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Atopic dermatitis (AD) and alopecia areata (AA) are chronic inflammatory skin diseases. While studies suggest a possible immune defense mechanism link between the two, the causal relationship remains unclear, and current methodologies have limitations. This study aims to investigate the causal relationship between AD and AA using genome-wide association study statistics from the Integrative Epidemiology Unit Open Genome-Wide Association Study (IEU Open Gwas) project. We utilized the inverse variance weighting (IVW) method as our primary analysis approach for assessing the causal association between AD and AA. To enhance the robustness of our findings, we also employed supplementary validation methods, including the weighted median, MR-Egger method, and other analytical approaches. Our analysis revealed a significant increase in the risk of AA associated with single-nucleotide polymorphisms (SNPs) linked to AD (odds ratio (OR) = 1.84, 95% confidence interval (CI): 1.19-2.85, p-value (p) = 0.006). While MR-Egger analysis did not show a significant association (OR = 1.04, 95% CI: 0.29-3.68, p = 0.957), weighted median analysis demonstrated a significant association (OR = 2.08, 95% CI: 1.16-3.71, p = 0.013). Additionally, MR-Egger intercept and MR-PRESSO analysis showed no evidence of potential pleiotropy or horizontal pleiotropy between AD and AA. This study indicates that AD increases the risk of AA, providing valuable insights into the pathogenesis and prevention of these two diseases. Future research should explore the underlying mechanisms to better understand this relationship., Competing Interests: Declarations. Ethical approval: The manuscript does not contain clinical studies or patient data. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We have previously demonstrated that receptor-interacting serine threonine kinase 1 (RIPK1) is expressed in hair follicles and regulates the hair cycle. In a mouse model, RIPK1 inhibitors also accelerated the telogen-to-anagen transition and elongated the anagen period. Here, we first investigated the involvement of RIPK1 in alopecia areata (AA). The mRNA and protein expression of RIPK1 was increased in the skin of an AA mouse model. Single-cell RNA sequencing and immunohistochemistry showed that RIPK1 was highly increased in dendritic cells (DCs) and CD8 + T cells. RIPK1 inhibitors (i.e., Necrostatin-1s and GSK2982772) delayed the onset of AA in the mouse model and reduced the numbers of DCs and CD8 + T cells in AA skin. The RIPK1 inhibitors also increased the hair length in a mouse hair organ culture mimicking AA. Collectively, these results suggest that RIPK1 is involved in AA onset via modulating immune cells, and RIPK1 inhibitors could prevent AA onset.

Background: Alopecia Areata (AA) is a T cell-mediated autoimmune disease characterized by sudden hair loss. It is associated with a significant familial predisposition and comorbidities such as thyroid disease, diabetes, atopic dermatitis, and vitiligo. This study aims to systematically review and meta-analyze the prevalence of familial AA and its associated comorbidities to better understand the hereditary nature of the disease., Methods: A systematic review and meta-analysis were conducted following the PRISMA guidelines. Relevant studies were identified from databases including EMBASE, Cochrane Library, PubMed, and Web of Science up to October 15, 2023. Studies were included if they reported on AA patients with a confirmed diagnosis and a family history of AA or related comorbidities. Data extraction and quality assessment were performed by two independent reviewers, with discrepancies resolved by a third reviewer. Pooled prevalence estimates were calculated using a random effects model., Results: The meta-analysis included 67 studies, encompassing 24,226 AA patients and their relatives. The prevalence of a family history of alopecia areata (AA) was found to be 17.6 %, indicating that 17.6 % of individuals with AA have a positive family history of the condition. (CI: 14.9 %-20.6 %, I 2  = 96 %). The prevalence among relatives was 0.90 % (CI: 0.55 %-1.47 %, I 2  = 98 %), with the highest prevalence observed in first-degree relatives at 3.22 % (CI: 2.31 %-4.48 %, I 2  = 94 %). Comorbid conditions were present in 9.61 % (CI: 6.98 %-13.1 %, I 2  = 95 %) of family members across first-, second-, and third-degree relatives of individuals with alopecia areata have comorbid autoimmune or related conditions, including thyroid disease (4.7 %), diabetes (10.1 %), atopic dermatitis (18.9 %), vitiligo (5.5 %), and other autoimmune disease (12.1 %)., Conclusion: This systematic review and meta-analysis highlight the significant familial risk and comorbidities in family members of AA patients. The findings emphasize the need for comprehensive family monitoring, which includes regular health screenings for autoimmune and related conditions among relatives of AA patients, and genetic counseling to educate families on hereditary risks and to guide early intervention and monitoring strategies. It can lead to improved outcomes. In the future, large population-based studies focusing on second and third-degree relatives are needed to further elucidate these associations., Competing Interests: Conflict of interest statement The authors have no conflict of interest to