Pathogenesis Of Alopecia Areata Research Articles

An overview of JAK/STAT pathways and JAK inhibition in alopecia areata.

Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.

Baricitinib Attenuates IFN-γ and Polyinosinic:polycytidylic Acid‒Induced Mitochondrial Damage and Inflammasome Activation in Human Keratinocytes

Alopecia areata (AA) is a common hair loss condition characterized by the acute onset of nonscarring hair loss (Shin et al., 2019). GWAS data have found several susceptibility loci involved in autoimmunity that have crucial roles in T-cell‒mediated pathways in AA pathogenesis (Betz et al., 2015; Petukhova et al., 2010). Especially, CD8+NKG2D+ T cells around the affected hair follicles contribute to the progression of inflammation, and the JAK‒signal transducer and activator of transcription (STAT) pathway plays an important role in mediating the CD8+NKG2D+T cell reaction.

Evaluation of antioxidant and oxidant status, including levels of Malondialdehyde (MDA) and Superoxide Dismutase (SOD), in the Indian population with alopecia areata

Abstract: Hair loss is caused by alopecia areata (AA), which is a non-scarring inflammatory and autoimmune disorder. The aetio pathogenesis of alopecia areata is uncertain, however autoimmune, genetic predisposition, emotional, and environmental stress are all thought to have a role in its development. Antioxidant/oxidant balance disruption is a common sign of autoimmune, psychological, and environmental stress. As a result, our research looks at the effects of oxidative stress in alopecia areata. Materials and Methods: This was observational prospective study, The present study included 150 A.A patients(cases) and 150 controls attended to Department of Dermatology in collaboration with Department of Biochemistry, LN Medical College and Research center & J.K Hospital, Bhopal. The levels of Iron and Ferritin was estimated by colorimetric Method Results: A total of 300(150 cases of AA +150 controls were included SOD & MDA with mean+ SD are given in the Table no.1. The two groups were comparable (P<0.0001), (P<0.0001). The difference in the values SOD and MDA parameters in respect of these groups was highly statistically significant (P<0.0001*).

063 CD4 T cells exhibit an effector phenotype and transfer disease in murine alopecia areata

Alopecia Areata (AA) is a common autoimmune disease characterized by T cell infiltration of the hair follicle, resulting in nonscarring hair loss. Although CD4 T cells comprise the majority of the infiltrate, little is known about their contribution to disease pathogenesis. Previously we have identified an increased number of IFN-γ producing CD4+ T cells in the skin-draining lymph nodes (SDLN) as compared to unaffected (UA) controls. The objective for this study was to determine the role that CD4 T cells play in the pathogenesis of AA.

064 Functional interrogation of lymphocyte subsets in alopecia areata using single-cell RNA sequencing

Alopecia areata (AA) is one of the most prevalent autoimmune diseases, yet the development of innovative therapeutic strategies has been hampered by an incomplete understanding of disease pathogenesis, such as the complex immunological mechanisms that underlie AA pathogenesis. Here, we performed single-cell RNA sequencing (scRNAseq) of skin-infiltrating immune cells from the well-established graft-induced C3H/HeJ mouse model of AA, together with antibody-based depletion experiments to systematically interrogate the role of specific immune cell types in disease pathophysiology in vivo.

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.

Role of Substance P in Regulating Micro-Milieu of Inflammation in Alopecia Areata.

BackgroundAlopecia areata (AA) is an autoimmune disease characterized by chronic inflammation, the pathogenesis of which is unknown. Stress is believed to play a role; however, evidence remains insufficient. A recent study showed that substance P (SP) damaged hair follicles by causing neurogenic inflammation, activating perifollicular mast cells, and inducing keratinocyte apoptosis.ObjectiveWe aimed at studying the role of SP in AA pathogenesis. We investigated the SP levels in the lesional scalp tissues and serum. We also studied the effect of SP on the inflammatory response and hair growth in the outer root sheath (ORS) cells.MethodsWe compared the serum levels of SP in 58 AA patients and 28 healthy subjects. Then, we checked the expression of SP and SP receptor, neurokinin-1 receptor (NK-1R) in the scalps of AA patients and healthy controls using immunohistochemical staining. Finally, we analyzed the mRNA expression of inflammatory cytokines and hair growth-related factors in ORS cells.ResultsSP and NK-1R expression were markedly higher in the hair follicles and interfollicular epidermis of the scalp lesions of AA patients. However, there was no statistically significant difference in serum SP levels between controls and patients, regardless of the type of alopecia. SP significantly increased the mRNA expression of inflammatory cytokines and decreased hair growth-related growth factors in ORS cells, but the results were not dramatic.ConclusionSP triggered a localized micro-inflammation in lesional hair follicles, provoked an inflammatory response, and inhibited hair growth, thereby confirming the pathogenic role of SP in AA.

