Projects

Molecular Pneumology

Head of Department:
Prof. Dr. rer. nat. Dr. Susetta Finotto

Role of Nuclear factor of activated T cells c1 in allergic diseases

The family of nuclear factor of activated T cells (NFAT) of transcription factors is crucial in regulating early gene transcription in response to T cell receptor-mediated signals in lymphocytes. However, the calcium-regulated members of the NFAT family of transcription factors (NFATc1, NFATc2 and NFATc3) are also present in other Th subsets, like Th17 cells, and cooperate with additional proteins to play a central role in the inducible transcription of different genes involved in the immune response to antigen. Further studies revealed that recombination-activating gene 2-deficient mice reconstituted with NFATc1 (also known as NFATc or NFAT2) -deficient lymphocytes show decreased IL-4 production. We focus our studies on further exploring NFATc1 function in T cells in allergic asthma, because Th2 immune responses, characterized by the production of the cytokines IL-4, IL-5 and IL-13, are associated with inflammatory conditions such as asthma and allergy.

Project manager: Dr. Sonja Koch

The role of interleukin IL-17A in allergic asthma

The T helper cell mediated immunity has recently enlarged to include a third subset of effector T helper cells, the Th17 cells. This cell type is characterized by producing large amounts of IL‑17A. The pro-inflammatory cytokine IL‑17A is not only produced by Th17 cells but also by mast cells, eosinophils, NK cells, neutrophils, NKT cells and γδ T cells. In several studies it became obvious that IL‑17A is up-regulated in lung tissues, bronchoalveolar lavage fluid (BALF), sputum and peripheral blood of patients with allergic asthma. It has been shown that IL‑17A causes neutrophilic inflammation in allergic asthma via IL‑8. In addition, IL‑17A enhances the development of neutrophils by inducing the release of IL‑6 from human bronchial fibroblasts. Furthermore, IL‑17A is able to synergize with IL‑4 and IL‑13 to increase Th2 cytokines and CCL11 (c-c motif chemokine 11) secretion and therefore IL‑17A is suggested to be responsible for the eosinophilia observed in the airways of asthmatic patients.
Since it is assumed that IL‑17A is involved in the establishment and course of asthma, it may offer a new therapeutic target in the treatment of asthma.

The aim of this project is to investigate the role of the cytokine IL‑17A in the development and course of allergic asthma. For this purpose we analyze IL‑17A deficient mice in an established murine model of asthma by using OVA as an antigen to analyze the influence of IL‑17A on different cell types in asthma.

Project manager: Dr. Anna Graser

Immunoregulatory role of NFAT-interacting protein NIP45 in allergic asthma

NFAT interacting protein 45 (NIP45), is a Th2 associated transcription factor known to potentiate NFATc2-driven IL4 expression. After TCR stimulation NIP45 is methylated at its amino-terminal region by the protein arginine methyltransferase PRMT1. The arginine methylation domain of NIP45 supports the interaction with NFAT and recruits PRMT1 to the NFAT transcription-activating complex, thereby enhancing the production of the Th2 cytokine IL-4. Moreover NIP45 deficient mice have been shown to be deficient in IL-4 and IFN-gamma production indicating that NIP45 controls both Th1 and Th2 cytokine production. Th2 cells are known to play an important role in the pathogenesis of allergic asthma. Therefore, we started to investigate NIP45 in a murine model of asthma. We want to find out how NIP45 influences T cell responses and innate immune responses to allergens.

