title: Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Neuropathology, Zurich, Switzerland.
authors.forename: Gitta M
authors.initials: GM
authors.lastname: Seleznik
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Switzerland.
authors.forename: Theresia
authors.initials: T
authors.lastname: Reding
authors.affiliation: Second Department of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Romrig
authors.affiliation: Division of Haematology, University Hospital Zurich, Switzerland.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Neuropathology & BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.affiliation: Division of Nephrology, University Hospital Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Switzerland.
authors.forename: Li-Kang
authors.initials: LK
authors.lastname: Sun
authors.affiliation: Division of Clinical Immunology, University Hospital Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Regenass
authors.affiliation: Medizinische Klinik IV, Klinikum der Universität München, Campus Innenstadt, Munich, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.affiliation: Medizinische Klinik IV, Klinikum der Universität München, Campus Innenstadt, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: Institute of Neuropathology, Zurich, Switzerland.
authors.forename: Donal
authors.initials: D
authors.lastname: McHugh
authors.affiliation: Gastroenterology and Metabology, Ehime University, Graduate School of Medicine, Shitsukawa To-on, Ehime, Japan.
authors.forename: Teru
authors.initials: T
authors.lastname: Kumagi
authors.affiliation: Gastroenterology and Metabology, Ehime University, Graduate School of Medicine, Shitsukawa To-on, Ehime, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.affiliation: Institute of Pathology, Medical University Graz, Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Institute of Pathology, Medical University Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Departments of Visceral Surgery and Pathology, Inselspital, University of Bern, Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Angst
authors.affiliation: Departments of Visceral Surgery and Pathology, Inselspital, University of Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Department of Gastroenterology, Inselspital, University of Bern, Switzerland.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Balmer
authors.affiliation: Department of Gastroenterology, Inselspital, University of Bern, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Department of Gastroenterology, Inselspital, University of Bern, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: MacPherson
authors.affiliation: Division of Haematology, University Hospital Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Institute of Clinical Pathology, Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Department of Immunology, Biogen-Idec, Cambridge, Massachusetts.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.affiliation: Second Department of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Melek Canan
authors.initials: MC
authors.lastname: Arkan
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Neuropathology, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.affiliation: Department of Neuropathology & BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Institute of Neuropathology, Zurich, Switzerland; Institute of Virology, Technische Universität München/Helmholtz-Zentrum München, München Germany. Electronic address: mathias.heikenwaelder@usz.ch.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D018925:Chemokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D018655:Lymphocyte Count; D053259:Lymphotoxin beta Receptor / Q000097:blood / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010196:Pancreatic Elastase / Q000235:genetics / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D016176:T-Lymphocyte Subsets; D015854:Up-Regulation
chemical_list: D000305:Adrenal Cortex Hormones; D001323:Autoantibodies; D018925:Chemokines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D012333:RNA, Messenger; D010196:Pancreatic Elastase