The role of caspase cascade on the development of primary Sjögren's syndrome.
Primary Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry eye and dry mouth due to insufficient secretion. Previously, we have identified the 120 kDa alpha-fodrin as an important autoantigen on the development of SS in both animal model and SS patients, but the mechanism of a -fodrin cleavage leading to tissue destruction in SS remains unclear. In murine primary SS model, tissue-infiltrating CD4+ T cells purified from the salivary glands bear a large proportion of Fas ligand (FasL), and the salivary gland duct cells constitutively possess Fas. Infiltrating CD4+ T cells identified significant 51Cr release against mouse salivary gland (MSG) cells. In vitro studies demonstrated that apoptotic MSG cells result in a specific alpha-fodrin cleavage into 120 kDa, and preincubation with caspase-inhibitor peptides blocked alpha-fodrin cleavage. The treatment with caspase-inhibitors in vivo prevented the development of autoimmune lesions in the salivary and lacrimal glands. Thus, an increased activity in caspase cascade may be involved in the progression of alpha-fodrin proteolysis and tissue destruction on the development of SS.
Hayashi
Yoshio
Y
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan.
Arakaki
Rieko
R
Ishimaru
Naozumi
N
D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D006801:Humans; D007114:Immunization; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology; D018987:Salivary Ducts / Q000378:metabolism / Q000473:pathology; D012469:Salivary Glands / Q000378:metabolism / Q000473:pathology; D012859:Sjogren's Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D019014:fas Receptor / Q000502:physiology; D013049:Spectrin
D001324:Autoantigens; D002352:Carrier Proteins; D053148:Caspase 3; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D011994:Recombinant Proteins; D019014:fas Receptor; D013049:Spectrin; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse