Defects of the innate immune system in autoinflammation and autoimmunity
Research
Our group investigates the molecular mechanisms driving autoinflammation and autoimmunity as a consequence of perturbations in the innate immune system. As the body´s first line of defense, the innate immune system provides rapid protection against pathogens through type I interferon (IFN) responses, inflammasome activation, and NF-κB-mediated signaling. A particular focus of our research is nucleic acid immunity, since nucleic acids that appear in the wrong place, in the wrong form, or at the wrong time can act as potent danger signals. The pathways that regulate nucleic acid immunity must be tightly controlled to maintain immune homeostasis and safeguard host integrity. Failure to do so results in inappropriate immune activation, which can trigger chronic inflammation, autoimmunity, and tissue damage.
Persistent or uncontrolled type I IFN production leads to a group of rare but severe inflammatory diseases known as type I interferonopathies. Beyond these disorders, we investigate how nucleic acid-sensing pathways, inflammasomes, and NF-κB signaling cooperate to maintain immune balance and how their disruption contributes to disease pathogenesis. Our work focuses on genetically determined autoinflammatory and autoimmune disorders in children, which serve as powerful models to dissect fundamental principles of innate immune regulation. Studying these rare conditions not only provides mechanistic insight into immune dysregulation but also reveals broader concepts underlying common inflammatory and autoimmune diseases. By combining human genetics with molecular and cellular immunology, and by pursuing translational approaches, we aim to uncover disease pathways and transform this knowledge into clinically relevant concepts.
Specific aims
- Identify novel genetic causes of monogenic and multifactorial autoinflammatory and autoimmune diseases in children and define their role in disease pathogenesis.
- Elucidate how nucleic acid-sensing pathways, inflammasomes, and NF-κB signaling regulate immune defense, inflammation, and tolerance, and how their impairment leads to immune dysregulation.
- Translate mechanistic insights from genetically determined immune dysregulation into precision diagnostics and targeted therapeutic strategies.
Group members
Collaborative networks
TRR237
TRR369
GAIN
SaxoChild
DZKJ
Alliance4Rare
ERN-RITA
Selected publications
Merold, V., Bekere, I., Kretschmer, S., Schnell, A.F., Kmiec, D., Sivarajan, R., Lammens, K., Liu, R., Mergner, J., Teppert, J., Hirschenberger, M., Henrici, A., Hammes, S., Buder, K., Weitz, M., Hackmann, K., Koenig, L.M., Pichlmair, A., Schwierz, N., Sparrer, K.M.J., Lee-Kirsch, M.A., de Oliveira Mann, C.C., 2025. Structural basis for OAS2 regulation and its antiviral function. Mol Cell. 85, 2176-2193.e13. https://doi.org/10.1016/j.molcel.2025.05.001, open access
Wolf, C., Lim, E.L., Mokhtari, M., Kind, B., Odainic, A., Lara-Villacanas, E., Koss, S., Mages, S., Menzel, K., Engel, K., Dückers, G., Bernbeck, B., Schneider, D.T., Siepermann, K., Niehues, T., Goetzke, C.C., Durek, P., Minden, K., Dörner, T., Stittrich, A., Szelinski, F., Guerra, G.M., Massoud, M., Bieringer, M., de Oliveira Mann, C.C., Beltrán, E., Kallinich, T., Mashreghi, M.-F., Schmidt, S.V., Latz, E., Klughammer, J., Majer, O., Lee-Kirsch, M.A., 2024. UNC93B1 variants underlie TLR7-dependent autoimmunity. Sci Immunol. eadi9769. https://doi.org/10.1126/sciimmunol.adi9769