Gut microbiota in alopecia areata.

In the past few years, the advancement of 16S rRNA metagenomic analysis sequencing has enabled assessing the impact of gut microbiota on the development of skin disease. Alopecia areata (AA) is a nonscarring hair loss disorder with an unknown etiopathogenesis, however, it is hypothesised that a combination of genetic and environmental factors might be involved. Although numerous studies have shown that the microbiome plays a key role at the beginning of skin diseases, the link between AA and gut dysbiosis remains unclear. To analyse the intestinal microbiome in patients suffering from AA. The study describes the conceivable involvement of gut microbiota in the unclear pathogenesis of AA. We enrolled 25 patients, over 18 years of age with an active state of AA who donated their stool samples. The samples were examined at the human gut microbial community at the species level by metataxonomic analysis of the full-length 16S V3-V4 sequencing. The four major genera that constitute the microbiome's core are Lachnoclostridium, Bifidobacterium, Streptococcus, and Eubacterium, as well as three major phyla: Firmicutes, Proteobacteria, and Actinobacteria. Firmicutes and Proteobacteria are overrepresented in the microflora, which might suggest a disturbed microflora. Furthermore, the composition of bacterial communities suggests a loss of overall richness and a decrease in taxonomic diversity across all samples. This study describes, for the first time, the characteristics of the gut microbiome in AA patients and may provide new insight into the gut microbiome that may play a role in the development of AA.

Oral tofacitinib for the treatment of alopecia areata in pediatric patients.

Alopecia areata (AA) is characterized by the loss of hair, often in well-demarcated areas. While the pathogenesis of AA is not entirely understood, it is known that CD8 T cell-mediated destruction of the hair follicle occurs. There are no curative therapies for AA, although several therapies have been utilized with variable results. Oral tofacitinib, a JAK inhibitor, has been demonstrated to be efficacious and well tolerated in the treatment of adult AA. However, few studies have examined the clinical efficacy and tolerability of oral tofacitinib in the treatment of pediatric AA. To summarize the clinical outcomes of pediatric patients with AA treated with oral tofacitinib at the University of Colorado Hospital Dermatology Clinic. This is a retrospective case series conducted at the University of Colorado Hospital Dermatology Clinic. We included patients with a diagnosis of AA who were 18years old or younger at the initiation of tofacitinib therapy. Demographics, treatment response, and adverse events were collected from electronic medical records. Eleven patients (seven females, four males) with AA presented to the University of Colorado Hospital Dermatology Clinic who were between the ages of 8 and 18years. Eight patients (72.7%) experienced hair regrowth with oral tofacitinib, while three patients (27.3%) experienced minimal to no hair regrowth. There were no serious adverse events recorded in the study population during the observed treatment period. Oral tofacitinib was clinically effective in the majority our of patients and well tolerated.

Evaluation of serum levels of IL-6, IL-10, and TNF-a in alopecia areata patients: A systematic review and meta-analysis