Project manager: Dr. Sonja Koch

The role of BATF in the generation of effector and regulatory T cell responses during Asthma bronchiale

The protein BATF (basic leucine zipper transcription factor, ATF-like) is a member of the AP-1 family of transcription factors. BATF forms dimers with Jun proteins, these dimers then bind to AP-1 consensus DNA sequences to influence the expression of target genes. The transcription factor is highly expressed in hematopoietic cells, especially in T and B cells.
BATF is induced by e.g. IL-6 and directly affects the differentiation of CD4+ T cells into Th17 and follicular T helper cells (Tfh). Additionally, in B cells the class switch recombination of immunoglobulins is mediated by BATF.
Th17 cells, as well as Th2 and Th9 cells are crucially involved in the pathogenesis of Asthma bronchiale. Furthermore, IgE antibodies are involved in allergic asthma. In this PhD project we want to determine the role of BATF in the generation of effector and regulatory T cell responses during experimental asthma.
To this end we are using a murine ovalbumin-induced model of allergic asthma, which we use in wild type, as well as in BATF-deficient mice. Moreover, we use different in vitro stimulation protocols in order to differentiate naïve CD4+ T cells into several T helper cell subsets.
In addition to the analysis of classical features of asthma, e.g. airway hyperresponsiveness, lung inflammation and bronchial mucus production, we want to examine the expression of BATF and its target genes.
We hope that the results of this study will contribute to the understanding of asthma pathogenesis and the maintenance of the disease.

Project manager: Nina Sopel, M.Sc.

The role of Tyrosinkinase 2 in a murine model of allergic asthma

Tyrosinkinase 2 (Tyk2) is a member of the Januskinase-family (Jak). These are protein-tyrosin-kinases which exist in mammals. They are relevant for the activation of the STAT-transcription factors (signal transducers and activators of transcription) and thereby for the JAK/STAT-signal transduction. Tyk2 is bound to subunits of receptors of hematopoietic cytokines and is activated through the binding of the corresponding ligands. Relevant cytokines are IL-6, IL-10, IL-12, IL-13, IL-23 and Interferon Type I (IFN alpha, beta). The activation of Tyk2 is leading to phosphorylation of STAT-1, STAT-3, STAT-4 or STAT-5. Afterwards, the phosphorylated STAT-proteins dimerize and translocate to the nucleus where they bind to the DNA of their respective target genes. So Tyk2 is playing a role regarding the innate as well as the adaptive immunity, for example during T cell development.

For humans a mutation of Tyk2 is associated with hypereosinophilia, completely abnormal signal transduction of IFN alpha and IL-12, abnormal signal transduction of IL-6-, IL-10- and IL-23 as well as an increased sensitivity for viral and bacterial Infections. Additionally it leads to the so-called hyper-IgE-syndrom. We work with Tyk2-deficient mice. These mice show a considerable defect of the IL-12 and IL-23 signal transduction, but IFN alpha, IL-6 and IL-10 signalling is regular. The target of this project is to investigate the role of Tyk2 in a murine model of allergic asthma.

The role of IL-6 in a murine model of allergic asthma

IL-6 is a pleiotropic cytokine, which operates with a specific receptor complex. This complex consists of a soluble (sIL-6R) or of a membrane-bound IL-6 receptor (mIL-6R) and the glycoprotein gp130. The binding of IL-6 to its receptor induces a dimerization of gp130 which leads to an activation of several signal transduction ways, which consists of Januskinases (Jak) and of signalling transducers and activators of transcription (STAT). We could show that patients with allergic asthma have a higher concentration of IL-6 in the bronchoalveolar lavage (BAL) after allergen challenge, which is associated with an increase of CD4+ T-cells of the Th2-type in the airways. In a murine model of asthma we also showed that IL-6 inhibits the development of regulatory T cells (Treg), a subgroup of T cells, which is important for the control of allergic and autoimmune diseases. We are now examining the influence of T-bet, a Th1-specific T-box transcription factor regarding the IL-6 mediated inhibition of Treg cells.

Further projects

  • The role of rhinovirus infection and interferon responses in allergic asthma (Annika Bergauer)
  • TGF-beta-mediated immune responses during rhinovirus infection (Carina Bielor)
  • The role of vitamin D in the immune system in Asthma bronchiale (Patricia Kahn)