Funded Research

Laboratory concept; Scientist uses a dropper to transfer chemical reagent to test tube. He observes the chemical reaction with a blurred background of research in the laboratory

NAAF’s research program funds investigations that advance the understanding of the mechanisms behind alopecia areata, help identify new therapeutic targets, provide information on the biological, psychosocial, and economic impacts, and further knowledge toward treatments and a cure. Since 1985, NAAF has awarded more than 208 research grants totaling more than $5.7 million. The studies we’ve invested in have enabled significant advances in research by helping to unravel the genetics of alopecia areata, identify important immune pathways, and yield clues to targeted treatments.

Find out about applying for a grant on the Research Grants and Awards page.

Uncovering autoimmune regulator function in alopecia areata

Year: 2024 PI Name: Ryan Hobbs, PhD, Assistant Professor, Department of Dermatology, Penn State Health Award Type: Early Career Award Status: In Progress Summary:
Although the exact cause of alopecia areata (AA) remains unknown, it is widely appreciated that AA occurs by immune cells inappropriately attacking and destroying skin cells within hair follicles. The ability to study how AA develops has been limited by a lack of animal model systems that mirror the progression of AA in patients. Dr. Hobb’s group recently reported that mice lacking the gene AIRE (pronounced like “air”, short for autoimmune regulator) will spontaneously develop hair loss that visually and molecularly mirrors human AA lesions. Human patients with mutations in AIRE also develop AA. The goal of this study is to investigate how loss of the AIRE gene leads to hair loss. The AIRE-deficient mouse model for AA along with genetically engineered cells in petri dishes will be used to reveal cellular and molecular reasons for AA onset and progression. By doing so, this research may help to uncover new targets for potential therapeutic intervention to treat AA patients.

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Hydrogel-based drug delivery in alopecia areata

Year: 2024 PI Name: Leo Wang, MD, PhD, Assistant Professor, Department of Dermatology, Perelman School of Medicine, University of Pennsylvania Award Type: Early Career Award Status: In Progress Summary:
Janus kinase (JAK) inhibitors play a large role in treating alopecia areata. The broad, long-term objective of this project is to develop a safe, effective, and durable treatment for alopecia areata (AA) by engineering an injectable hydrogel for the sustained, localized release of baricitinib, one of three FDA-approved JAK inhibitors for AA. A hydrogel is a large network of polymers that baricitinib can be chemically bound to. The hydrogel can be injected directly into the skin, where it then slowly releases the drug to the affected hair follicles, while preventing absorption into the rest of the body. This approach could thus make the use of JAK inhibitors safer and more efficacious. To validate this approach, we will create a hydrogel that can retain baricitinib and release it over time using a thioimidate chemistry. We will measure release profiles and injectability into the skin. Additionally, we will use a model where human skin is grafted onto mice to study how well the hydrogel delivers baricitinib to the skin while measuring systemic side effects. Finally, we will perform experiments to determine if the hydrogel can prevent hair loss and promote hair regrowth in a mouse model of AA. This research could have significant impact on how AA is treated, by potentially creating a safer, more targeted way to deliver JAK inhibitors. Additionally, this technology could be applied to other autoimmune and inflammatory skin diseases in the future.

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Investigating the role of keratinocyte phagocytosis and antigen presentation in alopecia areata

Year: 2024 PI Name: Monique Waldman, PhD, Postdoctoral Research Scientist, Department of Dermatology, Columbia University Award Type: Research Grant Status: In Progress Summary:
Alopecia areata (AA) is an autoimmune disease where immune cells known as T cells attack hair follicles (HFs), leading to hair loss. Despite its significant impact on AA patients, the exact mechanisms driving AA are still not fully understood. This proposal aims to uncover how cell death and immune cell regulation contribute to AA development and persistence. The hair cycle consists of growth (anagen), regression (catagen), and resting (telogen) phases, during which programmed cell death (apoptosis) remodels the lower HF during catagen. In a healthy HFs, keratinocytes in the hair matrix begin to apoptose as the follicle contracts in catagen. The dying cells are then cleared away by neighboring hair follicle stem cells and keratinocytes through a process called phagocytosis, where dead cells are engulfed and digested. This cleanup is essential for maintaining a healthy hair follicle environment. However, in AA, we believe this process may be disrupted, leading to an unintended immune response. Our study will address two questions: 1. Do hair follicle keratinocytes engulf necroptotic debris? If so, can these keratinocytes present antigens and activate T cells locally in the skin? 2. Is antigen presentation by keratinocytes required to initiate disease? WIth these investigations, we aim to determine how these cellular mechanisms contribute to the initiation of the immune response in AA.

