Unravelling the inflammatory landscape of hidradenitis suppurativa
Citation:
Smith, Conor, Unravelling the inflammatory landscape of hidradenitis suppurativa, Trinity College Dublin, School of Biochemistry & Immunology, Biochemistry, 2024Download Item:
Abstract:
Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease
characterised by painful lesions at hair follicles of the inframammary fold, genitals, groin,
buttocks and perianal areas. Follicular occlusion is an initiating event in HS, resulting in cyst
formation which subsequently rupture leading to a bloody, foul-smelling discharge. Severe
HS may also lead to the development of dermal tunnels and hypertrophic scarring. A poor
understanding of HS pathogenesis has limited the development of effective therapies, with
the only approved biologics, adalimumab and secukinumab, proving moderately effective
in a cohort of HS patients. Evidence suggests immune dysregulation plays an important role
in driving HS inflammation; however detailed investigation into both immune and non-
immune cells, and their interaction, has yet to be pursued. Identifying potential
interactions between immune and non-immune cells would be invaluable to the field.
This project utilised state-of-the-art bulk and single cell RNA sequencing and high-
parameter flow cytometry to study both immune and non-immune cells in HS skin.
The data presented in this thesis identified B cells and immunoglobulins as key features
which distinguish HS from other inflammatory dermatoses, psoriasis and atopic dermatitis.
For the first time, this study characterised the keratinocyte and fibroblast populations
present in HS lesions. Of note, T cells were shown to promote the development of
inflammatory phenotypes which are likely responsible for distinct clinical features including
epidermal hyperplasia, dermal tunnel formation and hypertrophic scarring. This study
identified a dendritic cell subset (cDC2) as the major source of IL-1 and the NLRP3
inflammasome and finally, provided proof of concept that targeting NLRP3 inflammasome
activation effectively inhibits IL-1, as well as other inflammatory mediators including IL-
17A, IFN- and TNF, in HS lesions.
These data highlight the complex nature of HS pathogenesis, implicating B cells, T cells,
keratinocytes, fibroblasts and dendritic cells in HS inflammation. Importantly, this study
outlines the potential for therapeutic suppression of the NLRP3 inflammasome in HS
patients, providing additional benefits to current therapies by reducing a broader range of
inflammatory mediators in HS lesions.
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:SMITHC35Description:
APPROVED
Author: Smith, Conor
Advisor:
Fletcher, JeanPetrasca, Andreea
Publisher:
Trinity College Dublin. School of Biochemistry & Immunology. Discipline of BiochemistryType of material:
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