Teilprojekt 7
Defekte der intrazellulären Nukleasen Trex1 und RNAse H2 sowie Mutationen des SAMHD1-Genes verursachen eine spontane inflammatorische Erkrankung, das Aicardi-Goutieres Syndrom (AGS). Für die Pathogenese scheint eine intrazelluläre Akkumulation von Nukleinsäuren, die eine Typ I-Interferon (IFN)-Antwort auslösen, von zentraler Bedeutung zu sein. Eine unkontrollierte Typ I-IFN-Produktion findet sich auch beim systemischen Lupus erythematodes. Interessanter Weise zeigt auch diese wichtige Autoimmunerkrankung eine Assoziation mit Mutationen der Gene TREX1 und RNASEH2A-C. Trex1-defiziente Mäuse entwickeln eine Typ I-Interferon-abhängige Entzündung des Herzmuskels. Für die Mutationen der übrigen AGS-Loci existieren keine Tiermodelle. Wir planen Mäuse mit vollständiger oder Zelltyp-spezifischer Defizienz für Trex1, RNAse H2 oder SAMHD1 zu generieren, um an diesen Mutanten die Pathogenese auf Ebene der Zelle und auf Ebene der zellulären Interaktionen im Immunsystem zu untersuchen. Eine Aufklärung der pathogenetischen Ereignisse in Tieren mit Defekten für Trex1, RNAse H2 oder SAMHD1 wird große Relevanz für unser Verständnis von Autoimmunität haben.
Teilprojektleiter
Homepage:
Mitarbeiter
Dr. med. Martin Achleitner, PhD student
Tel.: 0351-458 6510
Email: martin.achleitner@mailbox.tu-dresden.de
Dr. rer. nat. Anne Dudeck, Postdoc
Tel.: 0351-458 6502 / 6503
Email: anne.dudeck@mailbox.tu-dresden.de
Jan Dudeck, wissenschaftlicher Mitarbeiter
Tel.: 0351-458 6502 / 6503
Email: jan.dudeck@tu-dresden.de
Dr. rer. nat. Rayk Behrendt, Postdoc
Tel.: 0351-458 19329
Email: rayk.behrendt@mailbox.tu-dresden.de
Dr. rer. nat. Alexander Gerbaulet, Postdoc
Tel.: 0351-458 6510
Email: alexander.gerbaulet@tu-dresden.de
Shanawaz Ghouse, M. Sc., PhD student
Tel.: 0351-458 6502 / 6503
Email: shanawaz.ghouse@mailbox.tu-dresden.de
Tobias Häring, Technischer Assistent
Tel.: 0351-458 6525
Email: tobias.haering@tu-dresden.de
Dipl.-Biol. Björn Hiller, PhD student
Tel.: 0351-458 6502 / 6503
Email: bjoern.hiller@mailbox.tu-dresden.de
Christina Hiller, Technische Assistentin
Tel.: 0351-4586513/-6525
Email: christina.hiller@tu-dresden.de
Dipl.-Biol. Sebastian Lanvermann, PhD student
Tel.: 0351-458 6510
Email: sebastian.lanvermann@tu-dresden.de
Dipl.-Biol. Katrin Peschke, PhD student
Tel.: 0351-458 6502 / 6503
Email: katrin.peschke@tu-dresden.de
Anke Petzold, M. Sc., PhD student
Tel.: 0351-458 6502 / 6503
Email: anke.petzold@tu-dresden.de
Livia Schulze, Technische Assistentin
Tel.: 0351-458 6502
Email: livia.schulze@tu-dresden.de
Tina Schumann, PhD student
Tel.: 0351-458 6509
Email: tina.schumann@tu-dresden.de
Nadja Schubert, PhD student
Tel.: 0351-458 6509
Email: nadja.schubert@tu-dresden.de
Marian Schulz, PhD student
Tel.: 0315-458 6505
Annett Skupin, Technische Assistentin
Tel.: 0351-458 6506
Email: skupin@mail.zih.tu-dresden.de
Ausgewählte Publikationen
Lee-Kirsch MA, Günther C, Roers A. Nucleic acid-mediated autoinflammation and autoimmunity-type I interferonopathies. J Mol Med (Berl). 2016 Oct;94(10):1081-1084.
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 Sep 15;197(6):2157-66.
Schoedel KB, Morcos MN, Zerjatke T, Roeder I, Grinenko T, Voehringer D, Göthert JR, Waskow C, Roers A, Gerbaulet A. The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis. Blood. 2016 Jun 29. pii: blood-2016-03-706010. [Epub ahead of print]
Roers A, Hiller B, Hornung V. Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016 Apr 19;44(4):739-54.