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Use of microneedles for the management of alopecia areata

Year: 2023 PI Name: Natalie Artzi, PhD; Jamil R. Azzi, MD, PhD Award Type: Research Grant Status: In Progress Summary:
Alopecia Areata (AA) is a skin condition where patients experience hair loss due to a dysregulation of the immune system. The only solution to date requires local injection of corticosteroids, which is painful, or the use of immunosuppressants, which cause severe side effects and are associated with high rates of relapse as the hair falls again after treatment. Our group has developed a revolutionary approach to treat this disease by using a novel medical device containing tiny, microscopic needles—a microneedle patch. Given the dimensions of the microneedles, less than a millimeter in length, the patch can be self-administered and is painless. This is particularly important for kids and for patients where disease is manifested in areas that cannot be injected like the eyebrows. The patch can release drug molecules through the skin directly into the bald lesions to restore the balance in the immune system and encourage hair growth.

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Abstract:
Over the past two years, our multidisciplinary team including clinicians and biomedical engineers has focused on the development of revolutionary microneedle platform for the management of AA. In this proposal, we aim to rectify the local Treg deficiency in AA patients, by recruiting and amplifying Treg function, locally at the affected skin lesion, using our novel hydrogel-based microneedle (MN) platform for chemokine/cytokine delivery. Our proposal is built on the foundation of our work published recently (Artzi, Azzi, and colleagues, Advanced Functional Materials, 2021) 12, where we demonstrated that our engineered polymeric microneedle platform supports local delivery of CCL22 and IL-2 to promote Treg homing and expansion for prevention of allograft rejection in murine skin allograft model. The skin offers unique clinical opportunity for direct and easy access to an intricate network of immune cells including Tregs, which we leveraged for targeted transcutaneous-delivery of immunotherapies using MNs. Our MN-platform fabricated with hyaluronic acid (HA), allowed transdermal delivery of immunomodulators for local action in the skin allografts, while obviating systemic side effects in peripheral organs such as the spleen—a commonly observed phenomenon following systemic delivery of immune-suppressive agents. Moreover, our MNs allow sampling of interstitial skin fluid (ISF), a unique biofluid offering diagnostic insights into the perfusion of analytes. The matrix of our MN platform has been engineered to contain disulfide bonds, enabling us to dissolve the needles following retri eval and isolate cellular biomarkers which can be used to report on the disease state. Based on the foundation of this work and its relevance to restoring Treg homeostasis, we have used our MN platform to deliver chemokines and cytokines locally at the AA lesion site to recruit and restore Treg number and function. In an AA murine model, we have demonstrated that our MNs delivering CCL22 (for Treg recruitment), and IL-2 (for Treg proliferation) remodeled the immune profile at the hair follicle level, increasing Treg frequencies and reversing AA symptoms as targeted, sustained hair regrowth was observed in the AA lesions (manuscript submitted). We also demonstrated that the T cell immune profile in ISF when extracted with the MNs correlate with that in the skin. Here, we aim to expand our understanding on the cellular mechanism driving disease recovery and the potential of Treg-centric therapies, as opposed to immunosuppressive agents, for the management of AA. We predict that our technology solution will be able to provide efficacy and durability of the therapeutic effects, due to the unique mechanism of action of our agent combination that addresses the root cause of AA pathogenesis at the local lesion level, and will harbor the required safety profile by virtue of the minimally invasive, painless topical application of our novel polymeric MN-based platform to deliver nanogram level drug doses, eliminating systemic side effects and local pain. By establishing an optimal balance of the benefit/risk profile, a crucial piece missing from the current treatment strategies, in addition to enhancing the quality of life and compliance for the patient, our technology has the potential to be not only a strong contender, but a game -changer in the AA treatment landscape.

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Impact: Using a miconeedle patch, we have demonstrated in a mouse model that the hair can grow back in the affected areas while avoiding side effects and toxicities given the local and targeted nature of the patch. We believe that our platform will empower AA patients with a safer, superior, and easy-to-use treatment solution.

