Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis
Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis
复制标题
DOI：
10.1053/j.gastro.2012.07.112
复制
发表时间：
2012-11-01
期刊：
影响因子：
29.4
通讯作者：
Heikenwalder, Mathias
中科院分区：
文献类型：
--
作者：
Seleznik, Gitta M.;Reding, Theresia;Heikenwalder, Mathias
背景与目的：自身免疫性胰腺炎（AIP）是一种越来越被认可的免疫介导型慢性胰腺炎，目前对其致病机制知之甚少。目前的治疗方案有限，疾病复发也很频繁。我们研究了促进AIP发展的因素和新的治疗策略。方法：我们使用定量聚合酶链反应、免疫组织化学和酶联免疫吸附分析来测量AIP患者和非AIP患者组织和血清样本中细胞因子和趋化因子的表达。我们通过在腺泡细胞（Ela1-LTab小鼠）中特异性过表达淋巴感光素(LT) α和β，建立了人AIP小鼠模型。结果：与对照组相比，AIP患者胰腺组织中LT α和β的信使RNA水平升高，患者胰腺和血清样本中趋化因子（CXCL13、CCL19、CCL21、CCL1和b细胞活化因子）的表达升高。这些因子的上调不受皮质类固醇治疗的影响。在小鼠中，腺泡特异性过表达LT α β (Ela1-LT α β)导致具有AIP各种特征的自身免疫性疾病。慢性炎症仅发生在胰腺，但足以引起全身自身免疫。在没有淋巴细胞的小鼠中，腺泡特异性过表达LT α β不会引起自身免疫（Ela1-LTab/Rag1(-/-)）；此外，缺乏促炎单核细胞（Ela1-LTab/Ccr2(-/-)）不能预防AIP，但可以预防早期胰腺组织损伤。在Ela1-LTab小鼠中，皮质类固醇可减少胰腺炎，但不影响自身抗体的产生，如抗胰腺分泌胰蛋白酶抑制剂。相比之下，抑制LT β R信号可降低Ela1-LTab小鼠趋化因子表达、肾脏免疫复合物沉积和AIP特征。结论：小鼠腺泡细胞特异性过表达LT α - β可引起AIP的特征。中和LT β R配体的试剂可能用于治疗AIP患者。
BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. METHODS: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)alpha and beta specifically in acinar cells (Ela1-LTab mice). RESULTS: Messenger RNA levels of LT alpha and beta were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Upregulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LT alpha beta (Ela1-LT alpha beta) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LT alpha beta did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LT beta R signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS: Overexpression of LT alpha beta specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LT beta R ligands might be used to treat patients with AIP.