Mucosal Associated Invariant T Cells and Insulin Resistance in Hidradenitis Suppurativa

Abstract

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterised by recurrent painful nodules, abscesses and draining sinus tracts. There is a paucity of effective treatments and it severely impairs patients? quality of life1. The pathogenesis remains unclear, but emerging evidence suggests immune dysregulation and inflammation are key drivers of the disease2.

In addition, several studies have confirmed that patients with HS have a higher body mass index (BMI) compared to the general population3. It is known obesity is characterized by inflammation of the adipose tissue and this inflammation is a major driver of insulin resistance (IR)4 which, in turn, is a strong predictor of type 2 diabetes and the development of cardiovascular disease5. Interleukin (IL)-17 has been found to participate in this complex interplay between inflammation and metabolism6 and has also been implicated in HS pathogenesis, potentially explaining a link between the two.

Mucosal- associated invariant T (MAIT) cells are a novel subset of innate-like T cells. They are activated upon recognition of bacterial derivatives and can rapidly produce a milieu of cytokines including TNF?, IFN? and IL-177. The Retinoic acid receptor-related-?t (ROR?t ) is the key transcription factor in IL-17 producing T cells8 and is emerging as an important therapeutic target given its association with autoimmune diseases9. However, the implication of both MAIT cells and ROR?t in HS remains unknown.

In light of this, my thesis reports two main studies which have HS as a central theme. I first sought to explore the relationship between IR and HS. Next, I investigated the role of IL 17 producing MAIT cells in the disease and examined the potential of targeting IL-17+ MAIT cells using a small molecule ROR?t inhibitor.

To address my research questions, I established two well defined patient cohorts (94 patients and 15 patients). Firstly, I performed a prospective study to establish the prevalence of IR in our HS patients and to record the presence of its cutaneous manifestations. In the second cohort I prepared peripheral blood mononuclear cells (PBMC) and skin biopsies for flow cytometric analysis. MAIT cell cytokine production was determined by intracellular flow cytometry while MAIT cell ROR?t expression in patients and controls was determined by transcription factor flow cytometry.

This thesis presents several important findings; there was a high frequency of IR in our HS cohort and these patients were more likely to be obese. This study also highlights how close observation of cutaneous signs may be an indicator of internal disease and reminds me of why I pursued a career in Dermatology; we have the wonderful opportunity to diagnose with our eyes. Next, we made the novel observation that there is an accumulation of IL-17 producing MAIT cells in hidradenitis suppurativa lesions. Our results also provide supporting data for investigating ROR?t small molecule inhibitors in the treatment of patients with H.S. Collectively, this work enhances awareness of HS and provides further insights into the understanding of its pathogenesis and novel treatments.