A possible role of Fas-ligand-mediated "reverse signaling" in pathogenesis of rheumatoid arthritis and systemic lupus erythematosus.

Fas/FasL system is involved in pathogenesis of a variety of autoimmune diseases. In overwhelming majority of situations alterations in Fas and FasL expression are viewed in frames of Fas-mediated apoptosis. In the present work we tested a possible involvement of Fas-ligand-mediated "reverse signaling" in pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We show that high level of sFas in RA patient blood correlates with a high activity of disease; in SLE patients with elevated sFas level there was a correlation between sFas concentration and leucopenia, and tissue and organ damage. We showed for the first time that at high concentrations in serum sFas is present in oligomeric form. Oligomeric sFas demonstrated cytotoxicity in lymphocyte primary culture and in transformed cells, while non-toxic recombinant Fas-ligand partially blocked this effect. Besides, immunohistochemical analysis of PBLs and injured synovia of RA patients revealed the high expression of Fas-ligand. All this together allow assuming the involvement of cytotoxic "reversed signaling" in the pathogenesis of autoimmune diseases.