Roers group
© Roers
Prof. Dr. med. Axel Roers
Head of the Institute
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Research foci
We investigate mechanisms of uncontrolled activation of innate immunity leading to a break of self-tolerance and, thereby, to attacks of the T and B cell system on host tissues. Virus infection is detected by specialized sensor proteins of the innate immune system, which recognize viral nucleic acids and activate antiviral immune responses characterized by production of type I interferons and pro-inflammatory cytokines. This innate response pattern is essential for efficient antiviral defense. Inappropriate, chronic activation of innate antiviral responses, however, can trigger systemic autoimmunity with fatal consequences. This pathogenetic principle plays a prominent role in systemic lupus erythematosus (SLE) and related conditions, including dermatomyositis and systemic sclerosis. We are interested in mutations resulting in uncontrolled activation of cytosolic DNA (cGAS-STING) or RNA sensor pathways (RIG-I/MDA5-MAVS). We address how genetic defects of intracellular nucleases (Trex1, RNase H2) result in the appearance of pathogenic endogenous cGAS ligands that trigger chronic STING activation. We are trying to understand how this chronic innate response causes systemic autoimmunity.
projects:
DFG Klinische Forschergruppe 249, Teilprojekt 07 Analysis of disease mechanisms in animal models of Aicardi Goutieres syndrome: induction of autoimmunity by uncontrolled activity of endogenous retroelements?"
Else-Kröner Fresenius Stiftung ‘Schlüsselprojekt’: A novel concept for the pathogenesis of systemic sclerosis
DFG Transregio-Sonderforschungsbereich 237, Teilprojekt 17 Induktion pathogener Typ I-IFN Antworten als Folge aberranter Aktivierung von zytosolischen Sensoren durch endogene Nukleinsäuren
publications:
Hiller B., Hoppe A., Haase C., Hiller C., Schubert N., Müller W., Reijns M.A.M., Jackson A.P., Kunkel T.A., Wenzel J., Behrendt R. Roers A. Ribonucleotide excision repair is essential to prevent squamous cell carcinoma of the skin. Cancer Res. 2018 in press
Achleitner M, Kleefisch M, Hennig A, Peschke K, Polikarpova A, Oertel R, Gabriel B, Schulze L, Lindeman D, Gerbaulet A, Fiebig U, Lee-Kirsch MA, Roers A, Behrendt R. Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs. J Immunol. 2017;199:2261-2269.
Peschke K, Achleitner M, Frenzel K, Gerbaulet A, Ada SR, Zeller N, Lienenklaus S, Lesche M, Poulet C, Naumann R, Dahl A, Ravens U, Günther C, Müller W, Knobeloch KP, Prinz M, Roers A, Behrendt R. Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity. J Immunol. 2016;197:2157-66
Roers A, Hiller B, Hornung V. Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016;44:739-54
Lee-Kirsch MA, Günther C, Roers A. Nucleic acid-mediated autoinflammation and autoimmunity-type I interferonopathies. J Mol Med (Berl). 2016;94:1081-1084
Lee-Kirsch MA, Wolf C, Kretschmer S, Roers A. Type I interferonopathies--an expanding disease spectrum of immunodysregulation. Semin Immunopathol. 2015; 37:349-57.
Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol. 2014;192:5993-7.
Peschke K, Friebe F, Zimmermann N, Wahlicht T, Schumann T, Achleitner M, Berndt N, Luksch H, Behrendt R, Lee-Kirsch MA, Roers A, Günther C. Deregulated type I IFN response in TREX1-associated familial chilblain lupus. J Invest Dermatol. 2014;134:14569
Behrendt R, Roers A. Mouse models for Aicardi-Goutières syndrome provide clues to the molecular pathogenesis of systemic autoimmunity. Clin Exp Immunol. 2014;175:9-16.
Behrendt R, Schumann T, Gerbaulet A, ..., Weiss S, Dahl A, Naumann R, Dittmer U, Kim B, Mueller W, Gramberg T, Roers A. Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response. Cell Rep. 2013;4:689-96.
Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med.
