Apoptosis of Inflammatory Cells in Immune Control of the Nervous System: Role of Glia

Normal individuals have T lymphocytes capable of reacting to central nervous system (CNS) antigens such as myelin basic protein (MBP) (Martin et al., [1990]). In view of recent evidence indicating that T cells are much more cross-reactive than previously thought (Mason, [1998]), it is likely that these autoreactive T cells are often primed by exposure to cross-reacting environmental antigens. Indeed it has been shown that viral and bacterial peptides can activate myelin-reactive human T cells (Wucherpfennig and Strominger, [1995]; Hemmer et al., [1997]). Furthermore, normal healthy subjects experience surges of increased frequencies of circulating myelin-reactive T cells that might be driven by cross-reactive environmental antigens (Pender et al., [2000]). Such activated myelin-reactive T cells would be expected to enter the CNS in healthy individuals, because activated T cells of any specificity, including autoreactive T cells, enter the normal CNS parenchyma (Wekerle et al., [1986]; Hickey et al., [1991]). If CNS-reactive T cells survive in the CNS, they have the potential to attack the CNS, either directly or through the recruitment of other inflammatory cells, and thus lead to CNS damage such as demyelination. Therefore, the physiological control of autoreactive T cells in the CNS is likely to have an important role in preventing the development of autoimmune CNS disorders such as multiple sclerosis (MS) (Pender, [1998]). T-cell apoptosis in the CNS has been proposed to be an important mechanism for controlling autoimmune attacks on the CNS (Pender et al., [1992]; Schmied et al., [1993]). Although other mechanisms, such as immune deviation (Wenkel et al., [2000]), may possibly also contribute to the control of the immune response in the CNS, this review will focus on T-cell apoptosis in the CNS and the role of glia in this process

The Role of the Antigen-Presenting Cell in Fas-Mediated Direct and Bystander Killing: Potential In Vivo Function of Fas in Experimental Allergic Encephalomyelitis

AbstractCostimulatory molecules are critical in mediating Fas-dependent direct and bystander lysis. In direct lysis, the APC is the Fas-positive target. It presents Ag to the T cell, thereby activating the T cell. The activated T cell then up-regulates FasL, allowing it to kill the APC. In bystander lysis, the APC again induces FasL expression on the T cell, but the target is a third Fas-positive cell that may lack the appropriate MHC-restricting element to activate the T cell. This study shows that ICAM-1 and B7-1 can serve as important adhesion molecules in direct killing using CD4+ T cell effectors. In bystander killing, B7-1 appears to act as a signaling molecule as well. It has been demonstrated that lpr and gld mice are less susceptible to experimental allergic encephalomyelitis than their wild-type counterparts. In this study, we show that although microglia are poor targets of direct killing, they are capable of stimulating myelin basic protein-specific T cells to kill innocent Fas-positive targets. This presents a possible mechanism for the pathogenesis of experimental allergic encephalomyelitis.</jats:p