Lifestyle Factors Involved in the Pathogenesis of Alopecia Areata.

Alopecia areata is a representative inflammatory skin disease that is associated with various environmental stimuli. While psychological stress is believed to be a major pathogenetic trigger in alopecia areata, infants and newborns also suffer from the disease, suggesting the possible presence of other environmental factors. Daily lifestyle is well known to be involved in various inflammatory diseases and influences the severity of inflammatory skin diseases. However, only a limited number of studies have summarized these influences on alopecia areata. In this review article, we summarize lifestyle factor-related influences on the pathogenesis of alopecia areata and focus on environmental factors, such as smoking, alcohol consumption, sleep, obesity, fatty acids, and gluten consumption.

The Role of Serum Th1, Th2, and Th17 Cytokines in Patients with Alopecia Areata: Clinical Implications.

Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-ß) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.

Altered T cell subpopulations and serum anti-TYRP2 and tyrosinase antibodies in the acute and chronic phase of alopecia areata in the C3H/HeJ mouse model.

BACKGROUND: C3H/HeJ mouse models progress gradually in hair loss from acute to chronic phase and reflect the symptoms of patients with alopecia areata (AA). However, the underlying pathological characteristics alteration associated with disease progression and autoantigens remain unclear. OBJECTIVE: We aimed at elucidating the pathological differences between acute and chronic-AA in the C3H/HeJ mouse model. METHODS: We analyzed populations of PBMCs, skin-draining lymph node (SDLN) cells, and cutaneous cells of AA mice using flow cytometry. The cytokine and chemokine expressions in the serum and skin were determined using multiplex assay and qPCR. The antibody serum levels were determined using ELISA and the antigen-specific T cells were detected using the MHC class I tetramer. RESULTS: The CD8+NKG2D+ T and CD8+ TEM cell percentage in the chronic-AA SDLNs or among the unaffected and acute-AA mice PBMCs increased. The Th1 and CD4+ TEM cell percentage in the SDLNs and among PBMCs increased in the unaffected and AA mice. The percentage of CD8+ TEM/TRM cells and MHC class I expression increased in the lesions of acute-AA or the non-lesions and lesions of chronic-AA. The Th1 cells, dendritic cell-related cytokines, CD11c+ cells and MHC class II expression increased in the skin of AA mice. The antibody levels and TYRP2 and tyrosinase-specific CD8+ T cell percentages were upregulated in AA mice. CONCLUSION: These results suggest that the CD8+ and CD4+ T cell subpopulations, cytokine and chemokine expressions differ between the disease phases. Moreover, TYRP2 and tyrosinase are potential autoreactive targets in the AA mouse model.

Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle.

Murine γδT-cells have stress-surveillance functions and are implicated in autoimmunity. Yet, whether human γδT-cells are also stress sentinels and directly promote autoimmune responses in the skin is unknown. Using a novel (mini-)organ assay, we tested if human dermis resident γδT-cells can recognize stressed human scalp hair follicles (HFs) to promote an alopecia areata (AA)-like autoimmune response. Accordingly, we show that γδT-cells from healthy human scalp skin are activated (CD69+), up-regulate the expression of NKG2D and IFN-γ, and become cytotoxic when co-cultured with autologous stressed HFs ex vivo. These autologous γδT-cells induce HF immune privilege collapse, dystrophy, and premature catagen, i.e. three hallmarks of the human autoimmune HF disorder, AA. This is mediated by CXCL12, MICA, and in part by IFN-γ and CD1d. In conclusion, human dermal γδT-cells exert physiological stress-sentinel functions in human skin, where their excessive activity can promote autoimmunity towards stressed HFs that overexpress CD1d, CXCL12, and/or MICA.

T-Cell-Driven Fibroinflammation Inducing Follicular Dedifferentiation in Alopecia Areata and IgG4-Modified Disease.

ABSTRACT: The definition of IgG4-related diseases incorporates a broad range of systemic diseases particularly a subset dominated by fibroinflammation. CD4+cytotoxic T cells have emerged as the major driving force for the fibroinflammation, and the pathogenetic role of IgG4 still remains to be determined. Cutaneous involvement is uncommon and is not well defined as elevated tissue IgG4 plasma cells are not a specific marker and prominent cutaneous fibroinflammation is often absent in cutaneous disease. We report the case of a patient with longstanding alopecia universalis and severe atopic dermatitis who presented with diffuse induration and mottled dyspigmentation of his scalp. Multiple scalp biopsies revealed diffuse interfollicular fibroinflammation and IgG4 plasma cells with induction of distinctive dedifferentiated follicles not seen in alopecia areata. This complex case may provide insight into the role of specific subsets of T cells not only in respect to the fibroinflammation linked to IgG4-related diseases but also the capacity to modify disease, follicular stem cell activation, immune privilege, cytotoxicity in alopecia areata, and the presence of atopy that may have contributed to the pathogenesis of this case.

Alopecia y microbioma: ¿futura diana terapéutica? / Alopecia and the Microbiome: A Future Therapeutic Target?

