Collapse Of Hair Follicle Immune Privilege Research Articles

90 Exploring the therapeutic potential of DHODH inhibitor farudodstat for alopecia areata treatment in a novel ex vivo model of human hair follicle immune privilege collapse

90 Exploring the therapeutic potential of DHODH inhibitor farudodstat for alopecia areata treatment in a novel ex vivo model of human hair follicle immune privilege collapse

LB1777 A novel ex vivo model of human hair follicle immune privilege collapse reveals the potential of farudodstat, a DHODH inhibitor, as a therapeutic for alopecia areata treatment

LB1777 A novel ex vivo model of human hair follicle immune privilege collapse reveals the potential of farudodstat, a DHODH inhibitor, as a therapeutic for alopecia areata treatment

Oxidative stress and alopecia areata.

Alopecia areata (AA) is an inflammatory autoimmune disease characterized by non-scarring hair loss on the scalp or any other part of the hair-bearing skin. While the collapse of the immune privilege is considered as one of the most accepted theories accounting for AA, the exact pathogenesis of this disease remains unclear by now. Other factors, such as genetic predisposition, allergies, microbiota, and psychological stress, also play an important role in the occurrence and development of AA. Oxidative stress (OS), an unbalance between the oxidation and antioxidant defense systems, is believed to be associated with AA and may trigger the collapse of hair follicle-immune privilege. In this review, we examine the evidence of oxidative stress in AA patients, as well as the relationship between the pathogenesis of AA and OS. In the future, antioxidants may play a new role as a supplementary therapy for AA.

700 Tyrosine kinase 2 inhibition rescues hair follicles from IL-12–mediated immune privilege collapse and reverses the induction of human alopecia areata in a humanized mouse model

Alopecia areata (AA), an immune-mediated hair follicle (HF) disorder, leads to hair loss due to collapse of the HF’s physiologic immune privilege (IP), induced by elevated IFNγ levels and a Tc1-driven inflammatory response dominated by T and NK cells. Given that IL-12 signaling is crucial for IFNγ production by immune cells, we explored for the first time the role of IL-12 and tyrosine kinase 2 (TYK2)-mediated signaling in the induction and prevention of HF IP collapse via a selective TYK2 inhibitor (BMS-986202).

061 Selective inhibition of tyrosine kinase 2 prevents and restores interleukin-12-induced hair follicle immune privilege collapse: a novel approach to alopecia areata therapy?

Alopecia areata (AA) is an immune-mediated hair loss disorder characterized by elevated levels of IFNγ and Th1-driven inflammatory responses toward the hair follicle (HF) bulb. This results in immune privilege (IP) collapse, premature catagen development, and HF dystrophy. Given the critical role of interleukin (IL)-12 in priming Th1 responses, we investigated whether IL-12 could be directly involved in inducing HF-IP collapse and whether the selective tyrosine kinase 2 (TYK2) inhibitor, BMS-986202, could prevent or reverse the process. By quantitative immunohistomorphometry, we showed that ex vivo treatment of microdissected HFs with IL-12 (3 ng/mL) + IL-18 (20 ng/mL) upregulated MHC-I and II as well as MICA/B expression in the hair bulb (cardinal features of IP collapse), increased the numbers of CD3+ or CD56+ cells in HF epithelium and mesenchyme, and selectively enriched IFNγ-inducible genes. In addition, more peribulbar IL-12RB2+ cells were found in acute lesional scalp skin samples of AA patients than healthy controls. We further confirmed the role of IL-12 in the HF-IP collapse by selectively blocking IL-12 receptor signaling. BMS-986202 (300 nM), when administered to microdissected HFs before or after IL-12 + IL-18 stimulation, prevented or attenuated the expression of MHC-I and II as well as secretion of IFNγ. Therefore, our data demonstrate that local IL-12 directly promotes perifollicular immune cell expansion, IFNγ secretion, and HF-IP collapse. These findings support a potential role of IL-12 signaling in AA pathogenesis and highlight IL-12 as a potential new target for pharmacologic AA therapy.

The Effect of JAK Inhibitor on the Survival, Anagen Re-Entry, and Hair Follicle Immune Privilege Restoration in Human Dermal Papilla Cells.

