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

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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.

Section snippets

Selection of donors

This study was approved by the University of Tübingen and the National Institute of Neurological Disorders and Stroke (NINDS) Institutional Review Boards. We have previously found that CD95 levels were elevated in a group of 71 patients with relapsing remitting disease. Here, we compared relapsing remitting MS patients with a group of patients with chronic progressive disease course (n=17). All 88 patients had clinically definite MS.

Detection of soluble CD95

CD95 levels in the serum of patients, obtained at time points

Results

Previously reported (Zipp et al., 1998) patients with relapsing remitting disease had significantly higher serum CD95 levels than chronic progressive MS patients (194±45 U/ml vs. 66±37 U/ml) (mean±SEM) (p=0.005). Serum from eight patients with relapsing remitting MS and high CD95 levels and eight patients with chronic progressive disease and low levels were studied for inhibition of apoptosis. First, we used the highly sensitive LN-18 glioma cell line as a target for CD95 ligand-induced

Discussion

CD95/CD95 ligand interactions are crucial for the peripheral deletion of activated T cells (Alderson et al., 1995; Brunner et al., 1995; Dhein et al., 1995; Ju et al., 1995; Van Parijs et al., 1996). This is confirmed by autoimmune disorders which develop in mutant mice strains lacking functional CD95 (lpr) or CD95 ligand (gld). Here, we report that sera from MS patients with relapsing remitting disease contain elevated levels of soluble CD95 that inhibit CD95 ligand-induced apoptosis in

Acknowledgements

We thank Efi Faber for expert technical assistance. The work was supported by grants from the University of Tübingen (Fortüne 190, Interdisziplinäres Klinisches Forschungszentrum) and from the Deutsche Forschungsgemeinschaft (We 1502/5-1).

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