Serum CD95 of relapsing remitting multiple sclerosis patients protects from CD95-mediated apoptosis

Abstract

Failure of CD95-mediated apoptosis as a potential negative regulatory mechanism of T cell expansion may be involved in T cell-mediated autoimmune diseases such as multiple sclerosis (MS). Recently, soluble CD95 has been shown to be elevated in MS patients with active disease. Here, we report that the sera of MS patients inhibit CD95 ligand-induced apoptosis of susceptible target cells in a concentration-dependent manner and dependent on the amount of serum CD95 levels. Thus, MS sera contain biologically active inhibitors of T cell apoptosis that may allow for prolonged abnormal immune responses.

Introduction

Multiple sclerosis (MS) is considered as a T cell-mediated autoimmune disease of the central nervous system. Autoreactive T cells are not only found in MS patients, but are part of the normal immune repertoire. Potent regulatory mechanisms such as CD95-mediated apoptosis might contribute to prevent T cell-mediated tissue damage, e.g., in the central nervous system. CD95 is a cytokine receptor which mediates apoptotic cell death when bound by its natural ligand. Increasing evidence suggests a role for apoptosis and the CD95/CD95 ligand system in the pathogenesis of MS (Pender et al., 1991; Schmied et al., 1993; D'Souza et al., 1996; Dowling et al., 1996; Bonetti and Raine, 1997; Dowling et al., 1997). Recently, we and others showed that MS patients with relapsing remitting and active disease have significantly higher soluble serum CD95 levels than patients with inactive disease or controls (Inoue et al., 1997; Zipp et al., 1998). Here, we report that the soluble CD95 in MS sera is functionally active and blocks CD95 ligand-mediated apoptosis in susceptible target cells.