A possible role of Fas-ligand-mediated “reverse signaling” in pathogenesis of rheumatoid arthritis and systemic lupus erythematosus
Introduction
Evidences are accumulating that apoptosis may be implicated in the pathogenesis of autoimmunity. Apparently, one of the common features of a variety of autoimmune diseases is an involvement of Fas/Fas-ligand apoptotic system.
Initially, in the experiments on the lpr[1] and gld [2] murine models it has been shown that mutations in Fas и Fas-ligand (FasL) are responsible for the development of autoimmune disease similar to human one—systemic lupus erythematosus (SLE). Although further investigations did not reveal Fas [3] and FasL [4] mutations in the majority of SLE patients, nevertheless, it has been suggested that various events accompanying SLE such as an extensive death of CD4+ и CD8+ lymphocytes [5], bone marrow CD34(+) cells [6] and neutropenia, as well as resistance of autoimmune T-helper cells driving pathogenic autoantibody production result from impaired activation of Fas/FasL system [7].
Supposedly, Fas/FasL system is also involved in the pathogenesis of rheumatoid arthritis (RA) [2], [8]. On one hand, a reduced susceptibility to CD95-mediated apoptosis may contribute to the expansion of an activated CD4(+) lymphocyte subpopulation and thus to the maintenance of peripheral autoreactive T-cell clones in RA [9], [10], on the other hand, – a high sensitivity of RA osteoblasts to cytotoxic action of FasL produced by activated peripheral blood mononuclear cells, underlies osteoporosis, one of RA consequences [11], [12]. It has been also shown that Fas and FasL are involved in the pathogenesis of diverse autoimmune diseases—antiphospholipid syndrome (APS) [13], multiple sclerosis [14] and others. However the concrete molecular mechanisms provoked by Fas/FasL system in a course of autoimmune diseases are still obscure.
Elevated content of soluble Fas antigen (sFas) and/or soluble Fas-ligand is quite often a remarkable peculiarity observed in autoimmune patient serum [15], [16], [17], [18]. For the first time the elevated level of soluble Fas was found in patients with SLE and RA [19]. The authors demonstrated that administration of sFas to mice resulted in initiation of autoimmune diseases. Since sFas can suppress Fas-mediated apoptosis it was suggested that sFas helps autoreactive thymocytes bearing on their surface transmembrane Fas antigen, to escape the negative selection.
Silvestris et al. [20] found that the increase in the soluble Fas-receptor content in SLE patient serum correlates with a number of TUNEL-positive T cells. It was demonstrated that incubation with sFas significantly suppresses T cell proliferation. Based on these observations the authors concluded that soluble Fas causes proapoptotic effect. As it has been shown proapoptotic effects of sFas are executed by means of “reverse signaling” via Fas-ligand [21], [22].
In the present work we tested the possible involvement of Fas-ligand-mediated “reverse signaling” in pathogenesis of autoimmune diseases. We revealed that about 10% of RA and SLE patients display the increased level of sFas in serum. Peripheral blood lymphocytes (PBLs) of these RA and SLE patients are a source of the high level of sFas. In RA patients the high content of sFas in blood correlates with elevated number of painful and swollen joints and low lymphocyte level, in SLE patients—with leucopenia, tissue and organ damage. At high concentrations in serum, soluble Fas was present exclusively in oligomeric form. Oligomeric sFas exhibited cytotoxic effect. Immunohistochemical analysis of affected synovia revealed a high expression of Fas-ligand. All this together, the high Fas-ligand expression in synoviocytes and lymphocytes, that are cellular targets during autoimmune diseases, and the enhanced level of the oligomeric cytotoxic sFas at the same time, allow to assume the involvement of cytotoxic “reverse signaling” in the pathogenesis of autoimmune diseases.
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Patients
78 RA patients (male to female, 8/70; mean age, 55.9 ± 12.7) were included in the study. All patients fulfilled the diagnostic criteria of the American College of Rheumatology (ACR) for inflammatory active RA as revised [23]. Their disease activity was assessed using the 28 joint disease activity score (DAS28): a composite score based on erythrocyte sedimentation rate (ESR), number of painful and number of swollen joints (both by 28 joint count) assessed by the nurse, and patient global
Correlation of sFas level with the clinical parameters of the disease
Earlier it was shown that enhanced level of soluble Fas antigen is common for the patients with different types of autoimmune diseases [15], [17], [18], [35]. In the first set of experiments we analyzed the sFas content in serum of patients with RA and SLE and compared this level with healthy donors. We found that increased level of sFas was observed in 11% RA patients and 12.5% SLE patients. RT-PCR analysis of mRNA isolated from peripheral blood lymphocytes from patients with elevated sFas
Discussion
The elevated level of sFas in blood of patients with autoimmune diseases, in particular with RA and SLE, was demonstrated earlier. In general, the authors consider sFas as an inhibitor of Fas-mediated apoptosis only [15], [19]. However, some experimental observations cannot be explained only by sFas inhibitory effect. For example, a positive correlation between sFas level and the amount of apoptotic lymphocytes and antibodies to dsDNA was shown by Courtney et al. [43] in SLE patients. Similar
Acknowledgments
The authors thank Dr. V. Gogvadze for continuous interest and help in the project. This work was supported by The Program on Molecular and Cellular Biology of the Presidium of Russian Academy of Science.
None of the authors have a financial interest related to this work.
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