Immune system involvement in RDEB (2023)

This research will help us understand how the chronic inflammation in RDEB might be caused and, in the future, symptoms such as pain, debilitating scarring and skin cancer treated and prevented.

Dr Yanling Liao and Prof Mitchell Cairo work at New York Medical College, USA studying inflammation in recessive dystrophic epidermolysis bullosa (RDEB). Inflammation is how our own immune systems react to an injury or infection and it usually stops once the injury is healed. If it doesn’t stop, it can cause continuing damage, scarring (fibrosis) and may contribute to the development of skin cancer. This work is to study model skin with a broken COL7A1 gene to see how this chronic inflammation in RDEB might be caused and, in the future, treated and prevented.

Read more in our researcher's blog.

About our funding:

Research leader	Dr Yanling Liao
Institution	New York Medical College, New York, USA
Type of EB	RDEB
Patient involvement	None. This is pre-clinical work not involving people
Funding amount	€250,000.00 co-funded with DEBRA Ireland
Project length	3 years
Start date	July 2020
DEBRA internal ID	Liao1

Final progress summary 2023:

This research found that RDEB skin cells already have changes that would allow cancer to grow and spread before there is any noticeable skin cancer. Early treatment to reduce these changes may stop skin cancer from happening or slow it down.
RDEB symptoms that are caused by the skin’s natural process of inflammation may be helped by anti-inflammatory medications that reduce specific substances in the skin, particularly one called interleukin-1.
The results of this research were published in September 2023. Read an article about the findings for a general audience here.

About our researchers:

Lead Researcher: Dr Yanling Liao, Assistant Professor of Pediatrics.

Dr. Yanling Liao obtained her Bachelor of Science in Biology at Xiamen University, P.R. China and her PhD from the Department of Biochemistry at Albert Einstein College of Medicine, New York, investigating the mechanism of RNA transcriptional regulation. She did her postdoctoral training in Dr. Helen Blau’s laboratory at the Department of Immunology & Microbiology at Stanford University School of Medicine, California, and later joined Dr. Mitchell Cairo’s laboratory in the Department of Pediatrics, Columbia University Medical Center, New York. Dr. Liao became a Research Assistant Professor of Pediatrics in 2011 and an Assistant Professor of Pediatrics in 2014 at New York Medical College, where her main research has been focused on preclinical development of stem cell and protein therapies for RDEB.

Co-investigator: Professor Mitchell Cairo, Associate Chair of the Department of Pediatrics & Professor of Pediatrics, Medicine, Pathology, Microbiology, Immunology, Cell Biology & Anatomy at NYMC.

Professor Mitchell Cairo is currently the Associate Chairman and Professor (with tenure) in the Department of Pediatrics at New York Medical College (NYMC). His additional current leadership positions include being the Chief of the Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Program Director of the Adult & Pediatric BMT Program, Director of the Childhood and Adolescent Cancer and Blood Disease Center, Medical and Scientific Director of the GMP Cellular and Tissue Engineering Laboratory at Westchester Medical Center (WMC), Medical Director of the WMC Hematotherapy Program and Chair of the WMC Adult and Pediatric Cancer Program. Dr. Cairo’s additional academic appointments include being a Professor of Medicine, Pathology, Microbiology and Immunology and Cell Biology and Anatomy and Public Health at NYMC.

Why this research is important:

It has been well recognized that chronic inflammation and fibrosis contribute to squamous cell carcinoma development in patients with RDEB. The inflammatory response, which is a natural defense system in our body, is supposed to be resolved after defending infection and/or injury, yet it is not resolved in patients with RDEB. Instead, it evolves into an unwanted chronic condition in these patients. As such, our investigations will help us identify how immune cells in the skin change with time in response to changes within the dermal microenvironment. This research will help us understand the mechanism of chronic inflammation and identify novel targets for the treatment or prevention of chronic inflammation and fibrosis in patients with RDEB.

Dr Yanling Liao

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Researcher’s Abstract:

Grant Title: Identifying innate and adaptive immune mechanisms associated with fibrosis in animal models of RDEB

There are two types of inflammation, the first is microbial-mediated (e.g. the presence of bacteria), and the other one is in the absence of microbial organisms, also named sterile inflammation. A defining feature of sterile inflammation is that it can often result in a chronic inflammatory process and fibrosis. Based on our preliminary preclinical studies, it is possible that patients with RDEB could be born with sterile inflammation and further be confounded by microbial-mediated inflammation because of the lack of Collagen 7. This brings into question the systemic challenges associated with EB – far more than just a problem with the skin and mucosa. Continuous and unresolved inflammation then leads to a chronic problem, fibrosis and ultimately may be linked to the development of squamous cell carcinoma. It is therefore essential to understand the mechanisms of this early inflammatory process. The proposed studies will involve an RDEB model that lacks COL7A1 to investigate what types of immune cells infiltrate the skin under sterile conditions.

