Multiple Sclerosis and Allied Demyelinating Diseases

17 subsets. B cells and monocytes are also activated. These autoreactive T cells interact with adhesion molecules on the endothelial surface of CNS venules and, with antibodies and monocytes, cross the disrupted blood–brain barrier with the aid of proteases (e.g., matrix metalloproteinases) and chemokines. Within the CNS, target antigens are recognized (putative antigens include myelin basic protein, myelin-associated glycoprotein, myelin-oligodendrocyte glycoprotein, proteolipid protein [PLP], aB-crystallin, phosphodiesterases, and S-100 protein), T cells are reactivated, and the immune response is amplified. Proinflammatory T-helper cells proliferate and B cells continue their maturation to antibody-secreting plasma cells, whereas monocytes become activated macrophages. Together, these immune cells produce inflammatory cytokines (e.g., interleukin [IL]-12, IL-23, interferon g, tumor necrosis factor [TNF]-a), proteases, free radicals, antibodies, nitric oxide, glutamate, and other stressors that collectively lead to damage of myelin and oligodendrocytes. In the appropriate cytokine milieu, CD41 Th2 cells proliferate and secrete anti-inflammatory cytokines (e.g., IL-4, Il-5, IL-13, and transforming growth factor-b) that suppress the immune response. Depending on the location and extent of damage, demyelination may impair or block nerve conduction and result in neurologic symptoms. With a loss of trophic support from oligodendrocytes, axons may degenerate to cause irreversible neurologic deficits. Spontaneous improvement of symptoms is attributed to resolution of inflammation, adaptive mechanisms (e.g., reorganization of sodium channels), or remyelination. It had long been thought that Th1 and Th2 subsets arose from the terminal differentiation of the CD41 T cells. However, a third pathway has been identified, induced by IL-1, IL-6, and transforming growth factor-b, and then expanded and maintained by IL-23, which is secreted by APCs. This third subset, a proinflammatory T-helper cell, is known as Th17 because it produces IL-17. Th17 cells secrete a number of cytokines, including TNF-a and granulocyte macrophage colony stimulating factor (GM-CSF), which are critical for the development of EAE. MS patients have monocyte-derived dendritic cells that secrete higher levels of IL-23 than healthy controls. Higher levels of IL-17 mRNA-bearing mononuclear cells are found in the serum of MS patients having relapses than in patients in remission. Although MS is typically considered a T-cell–mediated disease, a growing body of evidence supports a pathogenic role of B cells, including the frequent observation of intrathecal production of immunoglobulin in MS patients, identification of antibodies that react to specific myelin antigens within MS lesions, a pathologic pattern of MS characterized by antibody-associated demyelination (see the following text), and the discovery of B-cell follicles in the meninges of patients with secondary progressive MS. Pathologic studies have shown that B-cell clones are shared between the meninges and parenchyma of individual MS patients. Furthermore, B cells INTRODUCTION