Immune system cells and RDEB wounds (2022)

The cells of our immune system can be helpful or harmful in RDEB. This project studied how these cells contribute to difficulties with wound healing and progression to skin cancer. The findings have been published and the contribution to our understanding of how the immune system is involved in skin function will be beneficial to patients with RDEB.

Professor Sabine Eming

Prof Dr Sabine Eming works at the University of Cologne, Germany and heads a large wound healing clinic. This project aims to understand cells of the immune system called macrophages that are involved in scarring and the development of skin cancer in people with RDEB. These cells respond aggressively to initial skin damage (pro-inflammatory) then change how they behave to help repair the damage (anti-inflammatory) with collagen (fibrosis). Skin samples and a laboratory model will be used to determine which genes are expressed during these stages in order to understand the role of macrophages in wound healing complications and the development of skin cancer.

About our funding:

Research leader	Prof Dr Sabine Eming
Institution	University Hospital of Cologne, Germany
Type of EB	RDEB
Patient involvement	None
Funding amount	€194,500 (co-funded by DEBRA Ireland)
Project length	3 years (extended due to Covid)
Start date	July 2018
DEBRA internal ID	Eming1

Final progress summary:

Covid severely interrupted this project, so the researchers developed an alternative experimental approach to address the original research questions. They report significant progress in understanding how the immune system is involved in skin function and believe the findings they have published in the following research articles will be beneficial to patients with RDEB:

About our researchers:

Lead researcher:

Sabine Eming: Professor and Leading Physician at the Dept. of Dermatology, University of Cologne, leads a programme of work in tissue damage and repair that encompasses the range from basic structure-function analysis, through in vivo models, to human disease. Her group is interested in understanding how the skin senses tissue damage and how these events translate into a regenerative response, scar formation or disease. One focus of the group is to dissect the interplay between tissue specific regenerative capacity and the immune response. She is Principal Investigator of multiple third party funded research projects and clinical trials, unraveling wound pathology in different underlying diseases and translating this knowledge to improved wound care in patients. She will coordinate the project and the interaction with the collaborating partners in Freiburg. She will be responsible for the successful realization of the project, guide the PhD student in experimental design, scientific evaluation of results, manuscript writing, and translation.

Co-researchers:

Dimitra Kiritsi: Consultant dermatologist and Junior Group Leader, has worked for 9 years as a physician-scientist at the Department of Dermatology and EB-Center Freiburg. She is integrated in the diagnostics, management and multi-disciplinary care of patients with EB. Her research focuses on the pathomechanisms and development of novel therapeutic approaches for inherited skin disorders, especially EB and skin mosaicism. She has substantial experience as co-principal and trial investigator in 11 clinical trials with blistering disorders (autoimmune and EB). She is currently the Head of the Immunofluorescence Laboratory, the “Fragile Skin Clinical Trial Unit” and the Wound Care Unit of the Dept. Dermatology in Freiburg. She will provide the patient material and respective information required for the suggested studies, and contribute to the analysis of the results after conclusion of the study and writing the respective articles.

Alexander Nyström: is a group leader at the Department of Dermatology, Medical Center – University of Freiburg. He has extensive experience with preclinical models of RDEB, and will share his practical experience with wound healing studies.

Why this research is important:

In this study we will gain better understanding of impaired wound healing in RDEB patients and how subsequent detrimental complications can be diagnosed early and can be prevented.

Prof Dr Sabine Eming

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Researcher's abstract:

Grant Title: Exploring innate immunity in wound healing complications in RDEB patients

In this proposal it is our primary interest to identify molecular targets playing a causative role in wound healing complications (excessive scarring and carcinogenesis) in RDEB patients and to bring the gained knowledge back to the patient to ameliorate local wound therapy and disease progression.

Cells of the immune system are an integral component of the body’s innate ability to restore tissue function after injury. After most types of tissue damage including blistering in EB patients, specific immune cells particularly monocytes/macrophages serve two key roles: to respond rapidly to pathogen- and damage-associated molecular patterns and subsequently to help repair the tissue damage.

This process requires macrophages to initially adopt a pro-inflammatory phenotype and then later when the immediate danger has passed to acquire an anti-inflammatory phenotype to promote resolution and repair.

It is now clear that the tightly controlled dynamics between this pro-inflammatory and resolution activation phenotype in macrophages is fundamental for an efficient healing response. We propose to uncover the role of macrophages in wound healing in RDEB patients and to identify strategies how to normalize macrophage functions in wounds of RDEB patients.

Macrophages are also integrally linked in cancer formation and mechanistically they are likely to be placed at the interface between a poorly healing wound associated with RDEB and the gradual transformation of the wound into a carcinoma. We strongly believe that by deciphering the fundamental mechanisms underpinning how immune cells impair wound healing in RDEB patients will not only advance the development of new local therapeutic compounds that accelerate wound closure (e.g. wound dressings that dampen chronic inflammation) but might also help to develop diagnostic tools to monitor when a poorly healing wound becomes malignant.

Researcher's progress update:

Experiments have been initiated as outlined in the original project plan. In addition, in parallel to the experiments proposed in the initial work plan of the project, the applicant’s laboratory has made significant progress in the understanding of how the immune system impacts maintenance of epidermal skin barrier function, in related and ongoing projects in the applicant’s group. We believe that these findings will contribute to the principle understanding how innate immunity impacts wound healing complications in RDEB patients, and that RDEB patients will profit from these discoveries. Here we see an opportunity for innovative research for the benefit of RDEB patients. (From 2019 progress report.)

Researcher's final progress update:

Experiments were initiated as outlined in the original project plan. There were initially some delays in generating a specific genetic model, which we had considered resolved by early 2020. However, unexpectedly in early 2020 the academic life and experimental laboratories were closed due to COVID-19 pandemic restrictions of the University. In 2020 and 2021 university life came to a partial standstill. Facilities and laboratories could not be used as planed and scientific exchange and discourse was severely restricted. The consequences of these limitations, at the own campus but also globally (delay in ordering and delivery from lab resources, personnel shortage due to illness), are still not entirely overcome. Overall, the pandemic limitation has severely impacted our work and original plan of the project. Therefore, as outlined in the interim report from 25 December 2019, the applicant has developed an alternative experimental approach that is expected to complement the initial work plan of the project and addresses the original research questions of the project. The applicant’s laboratory has made significant progress in the understanding of how the immune system impacts maintenance of epidermal skin barrier function, in related and ongoing projects in the applicant’s group. We believe that these findings will contribute to the principle understanding how type 2 immunity impacts wound healing complications in RDEB patients, and that RDEB patients will profit from these discoveries. Here we see an opportunity for innovative research for the benefit of RDEB patients. (From 2022 final progress report.)