Lee-Kirsch MA, Wolf C, Kretschmer S, Roers A. Type I interferonopathies--an expanding disease spectrum of immunodysregulation. Semin Immunopathol. 2015 Jul;37(4):349-57.
Heger K, Kober M, Rieß D, Drees C, de Vries I, Bertossi A, Roers A, Sixt M, Schmidt-Supprian M. A novel Cre recombinase reporter mouse strain facilitates selective and efficient infection of primary immune cells with adenoviral vectors. Eur J Immunol. 2015 Jun;45(6):1614-20.
Günther C, Kind B, Reijns MA, Berndt N, Martinez-Bueno M, Wolf C, Tüngler V, Chara O, Lee YA, Hübner N, Bicknell L, Blum S, Krug C, Schmidt F, Kretschmer S, Koss S, Astell KR, Ramantani G, Bauerfeind A, Morris DL, Cunninghame Graham DS, Bubeck D, Leitch A, Ralston SH, Blackburn EA, Gahr M, Witte T, Vyse TJ, Melchers I, Mangold E, Nöthen MM, Aringer M, Kuhn A, Lüthke K, Unger L, Bley A, Lorenzi A, Isaacs JD, Alexopoulou D, Conrad K, Dahl A, Roers A, Alarcon-Riquelme ME, Jackson AP, Lee-Kirsch MA. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest. 2015 Jan;125(1):413-24.
Jost NH, Abel S, Hutzler M, Sparwasser T, Zimmermann A, Roers A, Müller W, Klopfleisch R, Hengel H, Westendorf AM, Buer J, Hansen W. Regulatory T cells and T-cell-derived IL-10 interfere with effective anti-cytomegalovirus immune response. Immunol Cell Biol. 2014 Nov;92(10):860-71.
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 Jun 15;192(12):5993-7.
Heger K, Fierens K, Vahl JC, Aszodi A, Peschke K, Schenten D, Hammad H, Beyaert R, Saur D, van Loo G, Roers A, Lambrecht BN, Kool M, Schmidt-Supprian M. A20-deficient mast cells exacerbate inflammatory responses in vivo. PLoS Biol. 2014 Jan;12(1):e1001762.
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 May;134(5):1456-9.
Behrendt R, Roers A. Mouse models for Aicardi-Goutières syndrome provide clues to the molecular pathogenesis of systemic autoimmunity. Clin Exp Immunol. 2014 Jan;175(1):9-16. doi:
Ohyagi H, Onai N, Sato T, Yotsumoto S, Liu J, Akiba H, Yagita H, Atarashi K, Honda K, Roers A, Müller W, Kurabayashi K, Hosoi-Amaike M, Takahashi N, Hirokawa M, Matsushima K, Sawada K, Ohteki T. Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity. 2013 Sep 19;39(3):584-98.
Stewart CA, Metheny H, Iida N, Smith L, Hanson M, Steinhagen F, Leighty RM, Roers A, Karp CL, Müller W, Trinchieri G. Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J Clin Invest. 2013 Nov;123(11):4859-74.
Richter K, Perriard G, Behrendt R, Schwendener RA, Sexl V, Dunn R, Kamanaka M, Flavell RA, Roers A, Oxenius A. Macrophage and T cell produced IL-10 promotes viral chronicity. PLoS Pathog. 2013;9(11):e1003735.
Behrendt R, Schumann T, Gerbaulet A, Nguyen LA, Schubert N, Alexopoulou D, Berka U, Lienenklaus S, Peschke K, Gibbert K, Wittmann S, Lindemann D, Weiss S, Dahl A, Naumann R, Dittmer U, Kim B, Mueller W, Gramberg T, Roers A. MouseSAMHD1 has antiretroviralactivity and suppresses a spontaneous cell-intrinsic antiviral response. Cell Rep. 2013 Aug 29;4(4):689-96.
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(1):166-75.
Rabenhorst A, Schlaak M, Heukamp LC, Förster A, Theurich S, von Bergwelt-Baildon M, Büttner R, Kurschat P, Mauch C, Roers A, Hartmann K. Mast cells play a protumorigenic role in primary cutaneous lymphoma. Blood 2012;120(10):2042-54.
De Filippo K, Dudeck A, Hasenberg M, Nye E, van Rooijen N, Hartmann K, Gunzer M, Roers A, Hogg N. Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood. 2013 Jun 13;121(24):4930-7.
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 2012;209(8):1419-26.
