XIAP Deficiency and Intestinal Inflammation: Study of an Orphan Disease and Pathways relevant for Inflammatory Bowel Disease

• Applicant: Privatdozent Dr. Tobias Schwerd
• Subject Area: Pediatric and Adolescent Medicine ; Gastroenterology ; Immunology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240816342

Inflammatory bowel disease (IBD), mainly Crohn's disease, is increasingly recognized in the pediatric population. A subgroup of patients suffers from onset of intestinal inflammation during the first years of life, called early-onset IBD (EO-IBD). Recent studies demonstrated that intestinal pathology of EO-IBD can derive from single disease causing genetic variants with strong biologic impact on intestinal immune homeostasis, like mutations in the genes encoding IL-10 or IL-10 receptor alpha or beta. Studies of primary immunodeficiency syndromes with colitis-phenotype contribute to our understanding of molecular mechanisms in those orphan diseases but more importantly, reveal pathways relevant for IBD in general.Mutations in the X-linked inhibitor of apoptosis protein (XIAP)-gene cause the rare primary immunodeficiency, X-linked lymphoproliferative syndrome type 2 (XLP-2). XLP-2 syndrome is characterized by recurrent episodes of hemophagocytic lymphohistiocytosis and splenomegaly. One fifth of patients develops severe IBD-like immunopathology. However, so far it is not understood how XIAP-deficiency leads to intestinal pathology. XIAP protein is associated with several immune signaling pathways implicated in IBD pathogenesis by genome-wide association studies (e.g. NOD2 signaling). Given the incomplete penetrance of colitis in XLP-2 syndrome, more common modifier genes or polymorphisms may contribute to the profound biologic effect of mutations in XIAP-gene. It remains elusive whether innate immune responses towards commensal microorganisms of the gut are affected by XIAP-deficiency. Aberrant bacterial handling and cytokine production by innate immune cells may lead to uncontrolled activation of adaptive immune cells and ultimately predispose to colitis. Thus, the aim of this research project is to investigate children with XIAP-deficiency and dissect signalling pathways relevant for IBD pathogenesis. As XIAP-deficiency is a rare disease with a potentially severe disease course in pediatric patients, the study has inherent limitations due to the limited availability of biological specimens. To overcome this problem, somatic cells of patients will be reprogrammed into a state of pluripotency by the forced expression of a set of transcription factors and subsequently, differentiated into immune cells. Patient-derived induced pluripotent stem cells (iPSC) carry the disease-causing genetic variants and allow to model disease mechanism in vitro. In addition, studies with iPSC-derived immune cells hold the potential to directly compare immune function at the cellular level with the significant diversity of clinical and immunological phenotypes among patients with different mutations occurring in the XIAP-gene.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Hosts: Professorin Dr. Fiona Powrie, Ph.D.; Professor Dr. Holm Uhlig