1. CD2 expressing innate lymphoid and T cells are critical effectors of immunopathogenesis in hidradenitis suppurativa.
- Author
-
Kashyap MP, Mishra B, Sinha R, Jin L, Gou Y, Kumar N, Goliwas KF, Haque S, Deshane J, Berglund E, Berglund D, Elewski BE, Elmets CA, Athar M, Mukhtar MS, and Raman C
- Subjects
- Humans, Keratinocytes immunology, Keratinocytes metabolism, Keratinocytes pathology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Male, Skin immunology, Skin pathology, Skin metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Fibroblasts metabolism, Fibroblasts immunology, Interleukin-15 metabolism, Interleukin-15 immunology, Hidradenitis Suppurativa immunology, Hidradenitis Suppurativa pathology, Hidradenitis Suppurativa metabolism, Hidradenitis Suppurativa genetics, Immunity, Innate, CD2 Antigens metabolism, CD2 Antigens immunology
- Abstract
Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease with a poorly understood immunopathogenesis. Here, we report that HS lesional skin is characterized by the expansion of innate lymphocytes and T cells expressing CD2, an essential activation receptor and adhesion molecule. Lymphocytes expressing elevated CD2 predominated with unique spatial distribution throughout the epidermis and hypodermis in the HS lesion. CD2
+ cells were mainly innate lymphocytes expressing the NK cell marker, CD56, and CD4+ T cells. Importantly, these CD2+ cells interacted with CD58 (LFA3) expressing epidermal keratinocytes and fibroblasts in the hypodermis. Granzyme Abright NKT cells (CD2+ CD3+ CD56bright ) clustered with α-SMA expressing fibroblasts juxtaposed to epithelialized tunnels and fibrotic regions of the hypodermis. Whereas NK cells (CD2+ CD56dim ) were perforin+ , granzymes A+ and B+ , and enriched adjacent to hyperplastic follicular epidermis and tunnels of HS showing presence of apoptotic cells. The cytokines IL-12, IL-15, and IL-18, which enhance NK cell maturation and function were significantly elevated in HS. Ex vivo HS skin explant cultures treated with CD2:CD58 interaction-blocking anti-CD2 monoclonal antibody attenuated secretion of inflammatory cytokines/chemokines and suppressed inflammatory gene signature. Additionally, CD2:CD58 blockade altered miRNAs involved in NK/NKT differentiation and/or function. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation and is critical in the pathobiology of HS, including tunnel formation and fibrosis. Finally, CD2 blockade is a viable immunotherapeutic approach for the effective management of HS., Competing Interests: Competing interests statement:E.B. and D.B. are co-founders of ITB-MED. Patent application number: PCT/US2023/022364.- Published
- 2024
- Full Text
- View/download PDF