ABSTRACT
Impaired immune cell apoptosis may contribute to multiple sclerosis (MS) by prolonging the resolution of brain infl ammation aft er a clinical relapse. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, characterized by paralysis resulting from destruction of the myelin sheath. Accumulating evidence indicates that immune cells responsible for demyelination are resistant to death or apoptotic signals that normally eliminate them from the body. Th is increased resistance to apoptosis may be endowed by altered expression of members of the inhibitor of apoptosis (IAP) family. We have observed elevated levels of several members of the IAP family in T cells and mononuclear cells isolated from the peripheral blood of patients suff ering a clinical relapse. Elevated IAP expression, particularly XIAP, exacerbates the severity of EAE, and possibly
MS, by rendering autoreactive immune cells resistant to apoptosis thereby prolonging the central nervous system (CNS) infl ammation. Antisense-mediated knockdown of X-linked IAP (XIAP) markedly reduced paralysis while XIAP overexpression had the opposite eff ect in experimental autoimmune encephalomyelitis (EAE). Interferon-β (IFN-β) promotes the death of auto-reactive immune cells by triggering apoptosis through the expression of XIAP-associated factor-1 (XAF-1). XAF-1 induction may serve to limit infl ammation by facilitating the apoptosis of activated immune cells via the release of active caspase activity otherwise blocked by the IAPs. XAF-1 may be used to distinguish between MS patients that derive clinical benefi t from this treatment and those that do not. Treatments that increase the apoptotic sensitivity of immune cells, which participate in brain infl ammation, may therefore be an eff ective and safe therapeutic strategy for MS.
