Possible role of organ-specific autoantigen for Fas ligand-mediated activation-induced cell death in murine Sjögren's syndrome.
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 alpha-fodrin autoantigen was detected in the FLIM58-treated mice, and splenic T cell culture supernatants contained high levels of IFN-gamma. 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.
Ishimaru
N
N
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan.
Yanagi
K
K
Ogawa
K
K
Suda
T
T
Saito
I
I
Hayashi
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology / Q000502:physiology*; D002352:Carrier Proteins / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D005260:Female; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008840:Microfilament Proteins / Q000276:immunology / Q000502:physiology; D008954:Models, Biological; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000145:classification; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism; D013049:Spectrin
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D002352:Carrier Proteins; D016207:Cytokines; D053222:Fas Ligand Protein; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D019014:fas Receptor; D013049:Spectrin; C505661:FASLG protein, human; C505658:Fasl protein, mouse