Proinflammatory Progranulin Antibodies in Inflammatory Bowel Diseases

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-alpha as proinflammatory cytokine, a neutralizing antibody directed against its physiologic antagonist PGRN might entertain a proinflammatory environment. 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. 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-alpha-mediated cytotoxicity assays using HT29 cells and by examination of possible effects of PGRN and of PGRN-antibodies on TNF-alpha-induced downmodulation of FOXP3 expression in CD4(+)CD25(hi) Tregs. 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-alpha-induced downmodulation of FOXP3 in CD4(+)CD25(hi) Tregs. The results suggest that PGRN-Abs occur frequently in CD and UC, and have a proinflammatory effect.