P013 Role of IL-36RA mutations in Crohn’s disease

Abstract Background The interleukin 36 (IL-36) family consists of three agonists (IL-36α, IL-36β, IL-36γ), that activate the NF-κB pathway and lead to production pro-inflammatory cytokines natural antagonist (IL-36RA), which inhibits IL-36 signaling. While it is known signaling important in skin, has been only recently reported might play an role maintaining gut homeostasis development fibrosis (Scheibe et al., 2019). Here, we aim understand how IL-36RA mutations contribute maintenance intestinal inflammation Crohn’s disease. Methods By whole-exome sequencing (WES) subsequently targeted Sanger identified a disease (CD) patient with heterozygous missense mutation (p.Ser113Leu). To affects immune cells composition function, characterized peripheral blood mononuclear (PBMCs) by mass cytometry measured cytokine levels serum ELISA. In available WES dataset 177 CD patients, 47 ulcerative colitis (UC) patients 34 healthy donors (HD), searched for additional mutations. Finally, overexpressed HEK produced mutated recombinant proteins study effect on protein expression function. Results Our mutation-carrying presented severe course consecutive fibrosis, was resistant all commonly used treatment options. patient, detected increased IL-36RA, IL-18 IL-23 frequency TH17 blood. These findings could hint towards over-activation patient. data, two more (p.Leu133Ile, p.Pro76Leu), indicating are enriched patients. overexpressing cells, demonstrate (p.Ser113Leu p.Pro76Leu) reduced expression. Also, our current data shows p.Ser113Leu mutant capacity antagonize stimulation. However, further testing required other mutants. Conclusion suggests should be considered as possible cause therapy-refractory fibrotic