Open Research Projects

Healthy skin homeostasis? – Does anti-cytokine treatment restore the physiological and immunological function of the skin?

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and also preventive medicine. One of our translational research interests are chronic inflammatory autoimmune diseases of the skin. In addition to preclinical models and in vitro methods, we use skin and blood samples from patients for biomarker identification. We are particularly interested in specialized T cell responses and cytokine signaling pathways.

Project description:

The skin forms the outer barrier to the environment and is in constant contact with it. Besides its function as a physical barrier, it is rich in immune cells that serve as a defense against external stimuli. In chronic inflammatory skin diseases such as psoriasis (PSO) or atopic dermatitis (AD), there is a disturbance of the cutaneous immune microenvironment. The resulting imbalance in immunological homeostasis leads to overactivation of inflammatory signaling pathways. This effect is caused and amplified in AD, HS, and PSO by specialized T helper cells and their associated cytokines (TNF-α, IL-1, IL-4, IL-5, IL-12, IL-13, IL-17, IL-22, IL-36). While AD is dominated by IL-4/IL-13 and Th2 cells, PSO is dominated by IL-17/IL-23 and Th17 cells. As a result, there has been an increased focus on blocking these cytokines and their signaling cascades either with monoclonal antibodies (biologics) or small molecules such as tyrosine kinase inhibitors (JAK inhibitors) to treat psoriasis and atopic dermatitis.

With current anti-cytokine treatments significant improvement and skin clearance can be achieved in the majority of patients in all of the indicated chronic inflammatory skin diseases. However, it remains unclear, if cleared skin under anti-cytokine treatment is comparable to healthy skin. Therefore, it is key to understand the possible differences and similarities in treated healed skin in comparison to otherwise healthy skin. This may allow to better define the duration of anti-cytokine treatment and/or risks for disease flares.

In the context of the doctoral thesis, the aim is to recruit 15 patients per disease (AD and PSO) who have been successfully treated with systemic treatments. In comparison, healthy skin samples from individuals without any inflammatory skin diseases obtained from our dermatosurgery unit will be used. The differences (immunological, physiological, barrier function) between healthy and treated/healed skin will be investigated based on gene expression of the tissue samples by whole transcriptome sequencing (WTS). As part of the immunohistochemical workup of the tissue, we will assess the immune cell infiltrate, Ki67 as a marker for (keratinocyte) proliferation and KRT16 for keratinocyte differentiation. Routine H&E staining will be used for disease characteristics and the extent of epidermal thickness. In addition, the restoration of the physiological barrier function will be assessed by the expression of filaggrin, loricrin and layer specific keratins.

References

  1. Meier K, Holstein J, Zidane M, […], Ulrich C, Ghoreschi K, Solimani F. Paradoxical lichen planus induced during anti-IL-17A treatment is immunologically different from spontaneously occurring lichen planus. J Eur Acad Dermatol Venereol. 2022; doi: 10.1111/jdv.17996. Online ahead of print.
  2. Ghoreschi, K, Balato A, Enerbäck C, Sababt R. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet. 2021; 397:754-766. doi: 10.1016/S0140-6736(21)00184-7.
  3. Pietschke K, Holstein J, Meier K, […], Ghoreschi FC, Solimani F, Ghoreschi K. The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition. Exp Dermatol. 2021; 30:262-270. doi: 10.1111/exd.14226.
  4. Solimani F, Meier K, Ghoreschi K. Emerging Topical and Systemic JAK Inhibitors in Dermatology. Front Immunol. 2019; 10:2847. doi: 10.3389/fimmu.2019.02847.