate a local inflammatory cascade within the central nervous system (CNS); this leads to focal edema, destruction of myelin and neuronal and axonal damage. It is important to note that in many patients with MS, axonal damage also occurs in normal-appearing white matter in addition to focal lesions. Of the autoreactive lymphocytes, T cells are thought to play a key role. Both helper (CD4+) and cytotoxic (CD8+) T cells have been detected in abundance in inflammatory plaques (with CD8+ being the majority), and many of the polymorphisms associated with increased risk of MS are in T cell-related genes and regulatory regions. However, the paradigm has increasingly shifted to acknowledge the contribution of B cells as well, whose involvement is evidenced by the success of B cell-targeted DMTs (ocrelizumab, ofatumumab, ublituximab). After a relapse, local remyelination can occur, which has been proposed as an explanation for the clinical recovery (remission) following an acute attack; however, the extent of remyelination varies (40-50% of white matter and up to 90% of gray matter lesions may be remyelinated). Remyelination is more common in RRMS than in SPMS or Primary Progressive MS (PPMS).

Chronic lesions (which may be active or inactive) predominate in the later phases of MS. Chronic CNS inflammation, neuronal network dysfunction and decline of repair and remyelination, are also collectively known as “smoldering inflammation.” Both CNS-resident immune cells (microglia) and infiltrating immune cells (macrophages, compartmentalized T and B lymphocytes) contribute to chronic inflammation via a number of mechanisms, including inappropriate phagocytosis, demyelination and overactive synaptic pruning. Other pathways which may contribute to chronic CNS inflammation include oxidative stress, glutamate excitotoxicity, high intracellular calcium, ion channel dysregulation and mitochondrial dysfunction. A model of MS pathophysiology, showing both active and smoldering inflammation, is presented in Figure 1-4.

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Plaques may form in any part of the central nervous system (CNS) (in both the white and gray matter of the brain and spinal cord), and the heterogeneity of plaque distribution is thought to contribute to the heterogeneity of symptoms. Nevertheless, certain locations of plaque formation are more common than other, including the white matter around the ventricles of the brain, optic nerves, brainstem, cerebellar peduncles, spinal cord and corpus callosum.