Luca, D., Lee, S., Hirota, K., Okabe, Y., Uehori, J., Izawa, K., Lanz, A.-L., Schütte, V., Sivri, B., Tsukamoto, Y., Hauck, F., Behrendt, R., Roers, A., Fujita, T., Nishikomori, R., Lee-Kirsch, M.A., Kato, H., 2024. Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity. Sci Adv. 10, eadk0820. https://doi.org/10.1126/sciadv.adk0820, open access
Manoharan, J., Rana, R., Kuenze, G., Gupta, D., Elwakiel, A., Ambreen, S., Wang, H., Banerjee, K., Zimmermann, S., Singh, K., Gupta, A., Fatima, S., Kretschmer, S., Schaefer, L., Zeng-Brouwers, J., Schwab, C., Al-Dabet, M.M., Gadi, I., Altmann, H., Koch, T., Poitz, D.M., Baber, R., Kohli, S., Shahzad, K., Geffers, R., Lee-Kirsch, M.A., Kalinke, U., Meiler, J., Mackman, N., Isermann, B., 2024. Tissue factor binds to and inhibits interferon-α receptor 1 signaling. Immunity. 57, 68-85.e11. https://doi.org/10.1016/j.immuni.2023.11.017, open access
Wolf, C., Fischer, H., Kühl, J.-S., Koss, S., Jamra, R.A., Starke, S., Schultz, J., Ehl, S., Neumann, K., Schuetz, C., Huber, R., Hornung, V., Lee-Kirsch, M.A., 2023. Hemophagocytic lymphohistiocytosis-like hyperinflammation due to a de novo mutation in DPP9. J Allergy Clin Immunol. 152, 1336-1344.e5. https://doi.org/10.1016/j.jaci.2023.07.013, open access
König, N., Fiehn, C., Wolf, C., Schuster, M., Cura Costa, E., Tüngler, V., Alvarez, H.A., Chara, O., Engel, K., Goldbach-Mansky, R., Günther, C., Lee-Kirsch, M.A., 2017. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 76, 468–472. https://doi.org/10.1136/annrheumdis-2016-209841
Wolf, C., Rapp, A., Berndt, N., Staroske, W., Schuster, M., Dobrick-Mattheuer, M., Kretschmer, S., König, N., Kurth, T., Wieczorek, D., Kast, K., Cardoso, M.C., Günther, C., Lee-Kirsch, M.A., 2016. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun. 7, 11752. https://doi.org/10.1038/ncomms11752, open access
Gunther, C., Kind, B., Reijns, M.A., Berndt, N., Martinez-Bueno, M., Wolf, C., Tungler, V., Chara, O., Lee, Y.A., Hubner, N., Bicknell, L., Blum, S., Krug, C., Schmidt, F., Kretschmer, S., Koss, S., Astell, K.R., Ramantani, G., Bauerfeind, A., Morris, D.L., Cunninghame Graham, D.S., Bubeck, D., Leitch, A., Ralston, S.H., Blackburn, E.A., Gahr, M., Witte, T., Vyse, T.J., Melchers, I., Mangold, E., Nothen, M.M., Aringer, M., Kuhn, A., Luthke, K., Unger, L., Bley, A., Lorenzi, A., Isaacs, J.D., Alexopoulou, D., Conrad, K., Dahl, A., Roers, A., Alarcon-Riquelme, M.E., Jackson, A.P., Lee-Kirsch, M.A., 2015. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest. 125, 413–424. doi: 10.1172/JCI78001, open access
Yan, N., Regalado-Magdos, A.D., Stiggelbout, B., Lee-Kirsch, M.A., Lieberman, J., 2010. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol. 11, 1005–1013. doi: 10.1038/ni.1941., open access
Lee-Kirsch, M.A., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y.A., de, S.U., Bailey, S.L., Witte, T., Vyse, T.J., Kere, J., Pfeiffer, C., Harvey, S., Wong, A., Koskenmies, S., Hummel, O., Rohde, K., Schmidt, R.E., Dominiczak, A.F., Gahr, M., Hollis, T., Perrino, F.W., Lieberman, J., Hubner, N., 2007. Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 39, 1065–1067. doi: 10.1038/ng2091