CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment.

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.

Interleukin-15 is a hair follicle immune privilege guardian.

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key "danger" signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα-silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.

Deciphering the Complex Immunopathogenesis of Alopecia Areata.

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.

Single-cell transcriptome profiling reveals cell type-specific variation and development in HLA expression of human skin.

Skin, the largest organ of body, is a highly immunogenic tissue with a diverse collection of immune cells. Highly polymorphic human leukocyte antigen (HLA) molecules have a central role in coordinating immune responses as recognition molecules. Nevertheless, HLA gene expression patterns among diverse cell types within a specific organ, like the skin, have yet to be thoroughly investigated, with stromal cells attracting much less attention than immune cells. To illustrate HLA expression profiles across different cell types in the skin, we performed single-cell RNA sequencing (scRNA-seq) analyses on skin datasets, covering adult and fetal skin, and hair follicles as the skin appendages. We revealed the variation in HLA expression between different skin populations by examining normal adult skin datasets. Moreover, we evaluated the potential immunogenicity of multiple skin populations based on the expression of classical HLA class I genes, which were well represented in all cell types. Furthermore, we generated scRNA-seq data of developing skin from fetuses of 15 post conception weeks (PCW), 17 PCW, and 22 PCW, delineating the dynamic expression of HLA genes with cell type-dependent variation among various cell types during development. Notably, the pseudotime trajectory analysis unraveled the significant variance in HLA genes during the evolution of vascular endothelial cells. Moreover, we uncovered the immune-privileged properties of hair follicles at single-cell resolution. Our study presents a comprehensive single-cell transcriptomic landscape of HLA genes in the skin, which provides new insights into variation in HLA molecules and offers a clue for allogeneic skin transplantation.

Role of neurogenic inflammation in the pathogenesis of alopecia areata.

Alopecia areata refers to an autoimmune illness indicated by persistent inflammation. The key requirement for alopecia areata occurrence is the disruption of immune-privileged regions within the hair follicles. Recent research has indicated that neuropeptides play a role in the damage to hair follicles by triggering neurogenic inflammation, stimulating mast cells ambient the follicles, and promoting apoptotic processes in keratinocytes. However, the exact pathogenesis of alopecia areata requires further investigation. Recently, there has been an increasing focus on understanding the mechanisms of immune diseases resulting from the interplay between the nervous and the immune system. Neurogenic inflammation due to neuroimmune disorders of the skin system may disrupt the inflammatory microenvironment of the hair follicle, which plays a crucial part in the progression of alopecia areata.

Estudio inmunohistoquímico de la calretinina en el folículo piloso normal y neoplasias con diferenciación folicular / Immunohistochemical study of calretinin in normal hair follicles and tumors with follicular differentiation

Introducción. La inmunotinción selectiva con calretinina evidencia la capa más interna de la vaina radicularexterna del folículo piloso normal, difícil de distinguir con la tinción de hematoxilina-eosina. Objetivo. Conocer si calretinina nos permite identificar neoplasias anexiales con diferenciación hacia la vaina radicular externa del folículo piloso. Material y métodos. Hemos analizado el patrón de inmunotinción para calretinina en 49 biopsias de distintas neoplasias anexiales cutáneas con diferenciación folicular. Resultados. Quince de las 49 tinciones correspondían a tricolemomas/queratosis folicular invertida, observándose positividad con calretinina en el epitelio de las áreas más superficiales de la lesión y en los remolinos escamosos; 10 quistes tricolémicos con positividad en su pared, tres carcinomas basocelulares con positividad variable dependiendo del tipo de diferenciación folicular de cada variante, un panfoliculoma con positividad focal, dos hamartomas sebáceos infundíbulo-quísticos con positividad en el conducto excretor de las glándulas sebáceas, dos pilomatricomas y tres tumores tricolemales proliferantes con positividad en las capas celulares cercanas a la luz de las estructuras quísticas, 9 tricoblastomas/tricoepiteliomas, dos quistes infundibulares, un poro dilatado de Winer y dos acantomas de la vaina folicular resultaron negativos. Conclusión. El estudio inmunohistoquímico de la calretinina nos permite identificar neoplasias anexiales del folículo piloso o componentes de éste, con diferenciación hacia la vaina radicular externa del folículo piloso (AU)

Background. Selective immunostaining for calretinin labels the innermost layer of the outer root sheath of normal hair follicles, which is difficult to distinguish with hematoxylin-eosin staining. Objective. The aim of this study was to determine whether immunohistochemistry for calretinin allows identification of cutaneous adnexal tumors with follicular differentiation towards cells of the outer root sheath.Material and methods. We analyzed the staining pattern for calretinin by immunohistochemistry in 49 biopsies of cutaneous adnexal tumors with follicular differentiation. Results. Fifteen biopsies corresponded to trichilemmomas/inverted follicular keratosis and had staining for calretinin in the epithelium of the most superficial areas of the lesions and in squamous eddies. Ten were trichilemmalcysts, which displayed staining of the cyst wall. Three were basal cell carcinomas with variable staining according to the type of follicular differentiation in each variant. One was a panfolliculoma that had focal staining. Two were folliculosebaceous cystic hamartomas with staining of the excretory duct of the sebaceous glands. Two pilomatricomas and 3 proliferative trichilemmal tumors had positive staining in the cellular layers close to the lumen of the cystic structures. Nine trichoblastomas/trichoepitheliomas, 2 infundibular cysts, 1 dilated pore of Winer, and2 acanthomas of the follicular sheath were negative for calretinin. Conclusion. Immunohistochemistry for calretinin allows identification of cutaneous adnexal tumors of the hair follicle or a component of the follicle with differentiation towards cells of the outer root sheath (AU)