Background: The role of pro and anti-inflammatory cytokines in autoimmune and inflammatory disorders has always been discussed; several studies have assayed serum levels of Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), and Interleukin-10 (IL-10) in alopecia areata (AA) patients. Determining the cytokine profile of AA patients will help us understand the role of the immune system in the pathogenesis of AA. Due to a lack of comprehensive studies in this regard, we have performed this meta-analysis to evaluate previously mentioned cytokines in AA patients. Methods: We explored PubMed, Scopus, web of science, and ScienceDirect databases for research without a limited start date until May 2021. A number of 1098 studies were found in the initial database search and reference lists of relevant studies; 16 studies were finally included in the meta-analysis. Differences in the levels of IL-6, TNF-α, and IL-10 in sera of controls and patients were pooled as standardized mean differences. A random-effects model was used in this study. Begg's and Egger's tests were carried out to investigate publication bias. Results: 16 studies were included. This study found significantly elevated levels of IL-6 in AA patients compared to healthy subjects (SMD = 1.57, 95% CI 0.17 to 2.97). The levels of TNF-α were also significantly higher in the serum of AA patients (SMD = 2.05, 95% CI 0.98 to 3.13). Though IL-10 levels were lower in serum of AA patients, this difference was not significant (SMD = -0.22, 95% CI -0.95 to 0.50). Conclusion: According to the crucial role of cytokines in autoimmunity, alternation in the serum levels of cytokines in AA patients was not unexpected; our study shows that cytokines might have an essential role in the pathogenesis of AA, though further studies are needed to clarify the exact role of cytokines in the emergence and persistence of AA.

Alopecia areata: Current understanding of the pathophysiology and update on therapeutic approaches, featuring the Japanese Dermatological Association guidelines.

Alopecia areata (AA) is a relatively common nonscarring hairloss disease characterized by an autoimmune response to anagen hair follicles (HFs). Accumulated evidence suggests that collapse of the HF immune privilege subsequent to triggering events, represented by viral infection, leads to autoimmune response in which autoreactive cytotoxic CD8+NKG2D+ T cells mainly target exposed HF autoantigens. AA had been recognized as type 1 inflammatory disease, but recent investigations have suggested some roles of type 2- and Th17-associated mediators in AA pathogenesis. The significance of psychological stress in AA pathogenesis is less emphasized nowadays, but psychological comorbidities, such as depression and anxiety, attract greater interest in AA management. In this regard, the disease severity may not solely be evaluated by the extent of hair loss. Use of trichoscopy markedly improved the resolution of the diagnosis and evaluation of the phase of AA, which is indispensable for the optimization of treatment. For the standardization of AA management, the establishment of guidelines/expert consensus is pivotal. Indeed, the Japanese Dermatological Association (JDA) and other societies and expert groups have published guidelines/expert consensus reports, which mostly recommend intralesional/topical corticosteroid administration and contact immunotherapy as first-line treatments, depending on the age, disease severity, and activity of AA. The uniqueness of the JDA guidelines can be found in their descriptions of intravenous corticosteroid pulse therapy, antihistamines, and other miscellaneous domestically conducted treatments. Considering the relatively high incidence of spontaneous regression in mild AA and its intractability in severe subsets, the importance of course observation is also noted. Evidenced-based medicine for AA is currently limited, however, novel therapeutic approaches, represented by JAK inhibitors, are on their way for clinical application. In this review, the latest understanding of the etiopathogenesis and pathophysiology, and update on therapeutic approaches with future perspectives are summarized for AA, following the current version of the JDA AA management guidelines.

Increased serum interleukin- 17A levels correlate with disease severity and poor prognostic factors in patients with alopecia areata.

Alopecia areata (AA) is a tissue-specific autoimmune disease characterized by non-scarring and rapid onset of hair loss. Interleukin (IL)-17A is mainly produced by T helper 17 (Th17) cells and may play a crucial role in the pathogenesis of various autoimmune diseases including AA. We conducted this research to measure serum level of IL-17A in patients with AA and investigated its relationship with the clinical manifestations in patients with AA. We assessed 36 patients with AA and 20 healthy control subjects. Demographic information and clinical characteristics were determined by physical examination and via the review of medical history. Serum IL-17A was measured by using enzyme-linked immunosorbent assay. Serum IL-17A concentration was significantly higher in patients with AA than in the control group (P=0.004). The AA patients with severe presentation, personal atopy, nail abnormalities, or active phase had significantly higher serum IL- 17A levels compared to others without these signs. Increased serum IL-17A levels in patients with AA correlate with severity and indicate an active disease state. These findings suggest that IL-17A may play an important role in determining the pathogenesis of AA and may serve as a valuable clinical biomarker of this disease.