The group will also look at what molecular signals induce their infiltration, how they interact with each other and with the skin microenvironment. Based on these results, they will investigate if the molecular signals can be stopped or slowed to suppress the development of chronic inflammation and fibrosis.
Elements of the two types of immune response (innate and adaptive), have both been demonstrated to play an important role in triggering fibrosis in many organ systems such as lung and liver. However, their role in chronic inflammation and fibrosis in RDEB is remains poorly understood.
The proposed studies will investigate the sequence of immune responses and their correlation with signalling transduction in the skin to understand progression and alteration of the immune response.
It is hoped that by determining the signalling pathways, this work will reveal the mechanisms that correlate with inflammation and fibrosis, identify potential targets for early intervention and development of novel and more effective immune therapies in RDEB.

Researcher’s final progress update 2023:

Inflammation is the body’s natural defense system against infection and/or injury. However, many studies demonstrate that cutaneous squamous cell carcinomas in patients with RDEB arise at sites of persistent chronic inflammation. The skin of patients with RDEB is associated with trauma-induced lesions as well as microbial colonization. How the inflammatory responses evolve into an unwanted chronic condition in patients with RDEB is not clearly elucidated. In this study, we found that, even before tumors occur, dermal cells already exhibit features that support tumor growth and metastasis, similar to those observed in tumor-growing skin. These features include altered use of energy (Anaerobic metabolism), proliferative epidermal cells, enhanced immune cell proliferation and activation, fibroblast activation, enhanced angiogenesis etc. Our data showed that this tumor supporting RDEB dermal niche (dermal microenvironment) has been established before the onset of tumor transformation and suggest that early intervention to modulate this dermal microenvironment is needed for the individuals with RDEB, to possibly delay or prevent tumor development. We also measured different mediators of inflammation in the skin and identified interleukin 1 (IL-1α) as a major factor (cytokine) that initiated the inflammatory responses from birth and further maintained the chronic inflammation with other inflammatory cytokines (such as IL-6 and TNF). We also validated the effects of IL-1α on modifying the phenotypes of RDEB fibroblasts. Our studies suggest that inhibition of IL-1α, or in combination with inhibitors against other cytokines that appeared at a later timepoint than IL-1α, can serve as effective anti-inflammatory therapeutics. This research has been published with the link below: https://doi.org/10.3389/fimmu.2023.1211505

Researcher’s progress update 2022:

Our study is focused on understanding the mechanism of inflammation in RDEB mouse models. We examined the genes expressed in individual cell types (such as epidermal cells, dermal cells, immune cells, nerve cells and vascular cells within the skin) in RDEB mice and compared them with the healthy mice. We found that all the cells have undergone a metabolic shift toward aerobic glycolysis, in response to the hypoxia (less oxygen) dermal environment. Enhanced glycolysis is a prominent feature of cancer cells and a target for cancer therapy. We postulate that hypoxia induced signalling and glycolysis could also be the target for therapeutic intervention in RDEB. We also found some unique gene expression or cell populations in RDEB that related to the pathological development of RDEB. Based on increased expression of several factors that are in the negative feedback loop, we can picture that the RDEB skin is trying to compensate the tissue damage by creating an immune suppressive environment to promote wound healing. However, this is at the cost of decreasing T cell function (as demonstrated by increased PD-1 expression on T cells, which is a mechanism for tumor evasion) and increased risk for cancer development. On the other hand, this opens an option for PD-1 blockade to reinvigorating T cell function in RDEB. There was also activation of different signalling pathways in response to inflammation. We are trying to identify what factors mediate each pathway and at what time point the factors appear and/or disappear. This will provide us targets for therapeutic intervention. So far, one of the promising factors that can be a therapeutic target is interleukin (IL)-1a, whose level was significantly higher than all the other inflammatory factors at newborn and continued to increase with age. It is likely a danger signal in RDEB early on that activates all the following inflammatory cascades. The other danger signal could be an immune factor called complete 3 (C3). This factor was identified in the blister fluid of the newborn RDEB mice and was highly expressed in a particular fibroblast (dermal cells) population that shares similar properties as what would be found in cancer- associated fibroblasts. Our future studies will determine the effects of blocking IL1a and C3 on suppressing inflammation in RDEB. (From 2022 progress report.)