Laboratory of Molecular Immunology

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T-cells play an important role in autoimmunity and chronic inflammation. Our research group is interested in molecular and cellular mechanisms that regulate T-cell activity in rheumatic autoimmune diseases.

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Kurzbiografie

Priv.-Doz. Dr. David Kofler studierte von 1996 bis 2002 Humanmedizin an der Ludwig-Maximilians Universität München und der Universität Montpellier (Frankreich) und promovierte 2003 am Genzentrum der Ludwig-Maximilians Universität München (Direktor: Prof. Dr. Dr. h.c. E.-L. Winnacker). Von 2002 bis 2003 arbeitete Dr. Kofler als Assistenzarzt an der Medizinischen Klinik und Poliklinik III (Direktor: Prof. Dr. W. Hiddemann) am Klinikum Grosshadern der Ludwig-Maximilians Universität München. Ab 2003 setzte er seine Facharztausbildung an der Klinik I für Innere Medizin der Uniklinik Köln fort. Die Habilitation im Fach Innere Medizin erlangte Dr. Kofler 2012.

Von 2010 bis 2013 arbeitete Dr. Kofler unterstützt durch ein Forschungsstipendium der Deutschen Forschungsgemeinschaft (DFG) im Labor von Prof. David A. Hafler am Center for Neurologic Diseases des Brigham and Women’s Hospital an der Harvard Medical School und am Department of Immunobiology der Yale University. Während dieser Zeit befasste er sich mit der Funktion und Regulation von Th17-Zellen bei Autoimmunerkrankungen.

Seit 2013 leitet Dr. Kofler das Labor für molekulare Immunologie an der Klinik I für Innere Medizin der Uniklinik Köln. Klinisch ist Herr Dr. Kofler als Oberarzt in der Immunologisch-rheumatologischen Ambulanz und im rheumatologischen Konsildienst der Klinik I für Innere Medizin tätig.

Forschungsschwerpunkte

  • Autoimmun-reaktive Th17-Zellen in der Pathogenese der rheumatoiden Arthritis, der Psoriasis-Arthritis und der Spondylarthritiden
  • Rolle regulatorischer T-Zellen bei der Entstehung rheumatisch-entzündlicher Erkrankungen
  • Einfluss der Prostaglandin E2 Rezeptor-Signalwege auf die Funktion von Th17-Zellen bei Autoimmunerkrankungen

Klinischer Schwerpunkt

  • Rheumatologie
  • Klinische Immunologie

Th17 cells in the pathogenesis of autoimmune arthritis
Th17 cells are implicated in the pathogenesis of various autoimmune diseases, including ankylosing spondylitis and psoriatic arthritis. We could recently show that prostaglandin E2 receptor EP4 signaling contributes to the development of pathogenic Th17 cells in ankylosing spondylitis (Klasen et al., Arthritis Res Ther, 2019;21:159). EP4 drives Th17 cell expansion through upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. In contrast, Th17 cells from patients with rheumatoid arthritis overexpress the EP2 receptor, which has been previously linked to autoimmune diseases (Kofler et al, J Clin Invest, 2014;124:2513). Interestingly, recent genome-wide association studies (GWAS) have identified five risk alleles for ankylosing spondylitis in PTGER4, the gene encoding for EP4. Our results show that increased EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis.

IL-6 receptor signaling in rheumatoid arthritis
The cytokine IL-6 is a key regulator of Th17 cell induction. Differentiation of Th17 cells is induced by the combination of IL-6 and TGF-β, whereas TGF-β alone promotes the development of regulatory T (Treg) cells. IL-6 is therefore required at inflammatory sites to prevent Treg cell development and is an important modulator of the balance between Th17 cells and Treg cells. We aim to reveal why this balance is dysregulated in rheumatoid arthritis. Th17 and Treg cell plasticity is regulated by a complex network of signaling pathways, which are altered in rheumatoid arthritis. The IL-6 signaling pathway plays a major role in this network. We are investigating this network and try to find out if it can be modified to restore the balance between immune activity and immune tolerance.

Role of CD6 in rheumatic autoimmune diseases
The scavenger-like lymphocyte receptor CD6 is known as a regulator of T cell activity (Meyer et al, Cell Mol Immunol, 2018; Kofler et al, Curr Drug Targets, 2016). It has been previously shown that the multiple sclerosis susceptibility allele in CD6 is associated with alterations in CD4+ T cell proliferation (Kofler et al, J Immunol, 2011). Moreover, CD6 mediates the transmigration of CD4+ T cells into vessels and inflamed tissues. However, the specific contribution of CD6 to autoimmune reactions remains unknown. Our research group investigates the role of CD6 in various rheumatic autoimmune diseases.

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