El microbioma incluye microorganismos como virus, bacterias y hongos. Se ha evidenciado que el cuero cabelludo tiene su propio microbioma dado por factores únicos como la humedad, la protección de luz ultravioleta y el pH; adicionalmente hay diferencias entre distintas áreas corporales, etnias y sexos. Existen pocas publicaciones o datos sobre el microbioma folicular y se ha denotado el rol de la microbiota en la patogénesis de varias enfermedades, siendo un área de investigación emergente. Algunos estudios demuestran la influencia de esta composición en enfermedades capilares como la alopecia areata y la alopecia androgenética. Finalmente, se ha postulado que la manipulación del microbioma puede representar una opción terapéutica innovadora para muchas enfermedades (AU)

The human microbiome includes viruses, bacteria, and fungi. There is evidence that in addition to microbiome variation in different areas of the body or according to ethnicity and sex, the microbiome specific to the scalp is conditioned by such factors as humidity, protection from UV light, and pH. Although little information has yet been published about the microbiome of hair follicles and its role in the pathogenesis of diseases, interest in this area of research is emerging. Studies have shown that components of the follicular microbiome influence such disorders as androgenetic alopecia and alopecia areata. A current hypothesis is that interventions that target the microbiome may lead to innovative therapies for many diseases (AU)

Induction of alopecia areata in C3H/HeJ mice using cryopreserved lymphocytes.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease resulting in non-scarring hair loss. Animal models are useful means to identify candidates for therapeutic agents. The C3H/HeJ mouse AA model induced via transferring cultured lymphoid cells isolated from AA-affected mice is widely used for AA research. However, this conventional method requires the continuous breeding of AA mice. OBJECTIVE: We aimed to establish a new method to generate AA model using the transfer of cryopreserved cells, which allows the rapid induction of a large number of AA mice when needed. METHODS: We cryopreserved lymph node cells soon after isolation from AA-affected mice and injected thawed-cultured cells into recipient mice. H&E staining, immunohistochemical staining, quantitative real-time PCR and ELISA were conducted to identify pathological characteristics. Flow cytometry was performed to reveal the profile of transferred cells. RESULTS: More than 90 % of recipient mice developed AA-like hair loss and showed inflammatory cell infiltration around anagen hair follicles, markedly increased mRNA expressions of interferon-γ, CXCL11, and granzyme B, and elevated interferon-α protein levels in the skin compared with naïve mice. Higher percentages of effector memory T cells and dendritic cells in transferred cells resulted in a higher incidence of AA. CONCLUSION: This is the first report to establish a method for generating AA mice using cryopreserved lymphocytes. These AA mice have similar pathological characteristics to AA mice generated with the conventional method and AA patients. This convenient and reproducible method is expected to be valuable for AA study.

Gut microbiota characterization in Chinese patients with alopecia areata.

BACKGROUND: The gut microbiota is known to play a key role in autoimmune diseases. OBJECTIVES: To identify and compare the characteristics in the gut microbial composition of patients with alopecia areata (AA) and healthy controls (HCs). METHODS: In a cross-sectional discovery cohort, we enrolled 33 patients with AA and 35 HCs from the same geographic location in Shanghai, China. The 16S rRNA gene sequencing and bioinformatic analyses were conducted to analyze DNA extracted from the subjects. RESULTS: The α-diversity of the AA group demonstrated no statistically significant differences compared with the HC group (P > 0.05). However, the overall gut microbial communities in the AA group were distinct from the HCs (P = 0.0096). We also adopted a random forest model to select three AA-associated OTU biomarkers: OTU1237(Achromobacter), OTU257(Megasphaera), and OTU1784(Lachnospiraceae Incertae Sedis). CONCLUSION: The overall gut microbial composition for AA was distinct from that of HCs. The gut microbial markers we identified may potentially be used for earlier diagnosis and as therapeutic targets.

Immunological Properties of Atopic Dermatitis-Associated Alopecia Areata.

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.

CCL13 is upregulated in alopecia areata lesions and is correlated with disease severity.

Alopecia areata (AA) is a multi-factors disease characterized by non-scarring hair loss. AA could be classified into three main clinical phenotypes including patchy type AA (AAP), alopecia totalis (AT) and alopecia universalis (AU) based on the severity and areas of hair loss. Recent studies suggested immunological factor was critical in AA, but the precise aetiology and pathogenesis of AA still need exploration. In the work, we screened two gene expression profiles (GSE45512 and GSE68801) from Gene Expression Omnibus (GEO). Based on the two data sets, 10 upregulated genes and 107 downregulated genes in AA skin biopsies were identified. CCL13, as one of the remarkably upregulated genes, was found to have potential biological functions in aberrant immune response of AA according to the GO and KEGG analyses. The PPI network showed CCL13 was associated with multiple immune-related genes. The expression of CCL13 was increased depending on the severity of disease in AA patients. Cytotoxic lymphocytes, T cells and myeloid dendritic cells accumulated remarkably in scalp tissue depending on the severity of AA, and CCL13 was significantly correlated to cytotoxic lymphocytes, T cells and myeloid dendritic cells in AA patients. Our RT-PCR and ELISA results found CCL13 was upregulated in skin biopsy and serum of AA patients, and the immunohistochemistry (IHC) detection showed CCL13 was expressed by both the hair follicle epithelium and infiltrating immune cells. In conclusion, the upregulated of CCL13 and subsequent immune cell infiltration was related to AA, which could be a promising target for diagnosis and therapy in AA patients.

