Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata.
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.
Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Münster, Münster, Germany.
Marta
M
Bertolini
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Federica
F
Zilio
Department of Internal Medicine and Medical Specialties, University "La Sapienza", Rome, Italy.
Alfredo
A
Rossi
Department of Gynaecology and Obstetrics, University of Rostock, Rostock, Germany.
Patrick
P
Kleditzsch
Department of Pharmacology, Clinical Pharmacology and Biochemistry, Chuvash State University Medical School, Cheboksary, Russia.
Vladimir E
VE
Emelianov
Laboratory for Skin Research, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Flieman Medical Center, Haifa, Israel.
Amos
A
Gilhar
Laboratory for Skin Research, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Aviad
A
Keren
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Katja C
KC
Meyer
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
Eddy
E
Wang
Klinik Dr. Koslowski, Munich, Germany.
Wolfgang
W
Funk
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
Kevin
K
McElwee
Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Münster, Münster, Germany; Institute for Inflammation and Repair, University of Manchester, Manchester, United Kingdom.
Ralf
R
Paus
D000506:Alopecia Areata / Q000097:blood* / Q000276:immunology*; D000818:Animals; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D018859:Hair Follicle / Q000473:pathology; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000097:blood; D008407:Mast Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D010641:Phenotype; D012867:Skin / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D053773:Transforming Growth Factor beta1; D016753:Interleukin-10