title: Autoantibodies against the exocrine pancreas in autoimmune pancreatitis: gene and protein expression profiling and immunoassays identify pancreatic enzymes as a major target of the inflammatory process.
abstract: OBJECTIVE
  Autoimmune pancreatitis (AIP) is thought to be an immune-mediated inflammatory process, directed against the epithelial components of the pancreas. The objective was to identify novel markers of disease and to unravel the pathogenesis of AIP.
  
  
  METHODS
  To explore key targets of the inflammatory process, we analyzed the expression of proteins at the RNA and protein level using genomics and proteomics, immunohistochemistry, western blot, and immunoassay. An animal model of AIP with LP-BM5 murine leukemia virus-infected mice was studied in parallel. RNA microarrays of pancreatic tissue from 12 patients with AIP were compared with those of 8 patients with non-AIP chronic pancreatitis.
  
  
  RESULTS
  Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of the SPINK1 gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen.
  
  
  CONCLUSIONS
  These data indicate that the immune-mediated process characterizing AIP involves pancreatic acinar cells and their secretory enzymes such as trypsin isoforms. Demonstration of trypsinogen autoantibodies may be helpful for the diagnosis of AIP.
authors.affiliation: Molecular Gastroenterology, German Cancer Research Center, Heidelberg, Germany. matthias.lohr@ki.se
authors.forename: J-Matthias
authors.initials: JM
authors.lastname: Löhr
authors.forename: Ralf
authors.initials: R
authors.lastname: Faissner
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.forename: Peter
authors.initials: P
authors.lastname: Bewerunge
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Luca
authors.initials: L
authors.lastname: Frulloni
authors.forename: Anette
authors.initials: A
authors.lastname: Funk
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.forename: Ralf
authors.initials: R
authors.lastname: Jesenofsky
authors.forename: Ralf
authors.initials: R
authors.lastname: Jesnowski
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Burkhard
authors.initials: B
authors.lastname: Krüger
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Ralf
authors.initials: R
authors.lastname: Lösel
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Michael
authors.initials: M
authors.lastname: Neumaier
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nittka
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
authors.forename: Julian
authors.initials: J
authors.lastname: Sänger
authors.forename: Sonja
authors.initials: S
authors.lastname: Serafini
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Thierse
authors.forename: Silke
authors.initials: S
authors.lastname: Wandschneider
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zamboni
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D046790:Pancreas, Exocrine / Q000276:immunology* / Q000378:metabolism; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020543:Proteome; D014362:Trypsinogen / Q000097:blood
chemical_list: D001323:Autoantibodies; D020543:Proteome; D014362:Trypsinogen
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