Topical or systemic administration of JAK inhibitors has been shown to be a new treatment modality for severe alopecia areata (AA). Some patients show a good response to JAK inhibitors, but frequently relapse after cessation of the treatment. There have been no guidelines about the indications and use of JAK inhibitors in treating AA. The basic pathomechanism of AA and the relevant role of JAK inhibitors should support how to efficiently use JAK inhibitors. We sought to investigate the effect of JAK1/2 inhibitor on an in vitro model of AA and to examine the possible mechanisms. We used interferon gamma-pretreated human dermal papilla cells (hDPCs) as an in vitro model of AA. Ruxolitinib was administered to the hDPCs, and cell viability was assessed. The change of expression of the Wnt/β-catenin pathway, molecules related to the JAK-STAT pathway, and growth factors in ruxolitinib-treated hDPCs was also examined by reverse transcription PCR and Western blot assay. We examined immune-privilege-related molecules by immunohistochemistry in hair-follicle culture models. Ruxolitinib did not affect the cell viability of the hDPCs. Ruxolitinib activated several molecules in the Wnt/β-catenin signaling pathway, including Lef1 and β-catenin, and suppressed the transcription of DKK1 in hDPCs, but not its translation. Ruxolitinib reverted IFN-γ-induced expression of caspase-1, IL-1β, IL-15, and IL-18, and stimulated several growth factors, such as FGF7. Ruxolitinib suppressed the phosphorylation of JAK1, JAK2 and JAK3, and STAT1 and 3 compared to IFN-γ pretreated hDPCs. Ruxolitinib pretreatment showed a protective effect on IFN-γ-induced expression of MHC-class II molecules in cultured hair follicles. In conclusion, ruxolitinib modulated and reverted the interferon-induced inflammatory changes by blocking the JAK-STAT pathway in hDPCs under an AA-like environment. Ruxolitinib directly stimulated anagen-re-entry signals in hDPCs by affecting the Wnt/β-catenin pathway and promoting growth factors in hDPCs. Ruxolitinib treatment prevented IFN-γ-induced collapse of hair-follicle immune privilege.

Collapse and Restoration of Hair Follicle Immune Privilege Ex Vivo: A Model for Alopecia Areata.

Alopecia areata (AA) is a hair follicle (HF) autoimmune disease leading to hair loss. Interferon gamma (IFNγ) is regarded as the key cytokine involved in AA development, which has been shown to play a role in the collapse of HF immune privilege (IP), CD8+ T-cell-driven inflammation toward the HF bulb, and premature catagen development. We present here the procedure to induce IP collapse in human healthy HFs ex vivo. This assay can be suitable not only to investigate mechanisms involved in the HF IP collapse but also to test substances for either preventing and/or reversing the HF IP collapse for the management of AA or other autoimmune diseases sharing similar pathogenesis.

246 miR-486 plays a protective role in hair follicle immune privilege collapse in alopecia areata

246 miR-486 plays a protective role in hair follicle immune privilege collapse in alopecia areata

Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse.

Alopecia areata (AA) is an autoimmune disorder whose pathogenesis involves the collapse of the relative immune privilege (IP) of the hair follicle (HF). Given that vasoactive intestinal peptide (VIP) is an immunoinhibitory neuropeptide released by perifollicular sensory nerve fibres, which play a role in IP maintenance, it may modulate human HF-IP and thus be therapeutically relevant for AA. To answer the following questions: Do human HFs express VIP receptors, and does their stimulation protect from or restore experimentally induced HF-IP collapse? Is VIP signalling defective in AA HFs? Firstly, VIP and VIP receptor (VPAC1, VPAC2) expression in human scalp HFs and AA skin was assessed. In HF organ culture, we then explored whether VIP treatment can restore and/or protect from interferon-γ-induced HF-IP collapse, assessing the expression of the key IP markers by quantitative (immuno-)histomorphometry. Here we provide the first evidence that VIP receptors are expressed in the epithelium of healthy human HFs at the gene and protein level. Furthermore, VIP receptor protein expression, but not VIP(+) nerve fibres, is significantly downregulated in lesional hair bulbs of patients with AA, suggesting defects in VIP receptor-mediated signalling. Moreover, we show that VIP protects the HF from experimentally induced IP collapse invitro, but does not fully restore it once collapsed. These pilot data suggest that insufficient VIP receptor-mediated signalling may contribute to impairing HF-IP in patients with AA, and that VIP is a promising candidate 'HF-IP guardian' that may be therapeutically exploited to inhibit the progression of AA lesions.

