Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice.
Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice.
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DOI：
10.4049/jimmunol.1201216
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Pitzalis C
中科院分区：
文献类型：
--
作者：
Bombardieri M;Barone F;Lucchesi D;Nayar S;van den Berg WB;Proctor G;Buckley CD;Pitzalis C
干燥综合征 (SS) 患者的唾液腺会形成异位淋巴结构 (ELS)，其特征是 B/T 细胞区室化、高内皮小静脉 (HEV) 的形成、滤泡树突细胞网络 (FDC)、功能性 B 细胞激活并表达激活诱导的胞苷脱氨酶 (AID) 以及自身反应性浆细胞的局部分化。 SS 中触发 ELS 形成、自身免疫和外分泌功能障碍的机制在很大程度上尚不清楚。在这里，我们提出了一种新的模型，通过逆行排泄管插管将复制缺陷型腺病毒 5 (AdV5) 递送到 C57BL/6 小鼠的颌下腺中后，诱导异位淋巴组织形成、体液自我耐受破坏和唾液功能低下。在该模型中，AdV 递送后 2 周内，炎症持续快速地从弥漫性浸润发展为 SS 样导管周围淋巴聚集体。这些渗透物逐渐获得 ELS 特征并支持功能性 GL7+/AID+ 生发中心。 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，并且与高达 75% 的小鼠中抗核抗体的产生相关。最后，在 AdV 感染后 3 周内观察到唾液流量减少，这与炎症反应导致的外分泌腺功能障碍一致。这种新模型有可能揭示调节 ELS 形成的细胞和分子机制及其在 SS 外分泌功能障碍和自身免疫中的作用。
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 (HEV), follicular dendritic cell networks (FDCs), functional B cell activation with expression of activation-induced cytidine deaminase (AID) as well as local differentiation of autoreactive plasma cells. The mechanisms triggering ELS formation, autoimmunity and exocrine dysfunction in SS are largely unknown. Here we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance and salivary hypofunction following delivery of a replication-deficient adenovirus-5 (AdV5) in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration towards the development of SS-like periductal lymphoid aggregates within 2 weeks from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7+/AID+ 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 antibodies in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 weeks 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 regulating ELS formation and their role in exocrine dysfunction and autoimmunity in SS.
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影响因子：
27.4
作者：
Aziz, KE;McCluskey, PJ;Wakefield, D
通讯作者：
Wakefield, D
阻断淋巴毒素-β 受体信号传导可减少非肥胖糖尿病小鼠唾液腺中干燥综合征的症状。
影响因子：
4.9
作者：
Gatumu, Margaret K.;Skarstein, Kathrine;Papandile, Adrian;Browning, Jeffrey L.;Fava, Roy A.;Bolstad, Anne Isine
通讯作者：
Bolstad, Anne Isine
影响因子：
3
作者：
Humphreys-Beher, MG;Peck, AB
通讯作者：
Peck, AB
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影响因子：
15.3
作者：
Castigli, E;Wilson, SA;Scott, S;Dedeoglu, F;Xu, SL;Lam, KP;Bram, RJ;Jabara, H;Geha, RS
通讯作者：
Geha, RS
影响因子：
27.4
作者：
Bombardieri, Michele;Kam, Ngar-Woon;Pitzalis, Costantino
通讯作者：
Pitzalis, Costantino