Institute of Neuropathology, Zurich, Switzerland.
Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Switzerland.
Gastroenterology. 2012 Nov;143(5):1361-1374. doi: 10.1053/j.gastro.2012.07.112. Epub 2012 Aug 2.
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.
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)α and β specifically in acinar cells (Ela1-LTab mice).
Messenger RNA levels of LTα and β 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. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαβ (Ela1-LTαβ) 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 LTαβ 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 LTβR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice.
Overexpression of LTαβ specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTβR ligands might be used to treat patients with AIP.
自身免疫性胰腺炎（AIP）是一种日益被认识的、免疫介导的慢性胰腺炎，其发病机制知之甚少。目前的治疗选择有限，且疾病复发频繁。我们研究了导致 AIP 发生的因素和新的治疗策略。
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来自患有和不患有 AIP 的患者的组织和血清样本中的细胞因子和趋化因子的表达。我们通过在胰腺细胞中特异性过表达淋巴毒素（LT）α和β（Ela1-LTab 小鼠）来创建人类 AIP 的小鼠模型。
与对照组相比，AIP 患者的胰腺组织中 LTα 和β 的信使 RNA 水平增加，且患者的胰腺和血清样本中趋化因子（CXCL13、CCL19、CCL21、CCL1 和 B 细胞激活因子）的表达增加。这些因子的上调不受皮质类固醇治疗的影响。在小鼠中，特异性过表达 LTαβ（Ela1-LTαβ）导致具有各种 AIP 特征的自身免疫性疾病。慢性炎症仅在胰腺中发展，但足以引起全身自身免疫。在没有淋巴细胞的小鼠中（Ela1-LTab/Rag1(-/-)），特异性过表达 LTαβ 不会引起自身免疫；此外，缺乏促炎单核细胞（Ela1-LTab/Ccr2(-/-)）不能预防 AIP，但可防止早期胰腺组织损伤。皮质类固醇的给药可减轻胰腺炎，但不能影响自身抗体的产生，如 Ela1-LTab 小鼠中的抗胰蛋白酶抑制剂。相比之下，抑制 LTβR 信号可减少 Ela1-LTab 小鼠中的趋化因子表达、肾脏免疫复合物沉积和 AIP 的特征。
特异性过表达 LTαβ 在小鼠的胰腺细胞中可引起 AIP 的特征。中和 LTβR 配体的试剂可能用于治疗 AIP 患者。