declare., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alopecia areata (AA) is an autoimmune condition marked by hair loss, linked to inflammatory processes involving the interleukin-1 receptor type 1 (IL-1R1) pathway. This study aims to explore the relationship between IL-1R1 gene expression, serum IL-1R1 levels, and hsa-miR-19b-3p in relation to AA severity. Using a case-control design, we assessed 100 AA patients and 100 healthy controls, measuring serum IL-1R1 through enzyme-linked immunosorbent assay (ELISA) and analyzing IL-1R1 gene and hsa-miR-19b-3p expression levels via quantitative real-time PCR (qRT-PCR). Bioinformatic analysis predicted a binding site for hsa-miR-19b-3p on the IL-1R1 gene, suggesting a regulatory role for this miRNA in AA pathology. Demonstrated significantly higher serum IL-1R1, IL-1R1 gene expression, and hsa-miR-19b-3p levels in AA patients compared to controls. Within the AA cohort, severe cases showed the highest levels, with notable correlations between serum IL-1R1, IL-1R1 gene expression, and hsa-miR-19b-3p. Receiver Operating Characteristic (ROC) curve analysis revealed robust diagnostic potential, with area under the curve (AUC) values of 0.71, 0.73, and 0.76 for serum IL-1R1, hsa-miR-19b-3p, and IL-1R1 gene expression, respectively. Elevated IL-1R1 and hsa-miR-19b-3p levels are associated with AA and its severity, suggesting these markers have potential as diagnostic and prognostic indicators. These findings enhance the understanding of IL-1R1's role in AA and highlight potential molecular targets for future therapeutic approaches., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alopecia areata (AA) is a common non-scarring hair loss disorder associated with autoimmune conditions. However, the pathobiology of AA is not well understood, and there is no targeted therapy available for AA.  METHODS: In this study, differential gene expression analysis, immune status assessment, weighted correlation network analysis (WGCNA), and functional enrichment analysis were performed to identify shared genes associated with both immunological response and AA. Machine learning methods were then used to identify three hub genes as potential diagnostic markers for AA. External validation was performed, and the correlation of hub genes with immune infiltration, immune checkpoint genes, and key marker genes and pathways were evaluated., Results: Three hub genes were identified, which accurately predicted the progression of AA and the immune status. The hub genes were found to be diagnostic markers for AA with high predictive accuracy. External validation confirmed the efficacy of these markers in identifying AA patients., Conclusion: Overall, the study provides a novel approach for the diagnosis, prevention, and treatment of AA. The findings could potentially lead to the development of targeted therapies for AA based on the identified hub genes. The study also highlights the potential of machine learning and bioinformatics analysis in identifying new biomarkers for autoimmune diseases., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Third People's Hospital of Hangzhou (Approval number: 2022KA058). Written informed consent was obtained from all participants involved in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Autoimmune diseases (AID) are defined by immune dysregulation characterized by specific humoral and/or cell mediated responses directed against the body's own tissues. Cytokines in particular play a pivotal role in the pathogenesis of AID, with proinflammatory cytokines contributing to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate regression of inflammation and recovery from acute phases of the disease. Parallel work by our group evaluating a comprehensive set of pro- and anti-inflammatory serum cytokines in Pemphigus vulgaris (PV) as well as Alopecia areata (AA) uncovered a similar pattern of inheritance specific immune dysregulation in these two distinct autoimmune skin diseases. In AA, we found healthy control subjects who are blood related to AA patients exhibit the same cytokine dysregulation in Th1 and Th17 pathways as do patients with AA. In PV, patients as well as individuals who are healthy but yet carry certain PV-associated HLA alleles (termed here as HLA-matched controls) share a similar, but not fully overlapping pattern of cytokine expression that is distinct from control subjects who do not type for these HLA alleles. Specifically, PV patients as well as HLA-matched controls demonstrate immunological activation of several pro-inflammatory-, Th17-, Th2-pathway associated cytokines, and the chemokine IL-8. Thus, in both AA and PV, we reveal cytokine dysregulations that are linked to genetic background. The presence of disease promoting pathways in not only patients, but also genetically related, but healthy control individuals further evokes the novel hypothesis that there may be co-existing disease counteracting immune protective mechanisms at play in thwarting the threat of disease in genetically predisposed individuals who, despite harboring disease associated immune imbalances, remain healthy. Our data underscore the known tendency of AID to cluster in families and support the notion of the shared genetic/common cause hypothesis across multiple AID., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Schwartz, Seiffert-Sinha and Sinha.)

