Immune dysfunction in the skin disease hidradenitis suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. Painful lesions and boils present at hair follicles of the inframammary fold, genitals, groin, buttocks and perianal areas. Severe cases progress to dermal tunnelling and scarring, with ruptured cysts resulting in a bloody, foul-smelling discharge. HS affects patients’ physical, mental, social and economic wellbeing and is significantly associated with low quality of life scores. The cellular pathogenesis in HS is poorly understood and there is an urgent need for improved therapeutics. Immune dysregulation has been shown to play a major role, and so detailed characterisation of the immune cell component is invaluable. To study the immune cells within HS patient blood and skin, this study utilised state-of-the-art technologies including imaging cytometry, high-parameter flow cytometry and single cell RNA sequencing. This thesis has for the first time identified multiple B cell, T cell and myeloid cell subsets present at significantly enriched levels in HS lesional skin. It identified CD1c+ dendritic cells (cDC2) as the cellular source of the potent immune mediators IL-1β, IL-18, IL-23 and the activated NLRP3 inflammasome. Importantly, it demonstrated a substantial polyfunctional CD4 T cell population, dramatically skewed towards IL-17 production, leading to a Th17 cell: Treg cell imbalance. Finally, it showed this balance restored, and a reduction in the polyfunctional IL-17+ T cells, upon anti-TNF treatment. These data suggest that Th17 cells play a key role in HS pathogenesis and that their activation is likely driven by mediators produced by CD1c+ dendritic cells in HS lesional skin. Systemic inflammation is apparent given that HS patient blood and even clinically normal skin have significant inflammation. This study underscores the rationale for therapeutic suppression of the IL-17 pathway and suggests novel targets.