Identification of autoantigen epitopes in alopecia areata by T-Scan

Year: 2023 PI Name: Zhenpeng Dai, PhD Award Type: Research Grant Status: In Progress Summary:
Alopecia areata (AA) is an autoimmune disease that causes hair loss. Immune cells known as T cells recognize hair follicles’ own components (antigen) as foreign and elicit an immune response against hair follicle. We recently identified several alopecic T cell clones in the mouse model of AA. However, the protein that the alopecic T cells recognize in hair follicle remains unknown. T-Scan is a high-throughput method for genomewide identification of antigens recognized by T cells. To figure out what the T cells are recognizing in AA hair follicles, we will use T-Scan to find own protein components recognized by alopecic T cells.

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Abstract:
Alopecia Areata (AA) is one of the most common autoimmune diseases in the US with a lifetime risk of 1.7%. AA causes significant disfigurement and psychological distress to AAaffected individuals. The etiology of AA is still incompletely understood. The T -cell-mediated autoimmune hypothesis with the collapse of hair follicle (HF) immune privilege is most likely and develops under a genetic background [3]. We recently identified CD8+NKG2D+ T cells as the key pathogenic cells in AA [4]. The role of CD8+NKG2D+ T cells in the process of HF destruction has remained enigmatic. We previously used next-generation sequencing of the TCRβ repertoire in the C3H/HeJ mouse model of AA. We observed interindividual sharing of TCRβ chain protein sequences, which strongly supports a model of antigenic drive in AA. However, the relationship between CD8+ T cell clonality and pathogenicity is poorly understood. We leveraged recent advances in single-cell technology and performed parallel single-cell RNA and T cell receptor (TCR) sequencing in the graft-induced C3H/HeJ mouse model of AA to interrogate time-dependent changes in the AA immune landscape with respect to both gene expression profiles and T cell clonality. Using the highly expanded CD8+ TCR sequences identified in our study, we performed TCR retrogenic mice and TCR engineered T cells to demonstrate that expanded CD8+ T cell clones are sufficient and necessary for AA, establishing the causal relationship between CD8+ T cell clonality and pathogenicity in disease. However, in AA, the antigen epitopes recognized by alopecic T cells has remained unknown, mainly due to the lack of genome-scale and high-throughput antigen discovery tools. Previous studies showed that using online matrix-assisted algorithms could predict MHC binding peptide sequences for autoimmune diseases. One limitation of this method is that only a small number of antigens can be discovered. Cell-based screening methods for CD8+ T cells, such as T-Scan, have achieved proteome-wide success in identifying cognate antigens for TCRs from CD8+ cells. T-Scan utilizes the granzyme-mediated cytolytic ability of CD8+ cells toward target cells that express a library of candidate antigens that are processed and presented endogenously on MHC-I molecules as a functional readout. Given the power of T-Scan in finding T cell epitopes, we postulate that T-Scan would facilitate the discovery of HF auto-antigens recognized by alopecic CD8+ T cells. Successful identification of antigen epitopes in the AA mouse model will provide knowledge to find antigen epitopes in human AA and will enable the development of specific therapeutic modalities targeting antigen - specific T cells.

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Impact: Discovery of specific antigens recognized by alopecic T cells will help us to unravel the mechanisms underlying AA development as well as discovery of new therapeutic avenues

The genetics of alopecia areata: Integration of population studies and clinical data

Year: 2023 PI Name: Michal Linial, PhD Award Type: Research Grant Status: In Progress Summary:
Alopecia Areata (AA) is a rare autoimmune disorder that causes hair loss, typically in small, round patches on the scalp. While the exact cause of AA is not fully understood, genetics is believed to play a significant role in its development. AA tends to run in families, with a higher risk within family members with an affected individual. This research goal is to advance the genetic basis by focusing on the genetic signatures that dictate the AA risk score for individuals. We intend to address the genetics of AA by benefiting from the whole genome and full exomes from the UK Biobank (UKB). In the UKB there are approximately 800 participants with clinical manifestations of AA. With the detailed genome, we intend to: (i) identify significant candidate genes; (ii) seek rare variants that contribute to AA. (ii) Creating a polygenic risk score that focuses on the Chr. 6 MHC-extended loci. (iii) identifying sex-dependent genetic signals; (iv) using time-sensitive comorbidity analysis for the risk hazard for patient stratification. The project aims to compile variants, identify associated genes, infer functionality, and examine sex and age-dependent comorbidity.