It has been demonstrated that CXCL12 inhibits hair growth via CXCR4, and its neutralizing antibody (Ab) increases hair growth in alopecia areata (AA). However, the molecular mechanisms have not been fully elucidated. In the present study, we further prepared humanized CXCL12 Ab for AA treatment and investigated underlying molecular mechanisms using single-cell RNA sequencing. Subcutaneous injection of humanized CXCL12 Ab significantly delayed AA onset in mice, and dorsal skin was analyzed. T cells and dendritic cells/macrophages were increased in the AA model, but decreased after CXCL12 Ab treatment. Pseudobulk RNA sequencing identified 153 differentially expressed genes that were upregulated in AA model and downregulated after Ab treatment. Gene ontology analysis revealed that immune cell chemotaxis and cellular response to type II interferon were upregulated in AA model but downregulated after Ab treatment. We further identified key immune cell-related genes such as Ifng , Cd8a , Ccr5 , Ccl4 , Ccl5 , and Il21r , which were colocalized with Cxcr4 in T cells and regulated by CXCL12 Ab treatment. Notably, CD8+ T cells were significantly increased and activated via Jak/Stat pathway in the AA model but inactivated after CXCL12 Ab treatment. Collectively, these results indicate that humanized CXCL12 Ab is promising for AA treatment via immune modulatory effects., Competing Interests: Authors MZ and J-HS were employed by Epi Biotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 An, Zheng, Park, Park, Noh and Sung.)

Background and Objectives : Alopecia areata (AA) is a tissue-specific immune-mediated disorder that affects hair follicles and the nail apparatus. Due to the collapse of hair follicle immune privilege in AA, hair loss ranges in severity from small, localized patches on the scalp to the loss of entire body hair. Although AA is of uncertain etiology, the disease has a common genetic basis with a number of other autoimmune diseases. Materials and Methods : To identify candidate genes that confer susceptibility to AA in the Jordanian population and further understand the disease background, we performed DNA genotyping using case-control samples of 152 patients and 150 healthy subjects. Results : While no significant result was observed in the ten single-nucleotide polymorphisms (SNPs), CLEC4D rs4304840 variants showed significant associations with AA development within our cohort ( p = 0.02). The strongest associations were for the codominant and recessive forms of rs4304840 ( p = 0.023 and p = 0.0061, respectively). Conclusions : These findings suggest that CLEC4D gene variants may contribute to AA pathogenesis among Jordanians. Further advanced genetic analysis and functional investigations are required to elucidate the genetic basis of the disease.

Alopecia areata (AA) is an immune-mediated chronic alopecia disease, but its specific pathogenesis is unclear. Gene expression data for AA patients (AAs) and healthy controls (HCs) were retrieved from the GEO database, and the differentially expressed genes (DEGs) between AAs and HCs were identified. Then, GO, KEGG and GSEA analysis were performed. A PPI network for the DEGs was then constructed to screen for hub genes, which were validated by three additional datasets. Subsequently, the potential miRNAs interacting with the hub genes were obtained through TarBase and miRNet. The differentially expressed lncRNAs (DElncRs) were obtained for subcellular localisation analysis, and the DElncRs located in the cytoplasm were further screened to identify miRNAs that interact with them. The shared miRNAs interacting with the hub genes and lncRNAs were used to construct a network of mRNA-miRNA-lncRNA interactions. Lastly, ROC analysis was performed to evaluate the potential diagnostic value of the hub genes and DElncRs identified. A total of 173 DEGs were obtained, mainly enriched in cytokines, chemokines, hair follicle development and hair cycle related signalling pathways. Through PPI screening and validation based on 3 additional datasets, 24 hub genes were finally yielded. Of them, five hub genes were upregulated and the potential miRNAs that interact with these five hub genes were identified. Additionally, 26 DElncRs were obtained, including 9 upregulated lncRNAs located in the cytoplasm that were predicted to interact with the miRNAs. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed using five hub genes, four lncRNAs and their shared five miRNAs. The regulatory relationship between CD8A, mir-185-5p and FOXD2-AS1 might be crucial in AA pathogenesis, with CD8A and FOXD2-AS1 exhibiting diagnostic potential. CD8A and FOXD2-AS1 may serve as potential therapeutic targets in AA., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Observational studies have suggested a correlation between alopecia areata (AA) and thyroid dysfunction (TD). However, the causal relationship between AA and TD remains uncertain. The purpose of this study is to investigate the causal relationship between these two conditions. Understanding the potential causal relationship between AA and TD is valuable for elucidating the pathogenesis of AA and for designing innovative methods to prevent and treat AA and its related complications., Methods: All data for this two-sample Mendelian randomization (MR) study were sourced from public databases. This study selected hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, and Graves' disease as exposure factors, with AA as the outcome variable. Data for hypothyroidism, Hashimoto's thyroiditis, hyperthyroidism, subacute thyroiditis, Graves' disease, and AA were obtained from related genome-wide association studies (GWAS). Various MR analysis methods such as inverse variance weighted (IVW), MR-Egger, and weighted median were utilized. Additionally, Cochrane's Q test was used to detect heterogeneity in MR results, and the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to detect horizontal pleiotropy. A leave-one-out analysis was conducted