Influence of climate factors on pediatric alopecia areata flares in Philadelphia, Pennsylvania

Patients with alopecia areata (AA) may experience episodic disease flares characterized by increasing hair loss that follow a seasonal pattern. However, no studies have examined whether specific climate factors contribute to the seasonal pattern of AA flares. Using Spearman rank correlation analyses, we assessed the association between climate variables and AA flare frequency per month in 336 children with AA in Philadelphia, Pennsylvania. Region-specific monthly values for average ambient temperature, air pressure, cloudiness, hours of sunlight, relative humidity, number of days with sun, number of days with rain, volume of precipitation, wind gust, wind speed, and UV index from January 2015 to December 2017 were obtained from World Weather Online. We found significant (P < 0.05) correlations between AA flare frequency and UV index (R = − 0.66), precipitation (R = − 0.66), number of days with rain (R = − 0.70), number of days with sun (R = 0.62), and air pressure (R = 0.80). Stratified analyses showed even stronger associations with UV index and precipitation in patients with an atopic comorbidity. New significant correlations appeared with temperature, wind speed, and UV index of the prior month. However, in patients who did not have atopic comorbidities, we generally observed weaker and non-significant correlations between climate and AA flare frequency. This study suggests that certain climate factors may mediate the seasonal pattern of AA flares and may contribute to AA pathogenesis. Atopic AA patients may be more susceptible to the influence of climate compared to those with no history of atopy.

The epidemiology of alopecia areata: a population-based cohort study in UK primary care.

SummaryBackgroundThere is a lack of population‐based information on the disease burden and management of alopecia areata (AA).ObjectivesTo describe the epidemiology of AA, focusing on incidence, demographics and patterns of healthcare utilization.MethodsPopulation‐based cohort study of 4·16 million adults and children, using UK electronic primary care records from the Oxford‐Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database, 2009–2018. The incidence and point prevalence of AA were estimated. Variation in AA incidence by age, sex, deprivation, geographical distribution and ethnicity was examined. Patterns of healthcare utilization were evaluated in people with incident AA.ResultsThe AA incidence rate was 0·26 per 1000 person‐years. AA point prevalence in 2018 was 0·58% in adults. AA onset peaked at age 25–29 years for both sexes, although the peak was broader in females. People of nonwhite ethnicity were more likely to present with AA, especially those of Asian ethnicity [incidence rate ratio (IRR) 3·32 (95% confidence interval 3·11–3·55)]. Higher AA incidence was associated with social deprivation [IRR most vs. least deprived quintile 1·47 (1·37–1·59)] and urban living [IRR 1·23 (1·14–1·32)]. People of higher social deprivation were less likely to be referred for specialist dermatology review.ConclusionsBy providing the first large‐scale estimates of the incidence and point prevalence of AA, our study helps to understand the burden of AA on the population. Understanding the variation in AA onset between different population groups may give insight into the pathogenesis of AA and its management.

Serum Level of Interleukin 17 in Alopecia Areata Patients and Its Relation with the Severity of the Disease: a Case Control Study

Abstract Background Alopecia Areata (AA) is one of the most common autoimmune diseases that’s characterized by hair loss on the scalp and/or body. It is an organ-specific autoimmune disease characterized by T-cell infiltrates and cytokine production. T-helper 17 (Th17) cells are crucially involved in the pathogenesis of autoimmune diseases. Objectives Our aim was to compare the serum level of interleukin-17 (IL-17) between alopecia areata patients and healthy controls to demonstrate its proposed role in the pathogenesis of alopecia areata and to correlate it with the severity of the disease. Subjects and methods The serum concentration of IL-17 was measured in 26 patients with AA and 26 healthy controls. The clinical type of AA was determined, and the severity of scalp hair loss was assessed in accordance with the Alopecia Areata Investigational Assessment Guideline criteria. Results The serum concentration of IL-17 was significantly higher in patients with AA as compared with healthy. The IL-17 concentration among cases ranged from 133.38 – 325.99 pg/ml with a median of 195.38, while among controls, the IL-17 concentration ranged from 13.59 – 225.73 pg/ml with a median of 48.42. No statistically significant difference was found in IL-17 levels regarding age, sex, clinical type, duration of disease or severity. Conclusion The significantly higher levels of serum IL-17 in patients with AA suggest a possible role of IL-17 as a proinflammatory cytokine in the pathogenesis of AA. This could point to the potential benefit of IL-17 inhibitors in recalcitrant cases of alopecia areata.

