Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
J Immunol. 2012 Oct 1;189(7):3767-76. doi: 10.4049/jimmunol.1201216. Epub 2012 Aug 31.
Salivary glands in patients with Sjögren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterized by B/T cell compartmentalization, the formation of high endothelial venules, follicular dendritic cell networks, functional B cell activation with expression of activation-induced cytidine deaminase, as well as local differentiation of autoreactive plasma cells. The mechanisms that trigger ELS formation, autoimmunity, and exocrine dysfunction in SS are largely unknown. In this article, we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance, and salivary hypofunction after delivery of a replication-deficient adenovirus-5 in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration toward the development of SS-like periductal lymphoid aggregates within 2 wk from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7(+)/activation-induced cytidine deaminase(+) germinal centers. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL19, and lymphotoxin-β, and is associated with development of anti-nuclear Abs in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 wk post-AdV infection, consistent with exocrine gland dysfunction as a consequence of the inflammatory response. This novel model has the potential to unravel the cellular and molecular mechanisms that regulate ELS formation and their role in exocrine dysfunction and autoimmunity in SS.
干燥综合征（SS）患者的唾液腺会形成异位淋巴样结构（ELS），其特征为 B/T 细胞区室化、高内皮静脉形成、滤泡树突状细胞网络、表达激活诱导胞苷脱氨酶的功能性 B 细胞激活，以及自身反应性浆细胞的局部分化。引发 ELS 形成、自身免疫和 SS 外分泌功能障碍的机制在很大程度上尚不清楚。在本文中，我们提出了一个新的诱导性异位淋巴组织形成、体液自身耐受破坏和唾液分泌功能低下的模型，方法是通过逆行排泄管插管将复制缺陷型腺病毒 5 递送至 C57BL/6 小鼠的颌下腺。在该模型中，炎症迅速且一致地从弥漫性浸润发展为 SS 样的管周淋巴样聚集，从 AdV 给药后 2 周开始。这些浸润逐渐获得 ELS 特征，并支持功能性 GL7(+) /激活诱导胞苷脱氨酶(+)生发中心的形成。ELS 的形成先于淋巴趋化因子 CXCL13、CCL19 和淋巴毒素-β 的异位表达，并与高达 75%的小鼠中抗核抗体的产生有关。最后，在 AdV 感染后 3 周观察到唾液流量减少，与炎症反应导致的外分泌腺功能障碍一致。该新型模型有可能揭示调节 ELS 形成的细胞和分子机制及其在 SS 中外分泌功能障碍和自身免疫中的作用。