to investigate the sensitivity of this association., Results: We found statistically significant genetic predictions of AA with hypothyroidism, Hashimoto's thyroiditis, and subacute thyroiditis (IVW OR = 1.4009815, 95% confidence interval [CI]: 1.1210399-1.750829; p = 0.003030698, OR = 1.396101, 95% CI: 1.030134-1.89208; p = 0.03144273, OR = 0.732702, 95% CI: 0.604812-0.887634; p = 0.001483368). Furthermore, tests for pleiotropy showed no evidence of pleiotropy, enhancing the credibility of the study results. Finally, the leave-one-out test demonstrated the stability and robustness of this association., Conclusion: This study provides new evidence of a potential genetic link between thyroid issues and AA. By employing the two-sample MR method to eliminate confounding factors and reverse causation, unbiased results were obtained, confirming a causal relationship between hypothyroidism, Hashimoto's thyroiditis, subacute thyroiditis, and AA. This lays the foundation for further mechanistic studies and potential clinical applications. Future research should further explore the specific biological mechanisms between TD and the onset of AA., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Objective: The IKZF4(Ikaros family zinc finger 4) gene encodes Eos, a zinc finger transcription factor that belongs to the Ikaros family. High expression of Eos on Treg cells is important for the suppression of autoimmune responses and immune homeostasis. It has been suggested that the SNP in IKZF4 may influence the pathogenesis of AA(alopecia areata). The purpose of this study was to explore the relationship between IKZF4 polymorphism and AA in the Chinese Han population., Methods: We examined 459 patients and 434 controls in this study. The rs1701704 polymorphism was evaluated using HRM analysis and direct sequencing., Results: The prevalence of the C/C, A/C, and A/A genotypes in AA patients was 7.4%, 37.5% and 55.1%, respectively. There were significant differences in genotype distribution and allele frequencies between AA and the control group (P < .0001). The frequency of the C allele in the AA group was significantly higher (P < .0001), and the frequencies of the C allele and C/C genotype in patients with family history were higher (P < .0001; P = .001)., Conclusions: The rs1701704 SNP of IKZF4 may be a genetic marker for assessing the risk of AA in the Chinese Han population.

Previous studies have suggested a possible link between autoimmune diseases and graft dysfunction; however, a causal link remains unclear. Exposure factors were set as 13 autoimmune diseases, and outcomes were set as graft dysfunction. Mendelian randomization was used to analyze the causal link between exposure and outcome. Alopecia areata and asthma were linked to graft dysfunction (odds ratio 0.828; 95% confidence interval 0.699-0.980; P = .029; odds ratio 1.79; 95% confidence interval 1.069-2.996; P = .027). At the same time, primary sclerosing cholangitis was found to be heterogeneous as an exposure factor (P = .009), but no heterogeneity or pleiotropy was found in other exposure factors. Our preliminary findings show 2 autoimmune diseases as risk factors for graft dysfunction, 1 autoimmune disease as a protective factor for graft dysfunction and the mechanisms remain to be understood., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Alopecia areata (AA) is one of the most common autoimmune hair diseases. Long non-coding RNAs (lncRNAs) have been shown to be involved in the pathophysiological progression of a variety of diseases; however, how lncRNAs are involved in the pathogenesis of alopecia areata is not fully understood., Objective: In order to study the differential expression profiles of mRNA and lncRNA in patients with alopecia areata and provide experimental basis for the diagnosis and treatment of alopecia areata., Method: We collected skin tissues from the normal and bald areas of the scalp of five patients with alopecia areata. We used RNA sequencing to detect mRNA and lncRNA expression profiles in the skin, screen for differentially expressed genes, and then perform enrichment analyses to determine the functions of the differentially expressed genes and construct a lncRNA-mRNA interaction network., Results: Our results show that normal and bald areas of the scalp in patients with alopecia areata have different mRNA and lncRNA expression profiles, with a total of 344 mRNAs and 116 lncRNAs differentially expressed. Functional enrichment analysis of these co-expressed the differentially expressed genes (DEGs) was enriched for biological processes such as intermediate filament organization, keratinization, and epithelial cell differentiation and so on. Based on the co-expression of differential lncRNAs and DEGs obtained in this project, further overlap analysis of 100 kb of DEGs upstream and downstream of the lncRNAs ultimately revealed that 11 lncRNAs cis-regulate 15 target mRNAs., Conclusion: The pathogenesis of alopecia areata is closely related to multiple genes and multiple pathways, in which keratin family genes may play a key role. In conclusion, this study provides new and promising biomarkers for the diagnosis of alopecia areata.

Background: Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this study is to investigate the causal relationship between the two and the specific directions., Methods: We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves' disease (GD), Hashimoto's thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results., Results: Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P =0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P =0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (β=-0.029, 95%CI=-0.051 to -0.007, P =0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P >0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P >0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results., Conclusions: This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Li, Song, Gao and Chen.)

