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Medizinische Klinik III
Systemic autoimmunity; cancer immunity; Myeloid cells
Unintended stimulation of innate immune system can lead to the activation of self-reactive lymphocytes and the development of autoimmunity. Worldwide between 7 and 9 persons out of 100 are estimated to suffer from autoimmune diseases. Our lab is interested in how individual components of the innate immune system act in concert to instruct the lymphocyte response against the own body in chronic autoimmune diseases such as systemic lupus erythematous (SLE). Current research is centered on studying the specific contributions of classical monocytes and neutrophils to organ inflammation and destruction in mouse models of SLE.
Immune evasion of tumors is a major stumbling block in cancer therapy. Taking clues from our work on autoimmunity we have recently begun to develop new tools using CRISPR/Cas9 technology to study the role of myeloid cells in the adaptive immune response against autochthonous lung tumors in mice.
Maintenance of inflammatory organ infiltrates by ICOSL on CD11c+ myeloid cells
The inducible T cell costimulator (ICOS) is a potent promoter of organ inflammation in murine lupus. ICOS stimulates T follicular helper cell differentiation in lymphoid tissue, suggesting that it might drive autoimmunity by enhancing autoantibody produc-tion. Yet the pathogenic relevance of this mechanism remains unclear. It is also unknown whether other ICOS-induced processes might contribute to lupus pathology. Here we show that selective ablation of ICOS ligand (ICOSL) in CD11c+ cells, but not in B cells, dramatically ameliorates kidney and lung inflammation in lupus-prone MRL.Faslpr mice. Autoantibody formation was largely unaffected by ICOSL deficiency in CD11c+ cells. However, ICOSL display by CD11c+ cells in inflamed organs had a nonredundant role in protecting invading T cells from apoptosis by elevating activity of the PI3K-Akt signaling pathway, thereby facilitating T cell accrual. These findings reveal a mechanism that locally sustains organ inflammation in lupus.
Teichmann LL et al., Immunity 2015 Mar 17;42(3):552-65.
Cell-type specific role of TLR-MyD88 signaling in lupus
Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Faslpr mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted inter-feron-a production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
Teichmann LL et al. Immunity 2013 Mar 21;38(3):528-40.
Teichmann, L.L., Cullen, J.L., Kashgarian, M., Dong, C., Craft, J., and Shlomchik, M.J. (2015). Local Triggering of the ICOS Coreceptor by CD11c(+) Myeloid Cells Drives Organ Inflammation in Lupus. Immunity 42, 552-565.
Rongvaux, A., Willinger, T., Martinek, J., Strowig, T., Gearty, S.V., Teichmann, L.L., Saito, Y., Marches, F., Halene, S., et al. (2014). Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32, 364-372.
Teichmann, L.L., Schenten, D., Medzhitov, R., Kashgarian, M., and Shlomchik, M.J. (2013). Signals via the Adaptor MyD88 in B Cells and DCs Make Distinct and Synergistic Contributions to Immune Activation and Tissue Damage in Lupus. Immunity 38, 528-540.
Ahuja, A., Teichmann, L.L., Wang, H., Dunn, R., Kehry, M.R., and Shlomchik, M.J. (2011). An acquired defect in IgG-dependent phagocytosis explains the impairment in antibody-mediated cellular depletion in Lupus. J Immunol 187, 3888-3894.
Teichmann, L.L., Kashgarian, M., Weaver, C.T., Roers, A., Müller, W., and Shlomchik, M.J. (2011). B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice. J Immunol 188, 678-685.
Teichmann, L.L., Ols, M.L., Kashgarian, M., Reizis, B., Kaplan, D.H., and Shlomchik, M.J. (2010). Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33, 967-978.
Teichmann, L.L., and Fleck, M. (2010). [Current views on lipid metabolism: statin-induced myopathy]. Z Rheumatol 69, 696-8, 700-1.
Teichmann, L.L., Woenckhaus, M., Vogel, C., Salzberger, B., Schölmerich, J., and Fleck, M. (2008). Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology (Oxford) 47, 1256-1257.
Begonja, A.J., Teichmann, L., Geiger, J., Gambaryan, S., and Walter, U. (2006). Platelet regulation by NO/cGMP signaling and NAD(P)H oxidase-generated ROS. Blood Cells Mol Dis 36, 166-170.
Geiger, J., Teichmann, L., Grossmann, R., Aktas, B., Steigerwald, U., Walter, U., and Schinzel, R. (2005). Monitoring of clopidogrel action: comparison of methods. Clin Chem 51, 957-965.
German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
Bianca Jütte, PhD student
M. Sc., Molecular Medicine, Ulm University, 2014
Markus Späth, PhD student
M. Sc., Biology, Justus-Liebig University of Gießen, 2014
Kevin Cieslak, Lab Technician