Lymphotoxin ß receptor signaling promotes development of autoimmune pancreatitis.
Gastroenterology
; 143(5): 1361-1374, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22863765
ABSTRACT
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)α and ß specifically in acinar cells (Ela1-LTab mice).RESULTS:
Messenger RNA levels of LTα and ß 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 LTαß (Ela1-LTαß) 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 LTαß 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 LTßR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice.CONCLUSIONS:
Overexpression of LTαß specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTßR ligands might be used to treat patients with AIP.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes
/
Transdução de Sinais
/
Pancreatite Crônica
/
Receptor beta de Linfotoxina
Tipo de estudo:
Observational_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article