Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis

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.

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 β specifically in acinar cells (Ela1-LTab mice).

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism
  • Adrenal Cortex Hormones / pharmacology
  • Adrenal Cortex Hormones / therapeutic use
  • Analysis of Variance
  • Animals
  • Autoantibodies / blood
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Chemokines / drug effects
  • Chemokines / metabolism
  • Disease Models, Animal
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Lymphocyte Count
  • Lymphotoxin beta Receptor / blood
  • Lymphotoxin beta Receptor / metabolism*
  • Lymphotoxin-alpha / drug effects
  • Lymphotoxin-alpha / genetics
  • Lymphotoxin-alpha / metabolism
  • Lymphotoxin-beta / drug effects
  • Lymphotoxin-beta / genetics
  • Lymphotoxin-beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatic Elastase / genetics
  • Pancreatic Elastase / metabolism
  • Pancreatitis, Chronic / blood
  • Pancreatitis, Chronic / drug therapy
  • Pancreatitis, Chronic / immunology*
  • Pancreatitis, Chronic / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Statistics, Nonparametric
  • T-Lymphocyte Subsets
  • Up-Regulation


  • Adrenal Cortex Hormones
  • Autoantibodies
  • Chemokines
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • RNA, Messenger
  • Pancreatic Elastase