Type 2 immune responses, dominated by the cytokines IL-4, IL-5 and IL-13, Th2 cells and IgE, are mounted in response to helminthic parasites, ectoparasites and various animal venoms. This type of immune response also promotes wound repair, tissue regeneration and metabolic homeostasis. Uncontrolled type 2 responses on the other hand are central pathogenic events in allergy, asthma, atopic dermatitis, fibrotic diseases and also in cancer. Despite this broad importance in diverse areas of medicine, induction and regulation of type 2 responses are incompletely understood. We coordinate DFG-funded Research Unit (FOR) 2599 ‘Tissue type 2 immunity’ that brings together leading experts in the field of type 2 immunity to address these questions in a collaborative effort. In our FOR 2599-project, we investigate how innate type 2 responses are induced in barrier-defective atopic skin. This is an important question, since the local innate response of the skin is a key driver of systemic type 2 immunity and asthma.
An important effector cell of type 2 immunity is the mast cell. Mast cells are tissue-resident hematopoietic cells that bind IgE on their surface. Antigen that crosslinks mast cell surface IgE rapidly induces release of proinflammatory mediators from secretory granules. While mast cells have been known for decades as key effector cells in allergic diseases, including asthma, their physiological functions are much less clear and subject of intense debate. We have generated novel mouse models for mast cell deficiency, mast cell-specific gene inactivation and mast cell reporter mice which are ideal tools for investigation of mast cell in vivo functions. We found that many published findings on important functions of mast cells in the immune system were not reproducible in our novel models and we challenge the widely held view that mast cells are important amplifiers of innate immunity and essential promoters of adaptive immunity. Our findings do not support a role for mast cells in ‘standard’ adaptive immune responses. We propose that mast cells might serve to fill special functional gaps in the repertoire of mammalian immune responses, many of which potentially undiscovered until today.
projects:
DFG Forschergruppe (FOR) 2599 ‘Tissue type 2 immunity’:
Teilprojekt 8, Induction and regulation of type 2 immunity in healthy steady-state and in barrier-defective skin
Central Project 1, Single cell transcriptional profiling and bioinformatics
publications:
Schubert N., Lisenko K., Auerbach C., Weitzmann A., Ghouse S.M., Muhandes L., Haase C., Häring T., Schulze L., Voehringer D., Gunzer F., Müller W., Feyerabend T.B., Rodewald H.R., Dudeck A., Roers A. Unimpaired responses to vaccination with protein antigen plus adjuvant in mice with Kit-independent mast cell deficiency. Front. Immunol. 2018 in press.
Ghouse SM, Polikarpova A, Muhandes L, Dudeck J, Tantcheva-Poór I, Hartmann K, Lesche M, Dahl A, Eming S, Müller W, Behrendt R, Roers A. Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors. Cell Rep. 2018;22:27-35.
Chmelař J, Chatzigeorgiou A, Chung KJ, Prucnal M, Voehringer D, Roers A, Chavakis T. No Role for Mast Cells in Obesity-Related Metabolic Dysregulation. Front Immunol. 2016 Nov 24;7:524.
Peschke K, Dudeck A, Rabenhorst A, Hartmann K, Roers A.Cre/loxP-based mouse models of mast cell deficiency and mast cell-specific gene inactivation. Methods Mol Biol. 2015;1220:403-21
Peschke K, Weitzmann A, Heger K, Behrendt R, Schubert N, Scholten J, Voehringer D, Hartmann K, Dudeck A, Schmidt-Supprian M, Roers A. IκB kinase 2 is essential for IgE-induced mast cell de novo cytokine production but not for degranulation. Cell Rep. 2014;8:1300-7.
Willenborg S, Eckes B, Brinckmann J, Krieg T, Waisman A, Hartmann K, Roers A, Eming SA. Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J Invest Dermatol. 2014;134:2005-2015.
Cheng LE, Hartmann K, Roers A, Krummel MF, Locksley RM. Perivascular mast cells dynamically probe cutaneous blood vessels to capture immunoglobulin E. Immunity. 2013;38:166-75.
Dudeck A, Dudeck J, Scholten J, Petzold A, Surianarayanan S, Köhler A, Peschke K, Vöhringer D, Waskow C, Krieg T, Müller W, Waisman A, Hartmann K, Gunzer M, Roers A. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity. 2011;34:973-84.
Scholten J, Hartmann K, Gerbaulet A, Krieg T, Müller W, Testa G, Roers A. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res. 2008;17:307-15.