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Seleznik, G.M.* ; Reding, T.* ; Romrig, F.* ; Saito, Y.* ; Mildner, A.* ; Segerer, S.* ; Sun, L.K.* ; Regenass, S.* ; Lech, M.* ; Anders, H.J.* ; McHugh, D.* ; Kumagi, T.* ; Hiasa, Y.* ; Lackner, C.* ; Haybaeck, J.* ; Angst, E.* ; Perren, A.* ; Balmer, M.L.* ; Slack, E.* ; Macpherson, A.* ; Manz, M.G.* ; Weber, A.* ; Browning, J.L.* ; Arkan, M.C.* ; Rülicke, T.* ; Aguzzi, A.* ; Prinz, M.* ; Graf, R.* ; Heikenwälder, M.

Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis.

Gastroenterology 143, 1361-1374 (2012)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter tertiary lymphoid tissues; immune regulation; regulatory T cell; TNF superfamily; REGULATORY T-CELLS; B-CELLS; SCLEROSING PANCREATITIS; TRANSGENIC MICE; DISEASE; EXPRESSION; NEOGENESIS; ORGAN; INFLAMMATION; ACTIVATION
Sprache englisch
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 0016-5085
e-ISSN 1528-0012
Zeitschrift Gastroenterology
Quellenangaben Band: 143, Heft: 5, Seiten: 1361-1374 Artikelnummer: , Supplement: ,
Verlag Elsevier
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-551600-001
PubMed ID 22863765
DOI 10.1053/j.gastro.2012.07.112
WOS ID WOS:000310459700049
Erfassungsdatum 2012-12-03
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