Background: The specific role of oxidative stress (OS) in vitiligo and alopecia areata (AA) remains unclear. The aim of this study was to analyze and identify the key markers of OS in vitiligo and AA by bioinformatics., Methods: We obtained vitiligo and AA datasets from gene expression omnibus (GEO) database. The difference-expressed genes of vitiligo and AA were identified by differential analysis, and the functions of difference-expressed genes were identified by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis. Subsequently, Veen package was used to obtain the intersection genes of OS-related genes with vitiligo and AA. Finally, we used CIBERSORT to assess the infiltration of immune cells in vitiligo and AA., Results: Through enrichment analysis, we found that vitiligo and AA were mainly enriched in cell cycle and cell adhesion molecular channels. We identified KLB and EIF3C as key genes in OS regulation of vitiligo and AA, and found that KLB and EIF3C participate in disease progression by regulating T cells and neutrophils., Conclusions: According to our findings, KLB and EIF3C play a crucial role in the progression and development of vitiligo and AA, which have been identified as biomarkers and target for early diagnosis of patients., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Alopecia areata is an autoimmune hair loss disorder with an incompletely understood etiology. Although trace elements, serum metabolites, and inflammatory factors are implicated in the disease, the potential causal relationships between these factors and alopecia areata require further investigation., Methods: This study employed Mendelian randomization (MR), utilizing data from genome-wide association studies, to explore the causal relationships between 15 trace elements, 1400 serum metabolites, and 91 inflammatory factors and alopecia areata. The analysis was conducted using the inverse variance weighted (IVW) method complemented by various sensitivity analyses, including Cochran's Q test, MR-Egger regression intercept test, MR-PRESSO global test, and leave-one-out analysis, to assess the robustness of the results., Results: MR analysis indicated a negative correlation between copper levels and the risk of developing alopecia areata (odds ratio = 0.86, 95% confidence interval: 0.75-0.99, p = 0.041). Additionally, causal relationships were identified between 15 serum metabolites and 6 inflammatory factors and the risk of alopecia areata (IVW, all p values < 0.05)., Conclusion: This study provides genetic evidence of the relationships between trace elements, serum metabolites, and alopecia areata, underscoring the potential value of targeted therapeutic strategies and preventive measures. Future research should expand to diverse populations and further explore the specific roles of these biomarkers in the disease mechanism., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Objective: The objective of this study is to elucidate the causal association between asthma and alopecia areata (AA) through the application of Mendelian randomization (MR) analysis, leveraging summary data from genome-wide association studies (GWAS). Additionally, it explores potential mediating factors., Materials and Methods: Mendelian randomization (MR) analysis was employed to investigate the causal relationship between asthma and AA using genetic instrumental variables (IVs) for asthma, 91 circulating inflammatory proteins, and AA extracted from large-scale GWAS. The primary analytical approach utilized the inverse-variance weighted (IVW) method, supplemented by weighted median and MR-Egger methods to assess robustness. Tests for heterogeneity and pleiotropy were conducted to ensure result reliability. Furthermore, the study examined the mediating role of circulating inflammatory proteins in the asthma-AA relationship., Results: The findings revealed an increased risk of AA among asthma patients (odds ratio (OR) = 14.070; 95% confidence interval (CI) = 1.410-140.435; P = 0.024). Interleukin-33 (IL-33) emerged as a significant mediator in the asthma-AA relationship, explaining 13.1% of the mediation effect. Bidirectional Mendelian randomization analyses did not establish a causal effect of AA on asthma occurrence., Conclusion: This study, utilizing Mendelian Randomization, elucidates the causal link between asthma and AA, highlighting the mediating role of IL-33. These findings underscore the importance of considering AA risk in asthma management and offer insights for potential therapeutic strategies targeting IL-33. Future research should explore additional biomarkers and mediating mechanisms between asthma and AA to enhance treatment approaches and patient quality of life., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Purpose: The etiology of alopecia areata (AA) in relation to serum lipids remains unclear, thereby prompting our intention to do Mendelian study on this subject., Design: Two-sample Mendelian randomization (MR) analysis was performed in the study. The inverse variance-weighted method was used as the primary method., Methods: In our study, we integrated a set of 123 single-nucleotide polymorphisms (SNPs) into our analysis. These SNPs have been extensively studied and are known to exhibit associations with serum lipids. We sourced these SNPs from a variety of relevant studies and consortia