Role of hair follicle stem cells in Hidradenitis Suppurativa Pathogeny – HF-HS

Hidradenitis Suppurativa (HS; OMIM #142690) is a chronic recurrent inflammatory skin disease affecting hair follicles (HF) leading to draining sinuses, painful skin abscesses and disfiguring scars. HS is a common disease, with a point prevalence of 4% in Europe. HS is an orphan and frequent disease which severely impacts the quality of patients’ life and causes significant costs for health systems.
HS is notoriously difficult and challenging to treat with a high morbidity impact and could be classified as an unmet medical need with no efficient therapeutic options. By December 31th 2018, only 17 clinical trials dedicated to HS had been completed in the United States and there is only 1 US FDA-approved therapy. The initial pathological changes of HS are observed in the terminal hair infundibulum. The current understanding of the HS pathogenesis suggests that a fragile acroinfundibulum or an occlusion by hyperproliferative HF epithelial cells can lead to the rupture of the follicular epithelium, which initiates the inflammatory cascade.
One of the main obstacles for the development of efficient therapeutic strategies is certainly due to the lack of a clear physiopathological mechanism and the high heterogeneity of patients. To date, the different attempts to classify HS disease for clinical trials and to identify subpopulations prone to respond to specific therapies rely only on the clinical presentation. Despite these efforts to distinguish different HS clinical categories, establishing a robust genotype-phenotype correlation was not achieved so far.
The main objective of this project is to propose a new approach to characterize patients based on the new tools, and on the pathophysiological advances that they have enabled in recent years. The hypothesis behind this project relies on our recent demonstration that a subgroup of HS patients exhibited hair follicle stem cells (HF-SC) with features of replicative stress abnormalities. Our recent research has provided sound evidence that genomic DNA damage triggers an inflammatory response through the accumulation of cytosolic DNA fragments and the activation of STING. Accumulation of ssDNA and micronuclei in the cytosol of HF-SC isolated from HS patients was found to contribute to STING activation via the DNA sensor IFI16. Finally, our results showed that STING pathway activation induces IFN type I production in HF-SC (Orvain, JCI,2020). Globally, these findings support the concept that impaired HF-SC homeostasis promotes chronic inflammation in HS patients.
This observation: i) reconciles HF development abnormalities and chronic inflammation; ii) opens the way to identify new epigenetic and genetic hypotheses associated with these biological abnormalities; iii) provides new tools for defining biomarkers allowing the identification of a subgroup of patients and possibly new therapeutic avenues. To reach these goals we have developed a 3-year program with 3 Work Packages : i) In WP1, we will expand our biobank of ORS from HS patients to better define patients with or without HF-SC replicative stress; ii) WP2 will be focused on deciphering molecular mechanisms driving HF-SC replicative stress using well-categorized patients with or without replicative stress through an OMICs approach; iii) WP3 will use an integrated approach of clinical, biological and OMICs determinants in order to dissect HS heterogeneity.
Expected impacts of our results will help to elucidate if any distinct immunological signatures can be identified as related to specific clinical phenotypes that can be used as potential biomarkers for disease prognosis and patient care.