Establishment of a spontaneous single gene model for Sjogren's syndrome

常染色体隐性突变aly（淋巴增生症）纯合子小鼠缺乏淋巴结和Peyer's补片，并且在体液和细胞免疫方面都表现出缺陷。组织病理学分析显示纯合子（aly/aly）的外分泌器官如涎腺、泪腺和胰腺有慢性炎症改变，而杂合子（aly/+）的外分泌器官无慢性炎症改变。在这些外分泌器官中，主要由CD4^+ T细胞组成的单核细胞浸润导管周围区域，在某些情况下，细胞浸润扩展到小叶。在纯合子的肺部也观察到炎症变化。因为我们通过纯合子和杂合子的交配来维持aly小鼠。由于我们通过将纯合子与杂合子配对来维持aly小鼠，因此炎症变化与纯合子的关联强烈表明病变是由aly突变本身或aly基因附近的基因引起的。由于干燥综合征以弥漫性淋巴为特征，泪腺和唾液腺导管周围有更多的细胞浸润，并且偶尔与肺部疾病有关，aly/aly小鼠可能作为干燥综合征的独特单基因模型。外分泌器官的炎症变化是通过纯合子动物脾脏细胞的CD4^+ T细胞富集部分转移的。这些结果表明，尽管纯合子小鼠表现出免疫缺陷，但由自身反应性T细胞介导的自身免疫机制可能参与了各种外分泌器官的炎症损害。我们进一步评估了细胞因子如IL-10控制Th1分化的作用。当我们用抗il -10治疗aly/aly小鼠时，外分泌器官炎症变化的严重程度明显降低。提示IL-10在aly小鼠外分泌器官炎症的发病机制中起一定作用，提示可通过阻断IL-10活性治疗干燥综合征。少

Mice homozygous for an autosomal recessive mutation aly (alymphoplasia) lack both lymph nodes and Peyer's patches, and show defects in both humoral and cellular immunity. Histopathological analysis revealed chronic inflammatory changes in exocrine organs such as the salivery gland, lacrimal gland and pancreas of the homozygotes (aly/aly) but not the heterozygotes (aly/+). In these exocrine organs, mononuclear cells consisting mainly of CD4^+ T cells infiltrate periductal areas, and, in some cases, the cell infiltration extended to lobules. Inflammatory changes were also observed in the lung of the homozygotes. Because we maintained the aly mice by mating the homozygotes with heterozygotes. Because we maintained the aly mice by mating the homozygotes with heterozygotes, the association of the inflammatory changes to homozygotes strongly suggest that the lesions are caused by aly mutation itself or the gene close to the aly gene. Since Sjogren's syndrome is characterized by diffuse lymph … More ocyte infiltration in the periductal areas of the lacrimal and salivary glands and is occasionally associated with pulmonary disease, aly/aly mice may serve as a unique single gene model of Sjogren's syndrome.The inflammatory changes in exocrine organs were transferred by a CD4^+ T cell-enriched fraction of spleen cells from homozygous animals. These results suggest that autoimmune mechanisms mediated by self-reactive T cells may be involved in the inflammatory lesions of various exocrine organs in the homozygous mice although these mice show immunodeficiency. We further assessed the role of cytokines controling Th1 differentiation such as IL-10. When we treated aly/aly mice with anti-IL-10, the severity of the inflammatory changes in the exocrine organes were significantly reduced. This result indicates that IL-10 play some roles in the pathogenesis of the inlammation of the exocrine organs in aly mice and suggests that Sjogren syndrome may be treated by blocking the activity of IL-10. Less