that specifically focus on lipid-related research, such as the MRC Integrative Epidemiology Unit. These carefully curated SNPs were then utilized as instrumental variables in our analysis, allowing us to explore and evaluate the causal relationships between these genetic variants and serum lipids. By incorporating this comprehensive set of SNPs, we aimed to enhance the precision and robustness of our findings, shedding light on the intricate interplay between genetics and serum lipids., Results: In the MR analysis, a higher total lipid concentration in large low-density lipoprotein (LDL) particles (odds ratio [OR] = 1.502; 95% confidence interval [CI] = 1.086-1.953; p = 0.006), a greater ratio of cholesteryl esters to total lipids in chylomicrons and extremely large very LDL (VLDL) particles (OR = 2.174; 95% CI = 1.300-2.500; p = 0.010), and a greater ratio of cholesterol to total lipids in chylomicrons and extremely large VLDL particles (OR = 2.363;95% CI = 1.556-4.438; p = 0.004), were genetically predicted to be causally associated with an increased risk of AA, while patients with a higher triglyceride to total lipids ratio in chylomicrons and extremely large VLDL particles had a lower risk of AA (OR = 0.481; 95% CI = 0.191-1.270; p = 0.002)., Conclusion: This study found that serum lipids may be causally implicated in AA., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Many patients with asthma experience alopecia areata (AA) in their lives. However, it is unclear whether asthma causes or results from AA. Our objective was to investigate the genetic causal relationship between asthma and AA., Methods: Two-sample Mendelian randomization (MR) was used to assess the causal relationship between asthma and AA based on the largest publicly available genome-wide association study summary statistics. Androgenetic alopecia (AGA) and cicatricial alopecia (CA) were chosen as the control groups for AA. The main estimates were obtained using inverse variance weighting meta-analysis (IVW), Mendelian randomization-Egger (MR-Egger), maximum likelihood estimation, and the weighted median. Sensitivity analyses were conducted using Cochran's Q test, MR-Egger, and leave-one-out methods. Lastly, we conducted a reverse MR analysis to evaluate the possibility of reverse causation., Results: Genetically, asthma is associated with an increased risk of AA, while the association between genetically predicted AGA or CA and asthma was negative. The risk of AA increased by 1.86 times in patients with asthma under the IVW method (OR = 1.86, 95% CI = 1.31-2.629, p < 0.001). The reverse MR analysis did not find evidence supporting reverse causality from three phenotypes of alopecia to asthma. Sensitivity analyses yielded consistent causal estimates., Conclusion: This study suggests that asthma is causally associated with AA. The findings deepen our understanding of the role of asthma in the pathology of AA, which emphasizes the potential for opening a new vista for the prevention and diagnosis of AA., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Observational studies have shown an association between skin microbiota and alopecia areata (AA), but the causal connection remains ambiguous., Methods: We obtained data on skin microbiota and AA from summary statistics of Genome-Wide Association Studies and applied statistical methods from Mendelian randomization (MR) to assess causal relationships. Additionally, we investigated whether the skin microbiota acts as a mediator in the pathway from gut microbiota to AA., Results: In the MR analysis of KORA FF4 and AA, the inverse-variance weighting method indicated that Corynebacterium (odds ratio [OR] = 0.82, 95% confidence interval [CI]: 0.70-0.96, p = 0.02) and asv037 (OR = 0.87, 95% CI: 0.76-0.99, p = 0.05) exerted protective effects, while Betaproteobacteria (OR = 1.21, 95% CI: 1.01-1.44, p = 0.03), asv015 (OR = 1.27, 95% CI: 1.05-1.54, p = 0.02), and Burkholderiales (OR = 1.20, 95% CI: 1.04-1.38, p = 0.01) were identified as risk factors in AA. In the MR analysis of PopGen and AA, asv001 (OR = 1.12, 95% CI: 1.01-1.24, p = 0.04), asv054 (OR = 1.13, 95% CI: 1.01-1.25, p = 0.03), and asv059 (OR = 1.14, 95% CI: 1.02-1.27, p = 0.02) were found to potentially increase the risk in AA. Furthermore, in the influence of gut microbiota on AA, the skin microbiota did not act as a mediator., Conclusion: Our analysis suggests potential causal relationships between certain skin microbiota and AA, revealing insights into its pathogenesis and potential intervention strategies., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: MicroRNAs (miRNAs) are small RNA molecules that play a regulatory role in various biological processes by acting as intracellular mediators. They hold great potential as therapeutic agents for targeting human disease pathways; however, there is still much to be uncovered about their mechanism of gene regulation. Alopecia areata (AA) is a commonly occurring inflammatory condition characterized by the infiltration of T cells that specifically target the anagen-stage hair follicle. The limited understanding of its precise cellular mechanism may be the reason behind the scarcity of effective treatments for AA., Aim: The significance and function of hsa-miR-193a-5p as a genetic marker for AA and its potential influence on the advancement of the