Class of ..., Class of 2021

Immunophenotyping in bullous pemphigoid to identify new therapeutic targets

Student

Euna Bodner

Principle Investigator

Prof. Dr. Kamran Ghoreschi

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 preventive medicine. One group 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 (JAK/STAT).

Project description:

Blistering autoimmune dermatoses (bAD) represent a heterogeneous group of skin diseases characterized by autoantibodies against structural proteins. In pemphigoid diseases, the formation of IgG and, more rarely, IgA/IgM antibodies against hemi desmosomes lead to loss of contact of the lower keratinocyte layer with the basal membrane. Subepidermal cleft formation occurs, resulting in the formation of blisters.1 The most common pemphigoid disease of old age is bullous pemphigoid (7/8 LD), followed by rarer variants such as lamin γ1 and scarring mucinous pemphigoid. While B cells are primarily responsible for autoantibody production, T cells appear to play an important role in disease development.

In recent work on the pathogenesis of bAD, we were able to investigate the relationship between specialized T follicular helper (Tfh) cells and autoreactive B cells for the production of autoantibodies in bAD by comprehensive analyses of the immune system (RNA-seq, immunoprofiling, T/B cell cultures).2 In bullous pemphigoid, the risk of disease increases with age without knowing the immunological precursors for this. In this project, we aim to clarify whether specialized Tfh cells and their cytokines differ in healthy individuals and bAD patients in an age-dependent manner. The aim is to investigate their influence on the pathogenesis of the disease and to identify new markers to predict the risk for the manifestation of bAD or even to use them preventively.3

In this project, Tfh populations of peripheral blood will be studied by multiparametric flow cytometry. We are particularly interested in the differences between healthy and bAD patients and the changes in different age decades. Furthermore, the cytokine profile (IL-4, IL-17, IL-21, IL-6, IFN-y) will be investigated.4 These results will be compared on the one hand with antibody titers against BP180 and BP230 and on the other hand with transcriptome analyses of healthy and lesional skin (bAD). The goal of the PhD thesis is to determine disease-associated patterns relevant for early detection or risk of manifestation of bAD, by evaluating the Tfh populations, cytokine profile, autoantibody titers, and age-related parameters.

References

  1. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019; 394(10201):882-894. doi: 10.1016/S0140-6736(19)31778-7.
  2. Holstein J, Solimani F, Baum C, […], Pfützner W, Ghoreschi K, Möbs C. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. J Allergy Clin Immunol. 2020: S0091-6749(20)31624-9. doi: 10.1016/j.jaci.2020.11.008. Epub ahead of print.
  3. Eckardt J, Eberle FC, Ghoreschi K. Diagnostic value of autoantibody titres in patients with bullous pemphigoid. Eur J Dermatol. 2018; 28(1):3-12. doi: 10.1684/ejd.2017.3166.
  4. Li Q, Liu Z, Dang E, […], Yang L, Shi X, Wang G. Follicular helper T Cells (Tfh) and IL-21 involvement in the pathogenesis of bullous pemphigoid. PLoS One. 2013; 8(7):e68145. doi: 10.1371/journal.pone.0068145