Alopecia areata: a review on diagnosis, immunological etiopathogenesis and treatment options.

Patients suffering from alopecia areata (AA) can lose hair in focal regions, the complete scalp, including eyelashes and eyebrows, or even the entire body. The exact pathology is not yet known, but the most described theory is a collapse of the immune privilege system, which can be found in some specific regions of the body. Different treatment options, local and systemic, are available, but none of them have been proven to be effective in the long term as well for every treatment there should be considered for the possible side effects. In many cases, treated or non-treated, relapse often occurs. The prognosis is uncertain and is negatively influenced by the subtypes alopecia totalis and alopecia universalis and characteristics such as associated nail lesions, hair loss for more than 10 years and a positive familial history. The unpredictable course of the disease also makes it a mental struggle and AA patients are more often associated with depression and anxiety compared to the healthy population. Research into immunology and genetics, more particularly in the field of dendritic cells (DC), is recommended for AA as there is evidence of the possible role of DC in the treatment of other autoimmune diseases such as multiple Sclerosis and cancer. Promising therapies for the future treatment of AA are JAK-STAT inhibitors and PRP.

Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.

BACKGROUND: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile. OBJECTIVE: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity. METHODS: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49). RESULTS: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy. LIMITATIONS: Our analysis was limited to 350 proteins. CONCLUSION: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.

Bidirectional association between alopecia areata and thyroid diseases: a nationwide population-based cohort study.

Alopecia areata (AA) has long been associated with thyroid diseases; however, the temporality of their association remains unclear. This study aimed to investigate the bidirectional association between AA and thyroid diseases. In analysis 1, we included 5929 AA patients and 59,290 matched controls to assess the risk of thyroid diseases. In analysis 2, we included 35,071 patients with thyrotoxicosis, 19,227 patients with Graves' disease, 5460 patients with thyroiditis, 3352 patients with Hashimoto's thyroiditis, and their matched controls (1:10) to assess the risk of AA. Incidence of thyroid diseases and AA were the outcomes in analysis 1 and analysis 2, respectively. After adjusting the potential confounders, AA patients had an increased risk of all thyroid diseases, including toxic nodular goiter, (aHR 10.17; 95% confidence interval [CI] 5.32-19.44), nontoxic nodular goiter (aHR 5.23; 95% CI 3.76-7.28), thyrotoxicosis (aHR 7.96; 95% CI 6.01-10.54), Graves' disease (aHR 8.36; 95% CI 5.66-12.35), thyroiditis (aHR 4.04; 95% CI 2.12-7.73), and Hashimoto thyroiditis (aHR 4.35; 95% CI 1.88-10.04). On the contrary, a significantly increased risk of developing AA was observed among patients with thyrotoxicosis (aHR 9.29; 95% CI, 7.11-12.14), Graves' disease (aHR 8.66; 95% CI 6.03-12.42), and thyroiditis (aHR 6.42; 95% CI 3.15-13.11) but not in patients with Hashimoto's thyroiditis. In conclusion, our study found a bidirectional association between AA and thyroid diseases, suggesting shared biological mechanisms underlying these two diseases.

Pediatric Alopecia Areata.

BACKGROUND: Alopecia areata (AA) is a non-scarring hair loss disorder of autoimmune etiology. OBJECTIVE: To familiarize physicians with the clinical presentation, diagnosis, evaluation, and management of pediatric alopecia areata. METHODS: The search term "Alopecia areata" was entered into a Pubmed search. A narrow scope was applied to the categories of "epidemiology", "clinical diagnosis", "investigations", "comorbidities", and "treatment". Meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews were included. Only papers published in the English language were included. A descriptive, narrative synthesis was provided of the retrieved articles. RESULTS: AA is an autoimmune disease of unknown etiology. It is the third most common dermatologic presentation in children with a lifetime risk of 1-2%. Diagnosing AA can be made on the basis of the history and clinical findings. Patients will often present with patchy, non-scarring hair loss, generally affecting the scalp. History may reveal a personal or family medical history of autoimmune or atopic disease or a recent stressful event. Tricoscopic examination will classically show "exclamation point hairs" and "yellow dots". Nonspecific nail changes may be present. Other clinical variants include alopecia totalis, alopecia universalis, ophiasis, sisaipho, and Canitis subita. There are multiple treatment options for AA, including conservative treatment, and topical, oral, and injectable medications. CONCLUSION: AA is an autoimmune disease with a heterogeneous presentation and unpredictable clinical course. Although there is no cure for AA, there are many current treatment options available to help manage this disfiguring disease.