The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata.

The aetiology of alopecia areata (AA) is still not fully understood. However, recent clinical and experimental studies have provided insights into the pathomechanisms of AA and revealed that it is an organ-specific and cell-mediated autoimmune disease. Some triggers, such as viral infections, trauma, hormones and emotional/physical stressors, may cause activation of autoreactive T cells that target hair follicle (HF) autoantigens. In these immunological responses, cytokines and chemokines are regarded as key players that mediate the autoimmune inflammation. This results in the collapse of HF immune privilege, which is central to the pathogenesis of AA. This essay will focus on how cytokines and chemokines contribute to the immunological aspects of AA. The management of AA often remains difficult in a number of cases. Our review suggests that novel therapies for AA may involve targeting cytokines and chemokines.

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.

The Role of Hair Follicle Immune Privilege Collapse in Alopecia Areata: Status and Perspectives

Alopecia areata (AA) may represent a CD8+T cell-mediated, organ-specific autoimmune disease in which as yet elusive autoantigens are recognized, once they become exposed by ectopic major histocompatibility complex class I expression by anagen hair follicles (HFs) that have lost their relative immune privilege (IP). On this basis, AA research is chiefly challenged with identifying the autoreactive CD8+T cells and their cognate autoantigens as well as key inducers of HF-IP collapse and "HF-IP guardians" that prevent and/or can restore IP collapse. However, natural killer group 2D-positive (NKG2D+) cells (incl. NK, NKT, and CD8+T cells) and NKG2D-activating ligands from the MICA (MHC I-related chain A) family may also have a key role in AA pathogenesis, as a massive infiltrate of IFN-γ-secreting NKG2D+ cells alone suffices to induce the AA phenotype. Therefore, we speculate that AA may represent a stereotypic, but distinct HF response pattern to inflammatory insults associated with HF-IP collapse.

Effects of calcitonin gene-related peptide on the immune privilege of human hair follicles

The hair follicle is a widely available and instructive miniature organ in the human body that experiences major histocompatibility complex (MHC) class I dependent immune privilege (IP). There are various regulation factors that act on the generation, maintenance, and collapse of hair follicle IP. Neuropeptides such as calcitonin gene-related peptide (CGRP) are created in many organs, including skin, and display various immune regulation effects. The purpose of this study was to investigate the phenotypic effect of CGRP on the hair follicle’s IP. First, we used interferon-γ (IFN-γ) to generate ectopic MHC antigen expression model in cultured human hair follicles as previously described. Then, we examined the effects of CGRP on the regulation of ectopic MHC antigen expression in cultured human hair follicles using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical staining techniques. IFN-γ (75IU/ml) induced ectopic MHC expression. CGRP down-regulated INF-γ-induced ectopic MHC class I mRNA expression. These down-regulated effects were especially evident in 10−8M. In addition, CGRP also suppressed the staining intensity related to the expression of MHC class I and MHC class I-pathway related molecules (β2-microglobulin), but had no effect on MHC class II antigen expression. Taken together, these results indicate that CGRP might be an important regulatory factor for IP maintenance and restoration of IP via suppression of MHC class I antigen.

Lichen planopilaris following hair transplantation and face-lift surgery

Cosmetic surgical procedures, including hair transplantation and face-lift surgery, are becoming increasingly popular. However, there is very little information regarding the associated development of dermatological conditions following these procedures. Lichen planopilaris (LPP) is an uncommon inflammatory hair disorder of unknown aetiology that results in permanent alopecia and replacement of hair follicles with scar-like fibrous tissue. Frontal fibrosing alopecia (FFA), a variant of LPP, involves the frontal hairline and shares similar histological findings with those of LPP. We report 10 patients who developed LPP/FFA following cosmetic scalp surgery. Seven patients developed LPP following hair transplantation, and three patients developed FFA following face-lift surgery. In all cases there was no previous history of LPP or FFA. There is currently a lack of evidence to link the procedures of hair transplantation and cosmetic face-lift surgery to LPP and FFA, respectively. This is the first case series to describe this connection and to postulate the possible pathological processes underlying the clinical observation. Explanations include Koebner phenomenon induced by surgical trauma, an autoimmune process targeting an (as yet, unknown) hair follicle antigen liberated during surgery or perhaps a postsurgery proinflammatory milieu inducing hair follicle immune privilege collapse and follicular damage in susceptible individuals.