Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Abstract

Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFβ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4–1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4–1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA.

Lesional infiltration of mast cells, Langerhans cells, T cells and local cytokine profiles in alopecia areata

“…T cells infiltration, leading to regression of cycling hair follicle. In a recent study, Bertolini M et al [5] also showed that significantly more peri-and intrafollicular-activated CD8 ? T-cells, more pro-inflammatory MCs, as well as more physical MC/ CD8 ?…”

Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition

“…1c,d). Other cell types, including CD4 + T cells 4 and mast cells 8 , were present in much smaller numbers (Supplementary Fig. 1c and data not shown).…”

Special Stains and Immunohistochemical Stains in Hair Pathology

“…19 Several hair loss disorders outlined below have been associated with MCs. [20][21][22][23][24][25][26][27][28][29] Currently, these findings are of scientific value without direct diagnostic application to practice.…”

“…21,22 The presence of MCs is correlated with increases in perifollicular nerve-ending expression of neuropeptides such as nerve growth factor receptor and substance P, 21 which have been shown to induce MC degranulation. 23 Substance P and interferon gamma are implicated as the most important inducers of the collapse of the immune privilege of the hair follicle in AA.…”

“…23 Substance P and interferon gamma are implicated as the most important inducers of the collapse of the immune privilege of the hair follicle in AA. 24 Recently, Bertolini et al 22 showed that not only are MCs increased in lesional AA biopsies from human and mouse skin but they also interact with the CD8 + T cells, thus promoting their pathogenic responses against hair follicles. the vertex in men with AGA when compared with the vertex of men with normal hair density.…”