Identification of Pancreatic Glycoprotein 2 as an Endogenous Immunomodulator of Innate and Adaptive Immune Responses

Abstract

Pancreatic autoantibodies are Crohn disease-specific serologic markers. The function and immunological role of their recently identified autoantigen, glycoprotein 2 (GP2), are unknown. We therefore investigated the impact of GP2 on modulation of innate and adaptive immune responses to evaluate its potential therapeutic use in mucosal inflammation. Our data indicate a previously unknown function for GP2 as an immunomodulator. GP2 was ubiquitously expressed on cells vital to mucosal immune responses. The expression of GP2 was upregulated on activated human T cells, and it was further influenced by pharmaceutical TNF-α inhibitors. Recombinant GP2 significantly decreased human intestinal epithelial cells, mucosal and peripheral T cell proliferation, apoptosis, and activation, and it distinctly modulated cytokine secretion. Furthermore, intestinal epithelial cells stimulated with GP2 potently attracted T cells. In conclusion, we demonstrate a novel role for GP2 in immune regulation that could provide a platform for new therapeutic interventions in the treatment of Crohn disease.

Crohn’s disease specific pancreatic antibodies: clinical and pathophysiological challenges

“…Thus, GP2 on M cells can serve as a transcytotic receptor for bacterial antigens and, therefore, partake in the mucosal immune response to these particular bacteria [56]. Thus, the elevated phagocytosis of E. coli by monocytes observed after treatment with GP2 supports the notion that GP2 may have a broader pro-phagocytotic ability [71].…”

“…This ability has profound effects on the understanding of GP2 as dendritic cells play an important role in the generation of innate and adaptive immune responses [74]. Interestingly, the synthesis of GP2 appears to be up-regulated on activated human T cells and to be modulated by pharmaceutical TNFα inhibitors [71]. An intriguing finding was the reduction of human intestinal epithelial cell, mucosal, and peripheral T cell proliferation and apoptosis by GP2.…”

“…Likewise, a putative immunomodulating role of GP2 has been addressed recently [71,73]. Glycoprotein 2 has been identified as a binding partner of the scavenger receptor expressed on endothelial cells I (SREC-I), which can be also found on dendritic cells [73].…”

“…Altogether, these data seem to support an anti-inflammatory role of GP2 in the mucosal immune system. Investigating this putative immunosuppressive effect, Werner et al obtained data indicating that GP2 modulates such an effect through its interaction with regulatory T cells [71].…”

Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2

“…The self-aggregating, non-digestive autoantigenic GP2 is secreted along with digestive proenzymes and represents a major pancreatic plug component [4,16,[26][27][28]. GP2 does not appear to play a decisive intracellular role during secretion but rather an antimicrobial and immunomodulating one after its release into the intestine despite its reported regulation of acinar endocytosis or ZG assembly [29][30][31][32][33][34][35][36].…”