Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition

Activated T lymphocytes have a special permit to access the central nervous system (CNS) and to scan it for the presence of pathogens. The CNS hides its complex set of tissue-specific antigens to which there is no (complete) immunological tolerance by restricting MHC antigen expression. Phagocytic microglial cells report damage of the CNS parenchyma to T cells by expressing MHC class I and class II antigens during an inflammatory response. Neuronal and myelin antigens are hidden from T cells as neurons and oligodendrocytes do not express MHC molecules. In addition, the abundant myelin antigens, myelin basic protein (MBP) and proteolipid protein (PLP), are sequestered in the compact myelin. Presentation of these myelin antigens which are the targets for encephalitogenic, MHC class II-restricted T cells probably requires phagocytosis of myelin by microglial cells either as the result of normal myelin breakdown or as a consequence of pathological myelin damage. To gain access to the large quantities of MBP and PLP hidden in the myelin sheath behind the blood brain barrier, autoreactive T lymphocytes must be activated from their resting, "ignorant" state. Activation of autoreactive T cells which may turn them into autoaggressive T lymphocytes could be blamed on infectious agents that produce T cell superantigens or on pathogens that have limited yet sufficient sequence homology with these myelin proteins.