title: Proinflammatory progranulin antibodies in inflammatory bowel diseases.
abstract: BACKGROUND
  Recently, we identified neutralizing autoantibodies against progranulin (PGRN) in a wide spectrum of rheumatic diseases including cases with enteropathic spondylarthritis. PGRN is a secreted protein with strong anti-inflammatory effects, believed to be mediated by the direct inhibition of TNF receptors 1&2. Given the central role of TNF-α as proinflammatory cytokine, a neutralizing antibody directed against its physiologic antagonist PGRN might entertain a proinflammatory environment.
  
  
  OBJECTIVE
  The aim of the present study was to investigate a possible occurrence of PGRN-antibodies (PGRN-Abs) in inflammatory bowel disease (IBD), and to investigate a possible pathogenic effect.
  
  
  METHODS
  Sera samples of 141 patients with Crohn's disease (CD) and of 71 patients with ulcerative colitis (UC) were tested for PGRN-Abs by ELISA. PGRN plasma levels were detected by ELISA. Proinflammatory effects of progranulin-antibodies were analyzed by TNF-α-mediated cytotoxicity assays using HT29 cells and by examination of possible effects of PGRN and of PGRN-antibodies on TNF-α-induced downmodulation of FOXP3 expression in CD4(+)CD25(hi) Tregs.
  
  
  RESULTS
  PGRN-Abs were found in sera of 23/141 (16.31%) patients with CD, and 15/71 (21.13%) patients with UC. PGRN-Abs were more frequent than anti-neutrophil cytoplasmic autoantibodies (ANCAs) in UC, but less frequent than anti-Saccharomyces cerevisiae antibodies (ASCAs) in CD. PGRN-Abs belonged mostly to IgG1 (71.1%) and IgA (26.3%). They occurred in relevant titres and had significant neutralizing effects on PGRN plasma levels. Cytotoxicity assays comparing PGRN-antibody-positive sera with negative sera from matched patients with IBD showed a proinflammatory effect of PGRN-Abs on HT29 cells. Moreover, PGRN-antibodies led to an increase of TNF-α-induced downmodulation of FOXP3 in CD4(+)CD25(hi) Tregs.
  
  
  CONCLUSIONS
  The results suggest that PGRN-Abs occur frequently in CD and UC, and have a proinflammatory effect.
authors.affiliation: José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany, lorenz.thurner@uks.eu.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Thurner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stöger
authors.forename: Natalie
authors.initials: N
authors.lastname: Fadle
authors.forename: Philipp
authors.initials: P
authors.lastname: Klemm
authors.forename: Evi
authors.initials: E
authors.lastname: Regitz
authors.forename: Maria
authors.initials: M
authors.lastname: Kemele
authors.forename: Birgit
authors.initials: B
authors.lastname: Bette
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.forename: Marc
authors.initials: M
authors.lastname: Dauer
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Preuss
authors.forename: Vincent
authors.initials: V
authors.lastname: Zimmer
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000096:biosynthesis / Q000097:blood; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000473:pathology*; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000077153:Progranulins; D012441:Saccharomyces cerevisiae / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D014409:Tumor Necrosis Factor-alpha