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Defective T cell Fas function in patients with multiple sclerosis

From the Neurological Clinic (Drs. Comi, Leone, and Monaco) and Laboratory of Immunology (Drs. Comi, Bonissoni, DeFranco, and Dianzani, and F. Bottarel, C. Mezzatesta, and A. Chiocchetti), Department of Medical Science, "A. Avogadro" University of Eastern Piedmont, Novara; and the Department of Neurology (Dr. Perla), Ospedale S. Croce, Cuneo, Italy.

Address correspondence and reprint requests to Prof. Umberto Dianzani, Department of Medical Science, University of Eastern Piedmont, Via Solaroli 17, I-28100 Novara, Italy; e-mail: dianzani{at}med.no.unipmn.it

BACKGROUND: Fas (CD95) triggers programmed cell death and is involved in shutting off the immune response. Inherited deleterious mutations hitting Fas or its signaling pathway cause autoimmune/lymphoproliferative syndrome (ALPS).

OBJECTIVE: To assess the possibility that decreased Fas function plays a role in development of MS.

METHODS: The authors evaluated Fas function in long-term T cell lines (21 days of culture) from 32 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 15 with primary progressive MS (PPMS) by assessing cell survival upon Fas triggering by monoclonal antibodies (Mab).

RESULTS: Fas-induced cell death was significantly lower in all patient groups than in controls, and lower in SPMS than in RRMS. Moreover, 8/15 patients with PPMS, 10/15 with SPMS, and 8/32 with RRMS were frankly resistant to Fas. Frequency of resistance to Fas-induced cell death was significantly higher in all patient groups than in controls (2/75), and higher in SPMS than in RRMS. The findings that the parents of two Fas-resistant patients were Fas-resistant and that fusion of T cells from two Fas-resistant patients with Fas-sensitive HUT78 cells gave rise to Fas-resistant hybrid lines suggest that Fas-resistance is due to inherited alterations of the Fas signaling pathway, with production of molecules exerting a dominant negative effect on a normal Fas system.

CONCLUSIONS: Defects of the immune response shutting-off system may be involved in the pathogenesis of MS, particularly in its progressive evolution.

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