disease., Subjects and Methods: A case-control study comprised 77 individuals diagnosed with AA who were matched with 75 healthy controls. In order to measure the expression of miR-200c-3p in both groups, the real-time PCR technique was utilized. The prediction of suitable genes for hsa-miR-193a-5p, as well as the identification of pathways and gene-gene interactions, were carried out using bioinformatic tools., Results: The levels of hsa-miR-193a-5p expression were notably elevated in AA patients in comparison to healthy controls. Our prediction suggests that the involvement of hsa-miR-193a-5p in the development of AA is significant due to its influence on the inositol phosphorylation pathway and the Phosphatidylinositol signaling system, achieved through its direct impact on the IPPK gene., Conclusion: For the first time, our study demonstrates the significant over-expression of a new miRNA, hsa-miR-193a-5p, in the blood of AA patients compared to controls, and highlights its impact on the IPPK gene and the inositol phosphorylation and Phosphatidylinositol signaling pathways, suggesting a potential therapeutic role for hsa-miR-193a-5p in AA., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Previous observational studies revealed controversy about the effect of circulating antioxidants on risk of alopecia. In the present study, we investigated the causal relationships between diet-derived circulating antioxidants and 2 non-scarring alopecia using Mendelian randomization (MR). Instrumental variables for antioxidants (lycopene, retinol, ascorbate, β-carotene, α-tocopherol, and γ-tocopherol) were selected from published studies. Data for alopecia areata (AA) and androgenetic alopecia (AGA) was obtained from the FinnGen study project (R9 released in 2023), including 195 cases and 201,019 controls for AGA and 682 cases and 361,140 controls for AA. We used the inverse variance weighted method as the primary MR method. Three additional methods were used as sensitivity analysis to validate the robustness of the results. We found a causal relationship between absolute β-carotene levels and AGA risk (P = .039), but not with AA (P = .283). The results of Wald ratio showed a protective effect of absolute β-carotene levels against AGA, with per 0.1 ln-transformed β-carotene being associated with a 76% lower risk of AGA (OR: 0.24, 95% CI: 0.06-0.93). Based on the fixed effects inverse variance weighting results, we found that α-tocopherol was protective against both AGA (P = .026) and AA (P = .018). For each unit increase in α-tocopherol, the effects of change in AGA and AA were 0.02 (95% CI: 0.00-0.61) and 0.10 (95% CI: 0.01-0.67), respectively. The results did not reveal any other causal relationships. Our study identified 3 causal associations of antioxidants with the risk of non-scarring alopecia. These results provide new insights into the prevention of non-scarring alopecia through diet., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Alopecia areata (AA) is an autoimmune disease characterized by damage to hair follicles and hair loss. Cell-free DNA (cfDNA) has recently received attention as a biomarker of various disorders including inflammatory skin diseases. In this study, we aimed to investigate the clinical significance of cfDNA and the circulating DNAs of disease-associated cytokines in AA patients. Serum samples were obtained from 63 patients with AA and 32 healthy controls (HC). Using droplet digital polymerase chain reaction, circulating C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL11, C-X-C motif chemokine receptor 3, interferon (IFN)-γ, interleukin (IL) -7, IL-15, and Janus kinase (JAK) 2 were detectable in both HC and AA patients. Among the detectable DNAs, copies of circulating CXCL9, CXCL11, IL-15, IFN-γ, and JAK2 were significantly higher in AA patients than in HC. These results suggest that increased circulating DNA levels may reflect damage to hair follicles in AA patients.

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

Background: While observational studies have suggested a link between gut microbiota diversity and alopecia areata (AA), the causal relationship remains unclear., Methods: We leveraged data from the MiBioGen and FinnGen consortiums' Genome-wide association studies (GWAS) encompassing gut microbiota (n = 13,266) and AA (n = 211,428) datasets. A comprehensive Mendelian randomization (MR) and reverse MR approach were employed, utilizing five statistical methods to evaluate causality. Sensitivity analyses were also conducted to corroborate the MR results., Results: Inverse variance weighted (IVW) analysis indicated a protective effect against AA from Butyricimonas (OR = 0.37, 95% CI: 0.18-0.77, P = 0.01), Enterorhabdus (OR = 0.40, 95% CI: 0.16-0.95, P = 0.04), Eubacterium (xylanophilum group) (OR = 0.36, 95% CI: 0.15-0.84, P = 0.02), and Phascolarctobacterium (OR = 0.37, 95% CI: 0.15-0.91, P = 0.03), while Ruminococcaceae UCG003 posed as a risk factor (OR = 2.79, 95% CI: 1.27-6.14, P = 0.01). Reverse MR showed no significant causal link between AA and gut microbiota, with no significant heterogeneity or horizontal pleiotropy., Conclusions: Our analysis suggests probable causality between certain gut microbiota and AA, shedding light on its pathogenesis and potential intervention strategies., (© 2024 the International Society of Dermatology.)