Dietary Habits in Japanese Patients with Alopecia Areata.

PurposeAlopecia areata (AA) is characterized by non-scarring, patchy hair loss caused by autoimmune reactions to anagen hair follicles. The pathogenesis of AA may be affected by the diet. However, the dietary habits of patients with AA have not been precisely examined. Therefore, the aim of this study was to investigate the dietary habits of patients with AA in comparison to those of healthy controls.Patients and MethodsWe evaluated the dietary habits of 70 adult Japanese patients with AA using a brief-type self-administered diet history questionnaire and compared them to the habits of age- and sex-matched healthy controls.ResultsJapanese patients with AA had a higher body mass index (BMI) and higher intakes of vitamin C and fruit than the controls. Logistic regression analysis showed that AA was associated with BMI. Retinol intake was positively correlated with severity of alopecia tool (SALT) score, and linear regression analysis revealed that retinol intake was a predictor of SALT score. Retinol intake among patients with moderate to severe AA (ie, a SALT score >25) was higher than that in patients with mild AA (a SALT score ≤25). The mean age of AA patients with atopic dermatitis (AD) was lower than that of AA patients without AD; however, there were no differences in nutrient or food intake between these two groups. Logistic regression analysis showed that the comorbidity AD was negatively associated with age.ConclusionAA was associated with a high BMI, and high retinol intake was a predictor of SALT score. Further studies should be conducted to clarify whether dietary intervention to reduce BMI or limit retinol intake can alter the development or severity of AA.

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.

022 Exploring the potential of the novel IFNγ aptamer TAGX-0003 as a treatment for alopeciaareata in pre-clinical models

Alopecia areata (AA) is an autoimmune hair loss disorder in which hair follicles (HFs) that have lost their protective immune privilege (IP) are attacked by an inflammatory cell infiltrate including key effector CD8+NKG2D+ cells rapidly turn into catagen. IFNγ is recognized as a key pathological cytokine in driving IP collapse and AA pathogenesis. While recently JAK inhibitors are used off- label, despite the possible long-term effect associated to their broad immunosuppressive activities, the combination of steroid and minoxidil is still considered to be the first line of treatment for AA.

Diagnostic implications of MicroRNAs; 155, 146 a, and 203 lesional expression in alopecia areata: A preliminary case-controlled study.

Alopecia areata (AA) is an immune mediated disorder that attacks hair follicles with unknown pathophysiology. MicroRNAs (miRNAs) are small noncoding RNA molecules, and their aberrant expression or function has been involved in different autoimmune conditions. We aimed at exploring the association between some miRNAs lesional expression and AA pathogenesis by measurement of miRNAs-155, 146a, and 203 expression levels in the lesional skin from patchy AA patients and to evaluate their relation with the studied parameters. Skin expression levels of miRNAs-155, 146a, and 203 were evaluated in 50 patients with patchy AA and 25 healthy controls using reverse transcriptase-quantitative PCR (RT-qPCR). The activity and severity of alopecia were assessed according to AA Investigational Assessment Guidelines criteria. Studied patients showed significant up-regulation of miRNAs-203, 146a, and 155 lesional tissue expression levels when compared to control group (p<0.05 each). Only miRNA-146a skin expression level was significantly higher in patients with multiple lesions (p<0.001). However, patients with active AA had significantly higher tissue expression levels of the investigated miRNAs than those with inactive disease (P 0.001, 0.009, and 0.001, respectively). Investigated miRNAs seem to be role players in AA pathogenesis and may be considered potential indicators of disease activity. However, more research is needed to clarify their accurate role and clinical importance.

LB708 ILC1-like innate lymphocytes in human autoimmunity: Lessons from Alopecia Areata

Innate lymphoid cells type 1 (ILC1) express NKG2D and produce large amounts of IFN-γ, i.e. two key elements in the pathogenesis of alopecia areata (AA). In this study, we aimed to explore a possible involvement of ILC1-like cells in human AA by using ex-vivo and in-vivo models for human AA. Triple immunofluorescence staining of AA sections revealed pathological infiltrates of NKG2D+ ILC1-like cells in and around the anagen hair bulb of lesional AA HFs, but also (more discretely) in/around non-lesional AA HFs, together with a dominant infiltrate of CD8+/NKG2D+ cells.