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Abstract:
Alopecia areata (AA) is an autoimmune disorder characterized by hair loss in round patches on the scalp. The severity and extent of hair loss vary widely among individuals, and environmental factors (stress episodes, vitamin supply, diet) may affect the severity and flare of the disease. Emotional distress and a reduced quality of life are common consequences. AA is affecting approximately 1:500 to 1:1000 of the global population (McDonagh and Tazi-Ahnini, 2002). AA has a more severe manifestation with complete hair loss that is rare and will not be further discussed. Importantly, AA is not limited to a specific age group, gender, or ethnic background. It often begins in childhood or early adulthood, with females being more susceptible to the severe forms of the condition (Betz et al., 2015; Duvic et al., 2001; Green and Sinclair, 2000). The cause of AA is when immune cells (like T cells) mistakenly attack hair follicles. Like most autoimmune diseases, family history of AA is a risk factor that suggests a genetic component in the development of AA. Individuals with AA may have an increased risk of developing other autoimmune conditions, including thyroid disorders, vitiligo, and atopic dermatitis. Still, the exact triggers and mechanisms behind the dysregulation of the immune response are an enigma (Petukhova et al., 2011; Silverberg, 2022; Sundberg and King, 2003). This research project aims to investigate the genetic factors associated with AA by utilizing stateof-the-art gene-based approaches in the UK biobank dataset (UKB) (Karczewski et al., 2022). The study focuses on identifying genetic signals specific to AA diagnoses and the 5- to 10-fold larger cohort from self-reported data. By analyzing the genetic data of European-origin participants, we aim to identify candidate genes that are significantly associated with AA and explore their potential implications in disease management. One unique aspect of this research is the emphasis on coding genes, which, although they make up only a small percentage of the genome, offer greater interpretability in terms of gene function, pathways, biological relevance, and potential therapeutic targets. By focusing on coding genes, and specifically on the HLA loci, the study aims to provide clearer insights into the genetic mechanisms underlying AA. Comorbidity and gender differences will also be considered in the analysis. By examining the genetic data in relation to comorbidities and considering gender-specific effects, we aim to gain a more comprehensive understanding of the genetic underpinnings of AA. The study will employ complementary association tests in all GWAS, coding-GWAS, SKAT, PWAS, and knowledge-based focused signaling domains (Brandes et al., 2020; Zucker et al., 2023a; Zucker et al., 2023b). These tests will empower the genetic investigation of AA by identifying associated variants and genes. Additionally, the research project aims to infer functional implications from the identified genes and examine age-dependent comorbidities associated with AA. Our preliminary analyses already highlight the power of complementary approaches that benefit from clinical knowledge (Zucker et al., 2023a; Zucker et al., 2023b). The expected outcome of this research is to enhance our understanding of the genetic factors contributing to AA. By identifying candidate genes and potential therapeutic targets, the study aims to improve disease management and the well-being of individuals. The project also incorporates novel aspects, of focusing on the overlooked recessive inheritance and using complementary methods to extract biological relevance. Overall, this research project combines advanced genetic analysis techniques, extensive data resources, and a focus on clinical-genetics applications to shed light on the genetic basis of AA and provide insights that can lead to improved treatments, management strategies for individuals with this condition, and suggested targets for focused therapy.

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Impact: The novelty in our research stems from the integrative approach that focuses on coding gene knowledge, addressing the overlooked recessive inheritance in AA genetics, and using knowledge-based methods to provide a fresh view of this chronic disease that impacts individuals' quality of life from first occurrence through life. The research aims to enhance understanding, identify therapeutic targets, and improve disease management for the benefit of AA patients.

