TNF 家族成员：LTα在干燥综合征中作用机制研究

Sjögren’s syndrome (SS) is a systemic autoimmune disease in which injury to the salivary and lacrimal glands may be associated with systemic organ involvement and lymphoma. To date, the etiology of Sjögren’s syndrome is yet unknown. Lymphotoxin or LTα is a critical cytokine for the development of lymphoid organs, which includes soluble LTα3 and membrane-associated LTα1β2 as the member of TNF family. Overexpression of LTα has been related to autoimmune disorder. Our laboratory has utilized the Interleukin 14 alpha transgenic mouse (IL14αTG) for the study of SS because it reproduces features of SS in the same relative time frame as seen with patients. Work with this animal model has demonstrated the importance of Lymphotoxin early in the course of SS and the role of type 1 interferon (IFN-α) in later stages of disease. When inhibitors of LTα3 or LTβR-Ig were used early in the course of disease in IL14aTG mice, both prevented the destruction of the salivary glands but only the LTβR-Ig inhibitor prevented the infiltration of lymphocytes into the salivary glands. Our hypothesis is that LTα3 is involved with killing of salivary gland cells early in the course of the disease while LTα1β2 is involved with the activation of auto-reactive cells that participate in the pathophysiology of SS. The current studies are designed to investigate the role of LTα3, LTα1β2 as well as their associated receptors in early stage of Sjögren’s syndrome. The results of these studies will provide valuable new insights into the roles of LTα3 and LTα1β2 in the development of SS and their potential as therapeutic targets for drug development.

Sjögren’s 综合征即干燥综合征，是自身免疫紊乱疾病，有唾液腺和泪腺功能损害，目前发病机制不清。 LTα是TNF家族成员，有可溶性LTα3和膜结合蛋白LTα1β2两种形式，在淋巴样器官形成中具有重要作用。 LTα的过表达，与自身免疫紊乱相关。我们建立的IL14α转基因小鼠模型，重现了SS的病理过程和症状，为研究干燥综合症的发病机理提供了一个新的平台，前期研究表明，应用抗LTα3抗体和可溶性LTβR-Ig抗体治疗IL-14α转基因小鼠，可维持小鼠的唾液腺的正常功能。我们将建立新的动物模型、结合分子遗传学、分子生物学、免疫学技术，对LTα3、LTα1β2及其受体在SS发生的早期阶段的作用机制进行研究，阐释LTα在SS早期，对所累及器官的局部作用机制。有助于阐明SS的发病机制，为后继SS的临床早期诊断和治疗提供了新思路和新干预靶点，提供新的分子靶向药物的可能。

Sjögren’s 综合征即干燥综合征，是自身免疫紊乱疾病，有唾液腺和泪腺功能损害，目前发病机制不清。 LTα是TNF家族成员，有可溶性LTα3和膜结合蛋白LTα1β2两种形式，在淋巴样器官形成中具有重要作用。 LTα的过表达，与自身免疫紊乱相关。我们建立的IL14α转基因小鼠模型，重现了SS的病理过程和症状，为研究干燥综合症的发病机理提供了一个新的平台，前期研究表明，应用抗LTα3抗体和可溶性LTβR-Ig抗体治疗IL-14α转基因小鼠，可维持小鼠的唾液腺的正常功能。我们应用IL-14a动物模型、结合分子遗传学、分子生物学、免疫学技术，对LTα3、LTα1β2及其受体在SS发生的早期阶段的作用机制进行了相关研究，进一步阐释了LTα在SS早期，对所累及器官的局部作用机制。这一研究成果有助于阐明SS的发病机制，为后继SS的临床早期诊断和治疗提供了新思路和新干预靶点，为下一阶段应用以LTa为干预靶点的生物制剂的应用提供了坚实的理论依据。