Saegusa Kaoru, Ishimaru Naozumi, Yanagi Kumiko, Mishima Kenji, Arakaki Rieko, Suda Takashi, Saito Ichiro, Hayashi Yoshio
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan.
J Immunol. 2002 Jul 15;169(2):1050-7. doi: 10.4049/jimmunol.169.2.1050.
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.
自身抗原裂解在自身免疫性疾病细胞凋亡过程中的体内作用仍不清楚。此前，我们发现120 kDaα- fodrin的裂解产物是原发性干燥综合征（SS）发病机制中的一种重要自身抗原。在小鼠原发性SS模型中，从唾液腺纯化的组织浸润性CD4(+) T细胞携带大量Fas配体，而唾液腺导管细胞组成性地表达Fas。浸润的CD4(+) T细胞而非CD8(+) T细胞可识别针对小鼠唾液腺细胞的显著(51)Cr释放。体外研究表明，凋亡的小鼠唾液腺细胞会导致α- fodrin特异性裂解为120 kDa，并且与半胱天冬酶抑制剂肽预孵育可阻断α- fodrin裂解。在小鼠模型中体内注射半胱天冬酶抑制剂N-苄氧羰基-缬氨酸-丙氨酸-天冬氨酸氟甲基酮和N-乙酰-天冬氨酸-谷氨酸-缬氨酸-天冬氨酸-醛，可对自身免疫性病变的发展产生显著抑制作用，并恢复干燥综合征。此外，我们发现用与自身抗原相同的重组α- fodrin蛋白免疫正常受体可诱导出类似于SS的自身免疫性病变。这些数据表明，自身免疫性外分泌病的预防和诱导依赖于通过半胱天冬酶级联反应的自身抗原裂解，并且半胱天冬酶抑制剂可能为减少小鼠SS模型中的组织损伤提供一种新的治疗选择。
