Central nervous system (CNS) myelin, the likely major target of autoimmune attack in multiple sclerosis (MS), contains a number of unique components that are potential targets of the attack. Two classes of molecules that are greatly enriched in CNS myelin compared to other parts of the body are certain types of proteolipids and glycolipids. Due to the hydrophobic nature of both of these classes of molecules, they present challenges for use in immunological assays and have therefore been somewhat neglected in studies of T-cell reactivity in MS compared to more soluble molecules such as the myelin basic proteins and the extracellular domain of myelin oligodendrocyte glycoprotein. This review firstly looks at the makeup of CNS myelin, with an emphasis on proteolipids and glycolipids. Next, a retrospective of what is known of T-cell reactivity directed against proteolipids and glycolipids in patients with MS is presented, and the implications of the findings are discussed. Finally, this review considers the question of what would be required to prove a definite role for autoreactivity against proteolipids and glycolipids in the pathogenesis of MS. 1. Central Nervous System Myelin In multiple sclerosis (MS), damage selectively affects the central nervous system (CNS). Irrespective of the event(s) that initiate the damage to the CNS in MS, most studies agree that development of autoreactivity against molecules in the CNS myelin sheath is the most likely mechanism underlying the chronic relapsing and progressive nature of MS. Myelin is a unique lipid-rich specialized membrane found only in the nervous system of vertebrates. It acts as an insulator of the nerve axons and allows nerve impulses to pass rapidly along the axon in a series of jumps (saltatory conduction) from one gap between myelinated segments (node of Ranvier) to another, and also provides trophic support to the axon and maintains the integrity of the axon. Myelin is present in both the CNS, where it is produced by oligodendrocytes, and the peripheral nervous system (PNS), where it is produced by Schwann cells; however, there are distinct differences in the makeup of the myelin in the CNS and PNS (Table 1), and only the CNS myelin is damaged in MS. In addition, Schwann cells only myelinate a single segment of an axon, whereas each individual oligodendrocyte can myelinate numerous separate segments of axons in the CNS (Figure 1(a)). The oligodendrocytes extend membrane sheets which wrap around segments of axon and compact to form the multilamellae structure of compact myelin (Figure 1(b)). Despite
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