Elucidating psychological well-being and access to support in families of children with alopecia areata patients in underserved Mississippi communities

Year: 2023 PI Name: Thy Huynh, MD, FAAD; Vinayak K. Nahar, MD, PhD, MS Award Type: Pediatric AA Challenge Grant; cofunded with PeDRA Status: In Progress Summary:
Alopecia Areata (AA) is a common autoimmune disorder causing hair loss, affecting about 2% of the population, often starting in childhood. Managing AA is tough, with treatments having side effects and the condition often coming back. AA not only affects physical appearance but also mental health, leading to anxiety and depression. Parents of children with AA also go through emotional stress, trying to find the right treatments and seeing their child struggle. Unfortunately, many people with AA, especially in underserved areas, don't get the mental health help they need. Our study will look at how parents in underserved Mississippi communities cope with the emotional impact of AA. We'll ask parents about their experiences and analyze the data to understand how they seek mental health support. By doing this, we hope to find ways to better support families dealing with AA in underserved areas, improving their overall well-being.

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Abstract:
Alopecia Areata (AA), a common autoimmune disease causing hair loss, affects about 2% of the population, with childhood onset being prevalent. Managing AA is challenging, with immunosuppressive treatments often accompanied by side effects and relapses. AA carries a substantial psychological burden, with common psychological comorbidities such as anxiety and depression significantly impacting the health-related quality of life for individuals living with AA. Parents of children with AA also experience emotional distress, navigating treatment options and witnessing their child's struggles. Unfortunately, many AA patients, especially in underserved communities, do not seek mental health services, exacerbating disparities in mental healthcare access. This study employs Andersen's behavioral model to investigate the psychological health and mental health help-seeking behaviors of parents in underserved Mississippi communities. The primary study objectives encompass evaluating the Quality of Life for Children with AA, assessing the Quality of Life for Parents of Children with AA, and investigating the Mental Health Help-Seeking Behaviors among Parents of Children with AA. To achieve these objectives, statistical analyses including ANOVA, chi-square tests, and regression analysis will be employed, seeking to uncover disparities in psychological health and help-seeking patterns.

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Impact: This research aims to illuminate the pivotal factors influencing the mental well-being of families grappling with AA in underserved communities. These findings will pave the way for targeted interventions and support systems, addressing a critical gap in the provision of holistic care for AA.

High dimensional characterization of the systemic immune profile of pediatric alopecia areata

Year: 2022 PI Name: Benjamin Ungar, MD; Daniel Lozano-Ojalvo, PhD Award Type: Pediatric AA Challenge Grant Status: Completed Summary:
Alopecia areata (AA) is a common cause of non-scarring hair loss that affects around 2% of people worldwide. AA is known to be generally caused by the immune system attacking hair follicles, but many details of this process remain unknown. A few studies have suggested that the inflammation in AA is not restricted to the skin but involves systemic immune responses with measurable inflammatory markers in peripheral blood. However, the number of studies is limited and they have just evaluated AA adult patients. The objective of our proposal is to characterize the immune cell profile and circulating inflammatory biomarkers in blood from pediatric AA patients.

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Abstract:
Alopecia areata (AA) is an immune cell-mediated disease characterized by non-scarring hair loss with a 2.1% lifetime risk. The pathogenesis of AA remains incompletely understood, but a key role for T cells damaging the hair follicle is well-established. Recent studies have also demonstrated that AA is not skin-limited; AA is characterized by activated CD4+ and CD8+ T cell subsets in peripheral blood, with corresponding inflammatory biomarkers substantially elevated in serum samples. However, this evidence is restricted to T cell responses in adult AA patients without characterization of other immune cell components and data in pediatric AA subjects are lacking. Our goal, therefore, is to high-dimensionally describe systemic immune pathways involved in pediatric AA by characterizing peripheral innate and adaptive immune populations and their associated biomarkers. We plan to collect blood samples from pediatric subjects (12-18 years) with AA (n=30) and healthy controls (n=30). Phenotypical and functional characteristics of circulating immune cells will be established by spectral flow cytometry (~60 markers). Serum samples will be analyzed using Olink platform for the analysis of ~500 analytes. Circulating biomarkers will be evaluated and correlated with immune cell subsets and clinical severity (Severity of Alopecia Tool, SALT, scores). This proposal will expand our mechanistic understanding of pediatric AA, identifying potential therapeutic targets and paving the way for disease-modifying treatments.

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Impact: Improved understanding of the nuances of the systemic inflammatory process in alopecia areata is important to inform how current treatments should be applied as well as to identify new potential treatments.

