Prevention and induction of autoimmune exocrinopathy is dependent on pathogenic autoantigen cleavage in murine Sjögren's syndrome.
The in vivo role of autoantigen cleavage during apoptosis in autoimmune diseases remains unclear. Previously, we found a cleavage product of 120-kDa alpha-fodrin as an important autoantigen in the pathogenesis of primary Sjögren's syndrome (SS). In the murine primary SS model, tissue-infiltrating CD4(+) T cells purified from the salivary glands bear a large proportion of Fas ligand, and the salivary gland duct cells constitutively possess Fas. Infiltrating CD4(+) T cells, but not CD8(+) T cells, identified significant (51)Cr release against mouse salivary gland cells. In vitro studies demonstrated that apoptotic mouse salivary gland cells result in a specific alpha-fodrin cleavage into 120 kDa and that preincubation with caspase inhibitor peptides blocked alpha-fodrin cleavage. In vivo treatment with caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone and N-acetyl-Asp-Glu-Val-Asp-al-CHO into the murine model results in dramatic inhibitory effects on the development of autoimmune lesions and in restoration of sicca syndrome. Furthermore, we found that immunization with recombinant alpha-fodrin protein identical with an autoantigen into normal recipients induced autoimmune lesions similar to SS. These data indicate that prevention and induction of autoimmune exocrinopathy is dependent on autoantigen cleavage via caspase cascade and that caspase inhibitors might provide a new therapeutic option directed at reducing tissue damage in the murine model for SS.
Saegusa
Kaoru
K
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan.
Ishimaru
Naozumi
N
Yanagi
Kumiko
K
Mishima
Kenji
K
Arakaki
Rieko
R
Suda
Takashi
T
Saito
Ichiro
I
Hayashi
Yoshio
Y
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D061945:Caspase Inhibitors; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006868:Hydrolysis; D007114:Immunization; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D009928:Organ Specificity / Q000276:immunology; D012859:Sjogren's Syndrome / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D013049:Spectrin
D001324:Autoantigens; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D008840:Microfilament Proteins; D013049:Spectrin