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. MATERIALS AND 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. CONCLUSION: The results suggest that PGRN-Abs occur frequently in CD and UC, and have a proinflammatory effect.
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. MATERIALS AND 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. CONCLUSION: The results suggest that PGRN-Abs occur frequently in CD and UC, and have a proinflammatory effect.
Authors: Mark S Silverberg; Jack Satsangi; Tariq Ahmad; Ian D R Arnott; Charles N Bernstein; Steven R Brant; Renzo Caprilli; Jean-Frédéric Colombel; Christoph Gasche; Karel Geboes; Derek P Jewell; Amir Karban; Edward V Loftus; A Salvador Peña; Robert H Riddell; David B Sachar; Stefan Schreiber; A Hillary Steinhart; Stephan R Targan; Severine Vermeire; B F Warren Journal: Can J Gastroenterol Date: 2005-09 Impact factor: 3.522
Authors: Sarah K Browne; Peter D Burbelo; Ploenchan Chetchotisakd; Yupin Suputtamongkol; Sasisopin Kiertiburanakul; Pamela A Shaw; Jennifer L Kirk; Kamonwan Jutivorakool; Rifat Zaman; Li Ding; Amy P Hsu; Smita Y Patel; Kenneth N Olivier; Viraphong Lulitanond; Piroon Mootsikapun; Siriluck Anunnatsiri; Nasikarn Angkasekwinai; Boonmee Sathapatayavongs; Po-Ren Hsueh; Chi-Chang Shieh; Margaret R Brown; Wanna Thongnoppakhun; Reginald Claypool; Elizabeth P Sampaio; Charin Thepthai; Duangdao Waywa; Camilla Dacombe; Yona Reizes; Adrian M Zelazny; Paul Saleeb; Lindsey B Rosen; Allen Mo; Michael Iadarola; Steven M Holland Journal: N Engl J Med Date: 2012-08-23 Impact factor: 91.245
Authors: Xi Chen; Jianjun Chang; Qiudong Deng; Jie Xu; Thi A Nguyen; Lauren H Martens; Basar Cenik; Georgia Taylor; Kathryn F Hudson; Jaegwon Chung; Kimberley Yu; Phillip Yu; Joachim Herz; Robert V Farese; Thomas Kukar; Malú G Tansey Journal: J Neurosci Date: 2013-05-22 Impact factor: 6.167