Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Seleznik, GM; Reding, T; Romrig, F; Saito, Y; Mildner, A; Segerer, S; Sun, LK; Regenass, S; Lech, M; Anders, HJ; McHugh, D; Kumagi, T; Hiasa, Y; Lackner, C; Haybaeck, J; Angst, E; Perren, A; Balmer, ML; Slack, E; MacPherson, A; Manz, MG; Weber, A; Browning, JL; Arkan, MC; Rülicke, T; Aguzzi, A; Prinz, M; Graf, R; Heikenwalder, M.
Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis.
Gastroenterology. 2012; 143(5):1361-1374
Doi: 10.1053/j.gastro.2012.07.112
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- Co-Autor*innen der Med Uni Graz
- Haybäck Johannes
- Lackner Karoline
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- Abstract:
- BACKGROUND AND 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Acinar Cells - metabolism
- Adrenal Cortex Hormones - pharmacology
- Analysis of Variance -
- Animals -
- Autoantibodies - blood
- Autoimmune Diseases - blood
- Case-Control Studies -
- Cells, Cultured -
- Chemokines - drug effects
- Disease Models, Animal -
- Glomerulonephritis - immunology
- Humans -
- Immunoglobulin A - blood
- Immunoglobulin G - blood
- Immunoglobulin M - blood
- Lymphocyte Count -
- Lymphotoxin beta Receptor - blood
- Lymphotoxin-alpha - drug effects
- Lymphotoxin-beta - drug effects
- Mice -
- Mice, Inbred C57BL -
- Mice, Transgenic -
- Pancreatic Elastase - genetics
- Pancreatitis, Chronic - blood
- Promoter Regions, Genetic -
- RNA, Messenger - drug effects
- Signal Transduction -
- Statistics, Nonparametric -
- T-Lymphocyte Subsets -
- Up-Regulation -
- Find related publications in this database (Keywords)
- Tertiary Lymphoid Tissues
- Immune Regulation
- Regulatory T Cell
- TNF Superfamily