Transcriptional Regulation of the Immune system
Transcriptional regulation of immune cells
The immune system is designed to recognize and eliminate foreign pathogens while preserving immune tolerance to itself. Imbalance of the immune homeostasis and loss of self-tolerance results in autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel diseases. Therefore responses against pathogens on the one hand but prevention of attacks against the body itself needs to be tightly regulated. Several immune cells with different functions regulate immune homeostasis; differentiation, expansion and function of which is moreover controlled by transcription factors or even networks of transcription factors
The focus of our laboratory is on studying transcriptional regulation of inflammatory und suppressive immune cell subsets in health and disease. We therefore analyze mechanism and functions of particular transcription factors. Furthermore fundamental research is supplemented with analysis of human samples e.g. from patients with systemic lupus erythematosus, juvenile idiopathic arthritis.
1. CREM and CREB: Antagonists or co-operator in immune cell regulation?
CREM and CREB are activated in response to increased cAMP production or following phosphorylation by several protein kinases in response to different signalling routes. In the last years we identified CREMα as a key molecule that drives autoimmunity in systemic lupus erythematosus. Recent research moreover uncovered functions of CREM in acute lung injury, Th2 cell-mediated asthmatic disease and hepatitis. At present we analyse function of CREM in other diseases like juvenile idiopathic arthritis and also other cell types. CREB and CREM shares the same binding sites, we aim to answer how their interplay and dysregulation in autoimmune diseases contribute to cellular aberrancies.
2. Oxidative stress signaling pathways in immune cells (AG Kim Ohl)
Reactive oxygen species (ROS) were primarily considered as harmful mediators of inflammation but increasing number of findings suggest that ROS also have important cellular regulatory functions. Excessive amounts of ROS are produced especially in inflammatory conditions. A deeper analysis of ROS induced pathways in different immune cells is crucial to understand the ambivalent role of ROS molecules and how this affects chronic inflammatory conditions and autoimmune diseases. We study effects of oxidative stress and ROS molecules in immune cells by analysing Nrf2, the key transcription factor of the anti-oxidative stress response.
Within the scope of above mentioned topics we regularly offer master/medical doctoral thesis projects. All projects give the opportunity to learn a broad spectrum of immunological and cell biological methods and to conduct research in clinical relevant questions.
Research work in the Institute is currently funded by the RWTH/UKAachen START program grant, IZKF program grant, by Robert-Pfleger Stiftung and by BMBF.
Within the scope of above mentioned topics we regularly offer master/medical doctoral thesis projects. All projects give the opportunity to learn a broad spectrum of immunological and cell biological methods and to conduct research in clinical relevant questions.
Recent publications
Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI,Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P, Thomson W. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2016 Dec 7. pii: annrheumdis-2016-210324.
Yoshida N, Comte D, Mizui M, Otomo K, Rosetti F, Mayadas TN, Crispín JC, Bradley SJ, Koga T, Kono M, Karampetsou MP, Kyttaris VC, Tenbrock K, Tsokos GC. ICER is requisite for Th17 differentiation. Nat Commun. 2016 Sep 29;7:12993.
Kuttkat N, Mohs A, Ohl K, Hooiveld G, Longerich T, Tenbrock K, Cubero FJ, Trautwein C. Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease. Gut. 2016 Sep 29. pii: gutjnl-2015-311119.
Wiener A, Schippers A, Wagner N, Tacke F, Ostendorf T, Honke N, Tenbrock K, Ohl K. CXCR5 is critically involved in progression of lupus through regulation of B cell and double-negative T cell trafficking. Clin Exp Immunol. 2016 Jul;185(1):22-32.
Kim Ohl, Klaus Tenbrock, Markus Kipp, Oxidative stress in multiple sclerosis: central and peripheral mode of action. Exp. Neurol. 2015
Eberhardt CS, Haas JP, Girschick H, Schwarz T, Morbach H, Rösen-Wolff A, Foell D, Dannecker G, Schepp C, Ganser G, Honke N, Eggermann T, Müller-Berghaus J, Wagner N, Ohl K, Tenbrock K. No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015
Eva Verjans*, Kim Ohl*, Lucy K. Reiss, Femke van Wijk, Antoaneta Toncheva, Anastasia Wiener, Yin Yu, Annette D. Rieg, Vincent D. Gaertner, Johannes Roth, Edward Knol, Michael Kabesch, Norbert Wagner, Stefan Uhlig, Christian Martin, Klaus Tenbrock, The cAMP response element modulator regulates TH2 mediated inflammation. Oncotarget Immunology 2015
Horneff G, Foeldvari I, Minden K, Trauzeddel R, Kümmerle-Deschner JB, Tenbrock K, Ganser G, Huppertz HI. Efficacy and safety of etanercept in patients with the enthesitis-related arthritis category of juvenile idiopathic arthritis: results from a phase III randomized, double-blind study. Arthritis Rheumatol. 2015
Ohl, K*., A. Wiener*, A. Schippers, N. Wagner, K. Tenbrock, Interleukin-2 treatment reverses effects of cAMP-responsive element modulator alpha-over-expressing T cells in autoimmune-prone mice. Clin Exp Immunol, 2015.
Kim Ohl, Klaus Tenbrock: Regulatory T cells in systemic lupus erythematosus. Eur J Immunol 2014
Kim Ohl*, Christiane Eberhardt*, Clemens Spink, Katharina Zahn, Norbert Wagner, Markus Kemper, Sigrid Harendza, Klaus Tenbrock: CTLA4 polymorphisms are a risk factor for Minimal Change Nephrosis, AJKD, 2014
* shared authorship
Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014
Nora Honke, Kim Ohl, Anastasia Wiener, Joachim Peitz, Stefano Di Fiore, Rainer Fischer, Norbert Wagner, Stefan Wüller, Klaus Tenbrock: A p38-mediated rapid down-regulation of gp130 cell surface expression impairs IL-6 signaling in synovial fluid of juvenile idiopathic arthritis patients, Arthritis and Rheumatology, 2014
Eva Verjans, Kim Ohl, Yin Yu, Ralph Lippe, Anastasia Wiener, Angela Schippers, Johannes Roth, Norbert Wagner, Stefan Uhlig, Klaus Tenbrock, Christian Martin: Overexpression of CREMα in T cells aggravates LPS-induced acute lung injury, J Immunol, 2013
