| First Author | Seleznik GM | Year | 2012 |
| Journal | Gastroenterology | Volume | 143 |
| Issue | 5 | Pages | 1361-1374 |
| PubMed ID | 22863765 | Mgi Jnum | J:301576 |
| Mgi Id | MGI:6506366 | Doi | 10.1053/j.gastro.2012.07.112 |
| Citation | Seleznik GM, et al. (2012) Lymphotoxin beta receptor signaling promotes development of autoimmune pancreatitis. Gastroenterology 143(5):1361-1374 |
| abstractText | 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 LTalpha 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. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTalphabeta (Ela1-LTalphabeta) 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 LTalphabeta 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 LTbetaR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS: Overexpression of LTalphabeta specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTbetaR ligands might be used to treat patients with AIP. |
