The main goal of this project is to unravel the mechanisms governing immune homeostasis in the human gut. We use a novel approach by combining the power of clinical pediatrics, genome-wide sequence analysis, proteomic systems biology and application of state-of-the-art bioinformatic tools to elucidate the pathophysiology of inflammatory bowel diseases (IBD). We hypothesize that children with early-onset IBD may represent a human model system of how monogenic factors can provoke susceptibility to intestinal inflammation. A cohort of 90 families with early-onset IBD patients has been collected. In an attempt to discover novel genetic factors controlling immune homeostasis in the human gut, we will perform homozygosity mapping and next-generation genome sequencing. In a systems biology perspective, we plan to collaborate with BioSysNet partners to shed light on the biochemical networks affected by newly discovered gene defects in human cells. Furthermore, conditional murine knockout model systems will be established for further in vivo experiments. These studies will not only provide insights into basic immunological principles of gut inflammation but may also reveal novel therapeutic principles for patients with IBD.

Maximilian Witzel

Daniel Kotlarz

Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C (2014). Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci Transl Med 6(227):227ra33.

Murugan D, Albert MH, Langemeier J, Bohne J, Puchalka J, Järvinen PM, Hauck F, Klenk AK, Prell C, Schatz S, Diestelhorst J, Sciskala B, Kohistani N, Belohradsky BH, Müller S, Kirchner T, Walter MR, Bufler P, Muise AM, Snapper SB, Koletzko S, Klein C, Kotlarz D (2014). Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. J Clin Immunol 34(3):331-9. 

Glocker E, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, Pero M, Diestelhorst J, Allroth A, Murugan D, Hätscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal A, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C. Inflammatory Bowel Disease and Mutations Affecting the IL10 Receptor. New Engl J Med 361:2033-2045 2009

Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, Pfeifer D, Kreipe H, Pfister ED, Baumann U, Sauerbrey A, Buderus S, Güngör T, Bielack S, Koda YK, Guariso G, Weiss B, Corbacioglu S, Socha P, Wahbeh GT, Al-Herz W, Grimbacher B, Sauer M, Sykora KW, Koletzko S and Klein C. IL-10 and IL-10R deficiency in infantile inflammatory bowel disease – diagnosis and treatment. Gastroenterology (in press)