Alopecia & Us: Studying the impact of alopecia areata to adolescents and the family

Year: 2022 PI Name: Chantal Cotter, MD Award Type: Pediatric AA Challenge Grant (cofunded with PeDRA) Status: In Progress Summary:
Alopecia areata (AA) is one of the most common hair loss disorders characterized by loss of hair in round patches, usually on the scalp. The exact cause of AA is unknown, but it seems to be caused by the immune system attacking the hair follicles by mistake. Having AA can have impact on a child’s sense of well-being and increase their risk of mental health disorders including depression, anxiety, and OCD. Further, there may an impact on the family’s quality of life. Understanding this burden is paramount to ensuring we understand the full effect AA has on a child. We will do this via an online questionnaire which patients (aged 12-18) and their families can complete at home, anytime, anywhere in the world and in any language. Only through awareness of the full impact of this disease we will be able to advocate for access to treatments but also campaign for recognition and support of mental health in this group.

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Abstract:
Patients with alopecia areata (AA) in the adolescent population have consistently demonstrated poor health related quality of life measures with disease severity and increasing age correlating with poorer quality-of-life scores. In addition, there is research to suggest that there is a high prevalence of psychosocial comorbidities in adolescent patients suffering from AA. We hope to establish a research platform for adolescent patients with AA allowing the phenotypic and in-depth, crosssectional epidemiological studying of the illness. We will also study mental wellbeing, including psychosocial comorbidities, disease perception and stigma. Further we will examine the effect of childhood AA on the family and capture the sequalae of disease on family life. We aim to recruit 1000 patients worldwide in this observational study. Adolescents and their parents will have the opportunity to participate through a self-reporting online platform. Patients will complete several concise e-questionnaire-based metrics, including the Children’s Dermatology Life Quality Index, the Pediatric Index of Emotional Distress, the Family Reported Outcome Measure, the Family Dermatology Life Quality Index and EQ-5DY. This study will enable future research into therapeutic responsiveness by linking treatment effectiveness with research into predictive parameters such as the psychological and socioeconomic status of the adolescent patient and family. Further we hope to highlight the importance of the psychological impact of AA in adolescents and their families prompting a more holistic approach of such patients.

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IL-15 as a Candidate Key Cytokine in Alopecia Areata Pathobiology

Year: 2020 PI Name: Ralf Paus, MD Award Type: Research Grant Status: Completed Summary:
The purpose of this project is to test the hypothesis that blockade of interleukin-15 (IL-15) or IL-15 receptor-alpha can provide therapeutic benefit in alopecia areata.

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Abstract:
Effective alopecia areata (AA) treatment requires selective targeting of the key pathomechanisms to combine optimal, long-lasting therapy outcomes with reduced adverse effects. Recent research has suggested that the multi-function cytokine, interleukin-15 (IL-15), is important in AA pathobiology. Yet, convincing evidence for this remains to be generated in the human system. Specifically, since collapse of the hair follicle’s (HF) physiological immune privilege (IP) is an essential prerequisite for AA lesions to develop while HF-IP restoration is required for hair regrowth, it is critical to clarify the impact of IL-15 on human HF-IP - either directly, or indirectly. Here, we propose to do this by asking (in optimally suited, perfectly complementary human ex vivo and in vivo assay systems, i.e. AA patient skin biopsies, scalp HF organ culture and the humanized AA mouse model) whether: a) IL-15 and/or IL-15 receptor-alpha expression in/around lesional and non-lesional AA HFs is abnormal compared to healthy human scalp skin; b) IL-15 alone induces and/or enhances IFNγ-induced human HF-IP collapse; c) selectively antagonizing IL-15 receptor-alpha mediated signaling prevents experimentally induced HF-IP collapse and/or even restores HF-IP and promotes human hair regrowth in vivo; d) IL-15 promotes IFNγ secretion by pathogenic T/NK cells and/or promotes pathological perifollicular mast cell/T cell interactions in vivo. These clinically highly relevant studies will clarify whether IL-15 signaling really deserves selective targeting in future AA management, which adverse HF effects this could exert, and whether there is subgroup of AA patients who likely will benefit most from this.

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Impact: If successful, this study could provide new insights into the mechanism of alopecia areata pathogenesis mediated by IL-15 with important implications for future therapeutic intervention.