Characterization of the Cytokine Profile and the Microbiome in Darier's Disease

Overview

Darier disease is a rare genetic skin disease caused by mutations in the ATP2A2 gene. Clinically, patients present with inflammatory and keratotic papules, sometimes erosive and oozing, predominating in seborrheic areas and folds. The lesions are very visible, causing itching and pain and a significant impairment of quality of life. Complications such as superinfections of the skin (bacterial and viral) are very common and sometimes severe. Therapeutically, treatments are mainly symptomatic and often of limited effectiveness, particularly on inflammation and pruritus. The main objective of this clinical study is to compare the microbiota of the epidermis of patients with Darier disease in non-lesional areas versus lesional areas , making it possible to identify bacteria/clusters of bacteria, but also to analyze the metabolic pathways of the microbiota associated with the microbial signature, until now not described. The secondary objectives envisaged are to study the correlation between this microbiotic profile and both the clinical characteristics of patients and the cytokine profile. The research will be performed on 40 patients aged 18 or over, suffering from moderate to severe Darier Disease. For each patient, several samples will be collected including biopsies, blood sample, swabbing and tape-stripping, on lesional and non-lesional areas.

A study carried out in 75 patients showed the presence of Staphylococcus aureus in lesional skin in 68% of cases, this percentage being correlated with the affected surface and the severity of the disease. Histologically, there is a characteristic appearance of acantholytic dyskeratosis and the underlying dermis is the site of inflammation. On the physiopathological level, the mutations cause disturbances in calcium metabolism, causing a loss of cell adhesion and a disruption of keratinocyte differentiation. The mechanisms leading to inflammatory skin lesions and frequent superinfections are poorly understood and could be the consequence of the abnormality of the skin barrier, causing disturbances in the cytokine profile and the microbiota. This has been shown in hereditary ichthyoses, another group of diseases with keratinization disorders, in which microbiota abnormalities and a TH17 cytokine profile have been demonstrated. In Darier disease, a study published in 2023 also showed the presence of a TH17 profile in 6 patients. In 2 patients, clinical improvement was also noted when using biotherapy targeting interleukin 17 or 23. Also in 2023, Amar et al. studied the skin microbiota of 14 patients and showed the presence of Staphylococcus aureus and Staphylococcus warneri in the inflammatory areas, the abundance of which correlated with the severity of the disease. Our study will provide additional data to this recent work, by highlighting differential cytokine and microbiota signatures between the two skin areas studied, in order to validate our hypothesis of the involvement of cytokines and the microbiota in chronic skin inflammation.