Cøliaki er en vanlig glutenindusert inflammatorisk lidelse i tynntarmen. Den eneste tilgjengelige behandlingen for sykdommen er livslang gluten-fri diett.
Kroppens eget enzym transglutaminase 2 (TG2) deltar i sykdomsprosessene ved cøliaki. Svært sykdomsspesifikke autoantistoffer er rettet mot dette enzymet, og det genererer modifiserte glutenpeptider som immuncellene til cøliakipasienter reagerer på. Enzymet er dermed helt sentralt i patogenesen. Nylig ble det påvist at cøliaki kan behandles med en hemmer av enzymet (Schuppan et al., NEJM 2021). Imidlertid er stedet hvor TG2 utøver sin patogene virkning er fremdeles ukjent.
Prosjektet drives i felleskap med forskergrupper på Stanford University og University of Chicago.
This is a joint NIH-RO1 project between University of Oslo/Oslo University Hospital and two top-tier US Universities; Stanford University and the University of Chicago. Research groups at the three institutions are world-leading in the area of celiac disease (CeD), and and in this project the the three groups join forces to advance the knowledge of the pathogenesis of CeD.
CeD is a gluten-induced, HLA-DQ2 or -DQ8 dependent inflammatory disorder of the small intestine for which no non-dietary therapy is available. Transglutaminase 2 (TG2) is the target of CeD-specific autoantibodies and is also directly involved in disease pathogenesis. In a CeD patient TG2 catalyzes the formation of deamidated gluten peptides that bind tightly to HLA-DQ2/8 and are recognized as epitopes by disease-specific CD4+ T cells. However, the location where TG2 exerts its pathogenic action is unknown.
The overarching hypothesis of our proposal is that TG2 derived from enterocytes shed into the intestinal lumen is the source of pathogenically relevant enzyme in CeD. This luminal TG2 reacts with gluten peptides to form covalent complexes recognized by TG2-specific B cells in Peyer’s patches. In turn, these B cells present gluten antigens to disease-specific T cells, while also deriving help from these T cells. This hypothesis can explain how TG2 autoantibodies are formed in CeD. Three Aims involving in vitro and in vivo studies are designed to test our hypothesis, while taking advantage of the complementary capabilities of the three collaborating groups.