Possible Role of Organ-Specific Autoantigen for Fas Ligand-Mediated Activation-Induced Cell Death in Murine Sjögren’s Syndrome

Abstract

Activation-induced cell death (AICD) is a well-known mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). In this study, we demonstrate that the administration of a soluble form of anti-FasL Ab, FLIM58, results in severe destructive autoimmune exocrinopathy in the murine model of human Sjögren’s syndrome (SS), and we found that an organ-specific autoantigen may play an important role on down-modulation of AICD. A high titer of serum autoantibodies against 120-kDa α-fodrin autoantigen was detected in the FLIM58-treated mice, and splenic T cell culture supernatants contained high levels of IFN-γ. In vitro T cell apoptosis assay indicated that FasL-mediated AICD is down-regulated by autoantigen stimulation in spleen cells from the murine SS model, but not from Fas-deficient MRL/lpr mice and FasL-deficient MRL/gld mice. FasL undergo metalloproteinase-mediated proteolytic processing in their extracellular domains, resulting in the release of soluble trimeric ligands (soluble FasL). We showed that the processing of soluble FasL occurs in autoantigen-specific CD4+ T cells, and that a significant increase in expressions of metalloproteinase-9 mRNA was observed in spleen cells from SS model mice. These findings indicate that the increased generation of soluble FasL inhibits the normal AICD process, leading to the proliferation of effector CD4+ T cells in the murine SS model.

Role of soluble Fas ligand in autoimmune diseases

“…FasL can be upregulated when cells are responsive to UV irradiation or treated by cytotoxic drugs. Over expression of FasL can inhibit some autoimmue diseases by deleting auto-immune memory cells [4,5] . Moreover, Fas-FasL interaction can protect allografts from immune attack and induce anti-tumor responses.…”

“…Generally, membrane-bound FasL, or FasL is fully competent in transducing Fas-mediated signals for apoptosis and NF-kappaB nuclear translocation because membrane FasL could possess both Fas-focusing and signal transducing functions. While sFasL is known to be deficient in transducing signals upon engagement with membrane Fas [4,14] . But in some cases, sFasL was found to be involved in the deletion of potentially hazardous peripheral memory cells [10] .…”

Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance

“…34 The molecular mechanism may be mediated by activationinduced cell death (AICD), which is well known to act as a system to maintain the peripheral T cells through Fas-mediated apoptosis. [35][36][37] Activated or autoreactive T cells are considered to delete by …”

Regulation of T cell activation in Sjögren's syndrome

“…B Immunohistochemical staining of CD3 + T cells was performed using the paraffin-embed sections of salivary glands from SS patients. one of salivary gland-specific autoantigens for SS and the antigen-specific response of T H 1 cells, and define the breakdown of peripheral tolerance by dysfunction of activationinduced cell death (AICD) that is a system to delete autoreactive T cells in the periphery [18,19]. Besides, several KO mice have been reported that SS-like lesions are observed in salivary or lacrimal glands.…”