Untersuchung von XIAP-Mutationen und deren immunologischen Bedeutung für die Entwicklung einer chronisch-entzündlichen Darmerkrankung
Gastroenterologie
Immunologie
Zusammenfassung der Projektergebnisse
Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition comprising the major forms ulcerative colitis (UC) and Crohn’s disease (CD). Pathogenesis of inflammatory bowel disease (IBD) is characterized by disordered host-microbial interactions. To date, 163 genetic loci have been linked to IBD by association studies. Variants in genes that affect bacterial handling (such as NOD2) and autophagy (such as ATG16L1 or IRGM), a process involved in the intracellular degradation of bacteria in phagocytes, are associated with polygenic IBD. In addition to polygenic IBD, an increasing number of monogenic disorders presenting with intestinal inflammation highlights a role of bacterial handling in innate immune cells. For example, in male patients, mutations in the gene encoding X-linked inhibitor of apoptosis (XIAP) cause an immune-dysregulation syndrome characterized by haemophagocytic lymphohistiocytosis (HLH) and further inflammatory complications. Notably, one fifth of patients with XIAP deficiency develop severe CD-like colitis and XIAP is an essential transducer of the NOD2 pro-inflammatory signalling. Disordered host-bacteria interactions predispose to granuloma formation, the histologic hallmark of CD. Granuloma formation results of delayed clearance of bacteria, when the immune system attempts to wall off pathogens that it is unable to eliminate. We investigated bacterial handling and cytokine production in patients with granulomatous intestinal inflammation and compared functional defects between different patient groups. We report impaired bacterial handling in carriers of CD-associated NOD2 variants (R702W, G908R, 1007fs) and show that XIAP deficiency, a cause of monogenic IBD with intestinal granuloma, is associated with defective MDP-dependent bacterial handling and abrogated NOD2-mediated cytokine production. Consistent with the role of receptor-interacting kinase 2 (RIPK2) as part of the NOD2- RIPK2-XIAP complex, pharmacologic inhibition of RIPK2 with ponatinib completely abolished MDP-induced cytokine production and bacterial killing. In addition, we report early onset CD-like disease with granuloma formation in a case series of 14 patients with NPC1 mutations (NPC1-IBD). Mutations in NPC1 cause Niemann-Pick disease Type C1, a lysosomal lipid storage disorder that causes neurodegeneration and liver damage. We provide a mechanism of impaired MDP-dependent bacterial handling in NPC1 that conceptually links NPC1-IBD to other genetic defects associated with granulomatous intestinal inflammation, like NOD2 and XIAP. However, and in contrast, the lysosomal storage disorder NPC1 does not affect the NOD2-mediated cytokine production. Whereas mutations in NOD2 and XIAP impair the initiation of autophagic elimination of intracellular bacteria, NPC1 impairs autophagosome function. Although these molecules act at different checkpoints along the antibacterial autophagy or cytokine pathway, genetic variation in NOD2, XIAP and NPC1 results in a similar intestinal phenotype. Thus, heterogeneous genetic defects highlight bacterial handling as a likely defect of general importance in CD immune-pathogenesis with multiple cassettes or pathways contributing. Furthermore, we show that pharmaceutical induction of autophagy with approved drugs can restore bacterial killing suggesting a potential therapeutic strategy.
Projektbezogene Publikationen (Auswahl)
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A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome. Eur J Hum Genet. 2015 Oct 7
Schwerd T, Khaled AV, Schürmann M, Chen H, Händel N, Reis A, Gillessen-Kaesbach G, Uhlig HH, Abou Jamra R
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From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Jan;22(1):202-12
Uhlig HH, Schwerd T
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Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn’s disease. Gut. 2016 Mar 7
Tobias Schwerd, Sumeet Pandey, Huei-Ting Yang, Katrin Bagola, Elisabeth Jameson, Jonathan Jung, Robin H Lachmann, Neil Shah, Smita Y Patel, Claire Booth, Heiko Runz, Gesche Düker, Ruth Bettels, Marianne Rohrbach, Subra Kugathasan, Helen Chapel, Satish Keshav,1 Abdul Elkadri, Nick Platt, Alexio M Muise, Sibylle Koletzko, Ramnik J Xavier, Thorsten Marquardt, Fiona Powrie, James E Wraith, Mads Gyrd-Hansen, Frances M Platt, Holm H Uhlig