Sharma N, Kumar V, Everingham S, Mali RS, Kapur R, Zeng LF, Zhang ZY, Feng GS, Hartmann K, Roers A, Craig AW. SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice. Mol Cell Biol 2012;32(14):2653-63.
Abel S, Lückheide N, Westendorf AM, Geffers R, Roers A, Müller W, Sparwasser T, Matuschewski K, Buer J, Hansen W. Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection. J Immunol 2012;188(11):5467-77.
Freitas do Rosário AP, Lamb T, Spence P, Stephens R, Lang A, Roers A, Muller W, O'Garra A, Langhorne J. IL-27 Promotes IL-10 Production by Effector Th1 CD4+ T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection. J Immunol 2012;188(3):1178-90.
Teichmann LL, Kashgarian M, Weaver CT, Roers A, Müller W, Shlomchik MJ. B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice. J Immunol 2012;188(2):678-85.
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(6):973-84.
Sayi A, Kohler E, Toller IM, Flavell RA, Müller W, Roers A, Müller A. TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J Immunol 2011;186(2):878-90.
Gerbaulet A, Wickenhauser C, Scholten J, Peschke K, Drube S, Horny HP, Kamradt T, Naumann R, Müller W, Krieg T, Waskow C, Hartmann K, Roers A. Mast cell hyperplasia, B-cell malignancy, and intestinal inflammation in mice with conditional expression of a constitutively active kit. Blood 2011;117(6):2012-21.
Arnold IC, Lee JY, Amieva MR, Roers A, Flavell RA, Sparwasser T, Müller A. Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 2011;140(1):199-209.
Drube S, Heink S, Walter S, Löhn T, Grusser M, Gerbaulet A, Berod L, Schons J, Dudeck A, Freitag J, Grotha S, Reich D, Rudeschko O, Norgauer J, Hartmann K, Roers A, Kamradt T. The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. Blood 2010;115(19):3899-906.
Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, Roers A, Eming SA. Differential roles of macrophages in diverse phases of skin repair. J Immunol 2010;184(7):3964-77.
Igyarto BZ, Jenison MC, Dudda JC, Roers A, Müller W, Koni PA, Campbell DJ, Shlomchik MJ, Kaplan DH. Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and langerhans cell-derived IL-10. J Immunol 2009;183(8):5085-93.
Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, Yogev N, Gu Y, Khodoun M, Hildeman D, Boespflug N, Fogolin MB, Gröbe L, Greweling M, Finkelman FD, Cardin R, Mohrs M, Müller W, Waisman A, Roers A, Karp CL. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol 2009;183(4):2312-20.
Frommer F, Heinen TJ, Wunderlich FT, Yogev N, Buch T, Roers A, Bettelli E, Müller W, Anderton SM, Waisman A. Tolerance without clonal expansion: self-antigen-expressing B cells program self-reactive T cells for future deletion. J Immunol 2008;181(8):5748-59.
Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR Jr, Muller W, Rudensky AY. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28(4):546-58.
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(2):307-15.
Eming SA, Werner S, Bugnon P, Wickenhauser C, Siewe L, Utermöhlen O, Davidson JM, Krieg T, Roers A. Accelerated wound closure in mice deficient for interleukin-10. Am J Pathol 2007;170(1):188-202.
Siewe L, Bollati-Fogolin M, Wickenhauser C, Krieg T, Müller W, Roers A. Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA. Eur J Immunol 2006;36(12):3248-55.
Roers A, Siewe L, Strittmatter E, Deckert M, Schlüter D, Stenzel W, Gruber AD, Krieg T, Rajewsky K, Müller W. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med 2004;200(10):1289-97.
Skulina C, Schmidt S, Dornmair K, Babbe H, Roers A, Rajewsky K, Wekerle H, Hohlfeld R, Goebels N. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci U S A 2004;101(8):2428-33.
Hofbauer M, Wiesener S, Babbe H, Roers A, Wekerle H, Dornmair K, Hohlfeld R, Goebels N. Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis. Proc Natl Acad Sci U S A 2003;100(7):4090-5.
Willenbrock K, Roers A, Seidl C, Wacker HH, Küppers R, Hansmann ML. Analysis of T-cell subpopulations in T-cell non-Hodgkin's lymphoma of angioimmunoblastic lymphadenopathy with dysproteinemia type by single target gene amplification of T cell receptor- beta gene rearrangements. Am J Pathol 2001;158(5):1851-7.
Babbe H, Roers A, Waisman A, Lassmann H, Goebels N, Hohlfeld R, Friese M, Schröder R, Deckert M, Schmidt S, Ravid R, Rajewsky K. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000;192(3):393-404.