Background: As research progresses, there has been growing interest in the association between Alopecia areata (AA) and anxiety, as well as depression. However, there have been limited reports on the genetic variation level of AA in relation to mental disorders., Method: We performed large-scale Two sample Mendelian randomization (MR) analyses to examine whether there is a association between AA with anxiety and depression. The data utilized for AA analysis were sourced from the FinnGen release 9 databases, including 682 cases and 361,822 controls. Summary statistics for major depression disorder (MDD) were obtained from a genome-wide meta-analysis dataset, incorporating 170,756 cases and 329,443 controls. The anxiety disorder data was conducted by the Anxiety Neuro Genetics Study Consortium, including 5580 cases and 11,730 controls. We employed four distinct approaches, including MR-Egger, weighted median, random-effect inverse variance weighted (IVW), and weighted mode, to conduct the MR analysis., Results: Genetic liability to AA was associated with an increased risk of Major depression disorder (MDD) and anxiety demonstrated an odds ratio (OR) of 1.01 (βivw = 0.011, PIVW = 0.023) and OR of 1.16 (βivw = 0.150, PIVW = 0.002). Upon conducting the Bonferroni correction, the P-values were 0.046 and 0.004, respectively. For reverse analysis, we observed no significant association between anxiety and MDD with the risk of AA., Conclusions: Our research unveil a unidirectional causal association whereby AA exerts a risk effect against MDD and anxiety, which serves as a valuable complement to prior meta-analyses, enriching the existing body of knowledge on the subject matter., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression in diverse biological processes. They hold promise as therapeutic candidates for targeting human disease pathways, although our understanding of their gene regulatory mechanism remains incomplete. Alopecia areata (AA) is a prevalent inflammatory ailment distinguished by the infiltration of T cells targeting the anagen-stage hair follicles. The scarcity of effective remedies for AA may stem from limited understanding regarding its precise cellular mechanism., Aim: To investigate and examine the importance and role of the miR-200c-3p as a genetic indicator for AA, and its possible impact on disease progression., Subjects and Methods: Case-control study included 65 patients with AA and 65 matched healthy controls. A real-time PCR technique was used to measure the expression of miR-200c-3p for both groups. Bioinformatic tools were used for prediction with genes and gene-gene interaction, and protein-protein interaction., Results: The expression levels of miR-200c-3p were significantly higher in AA patients than in healthy controls. We predicted that miR-200c-3p plays a markable role in the development of AA by its effect on the EGFR tyrosine kinase inhibitor resistance pathway., Conclusion: We were able to identify the influence of miR-200c-3p on both PLCG1 and RPS6KP1 genes which in turn regulate the EGFR tyrosine kinases resistance pathway that displayed the most substantial increase in activity. Our outcomes shed light on the era of the potential theranostic role of this innovative miRNA in AA., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Alopecia Areata (AA) is an acquired autoimmune form of non-scarring hair loss. Adiponectin and its gene polymorphism were related to many autoimmune disorders., Objective: Assessment of adiponectin serum levels and adiponectin gene (ADIPOQ) (rs2241766) Single Nucleoid Polymorphism (SNP) in AA patients and correlating the results with the disease severity in those patients., Methods: This study included 75 AA patients and 75 age and gender-matched healthy subjects (controls). The severity of Alopecia Tool (SALT) score assessment to evaluate AA severity was done. Adiponectin serum levels by ELISA and ADIPOQ (rs2241766) SNP using PCR were performed., Results: Adiponectin serum levels were significantly lower in AA patients than controls (p = 0.001). ADIPOQ (rs2241766) TG genotype and G allele were significantly predominant in AA patients increasing its risk by 5 and 4 folds (OR = 5.17, p = 0.001), (OR = 3.82, p = 0.001) respectively. Serum adiponectin levels were negatively correlated with SALT score (r = -0.435, p = 0.001) and associated with alopecia totalis (p = 0.016). ADIPOQ (rs2241766) TG genotype was significantly associated with low serum adiponectin levels and higher SALT score (p = 0.001)., Study Limitations: The small sample size., Conclusions: ADIPOQ (rs2241766) gene polymorphism (TG genotype and G allele) may modulate AA risk and contribute to the development of AA in Egyptian populations. Decreased circulating adiponectin levels may have a dynamic role in AA etiopathogenesis. Adiponectin serum concentration can be considered a severity marker of hair loss in AA., (Copyright © 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Alopecia areata (AA) is an autoimmune condition characterized by sudden and unpredictable hair loss, with a lifetime incidence of 2%. AA can be divided into three categories: patchy alopecia, alopecia totalis, and alopecia universalis. It can affect a person's psychological health and overall quality of life. Elevated C-reactive protein (CRP) levels in the liver may indicate an inflammatory response in autoimmune diseases. Vitamin D, essential for immune system control and skin health, may be related to AA. Hair follicles contain vitamin D receptors, which control immunological responses in the skin. However, no study has found a relationship between CRP and vitamin D in AA patients in our region., Subjects and Methods: An analytical cross-sectional study with a case-control design research investigation of 82 AA patients and 81 healthy controls was carried out. Both groups' medical histories were taken. Biochemical analysis was done for both groups as well as the serum vitamin D levels, and CRP. Genetic analysis for CDX2 rs11568820 variant detected by PCR (T-ARMS-PCR) method and vitamin D receptor (VDR) gene expression measured by real-time PCR analysis for both patients and healthy subjects., Results: CRP levels are higher in AA patients, AA patients with G/G genotypes exhibited higher concentrations of CRP when compared to those with A/A and A/G genotypes while patients with A/A genotypes have higher levels of Serum vitamin D as compared to the A/G and G/G genotypes. G allele was more abundant in AA patients. VDR gene expression was lower in AA compared to control and lower in ophiasis compared to localized and multiple patchy AA. An important inverse linear correlation was observed between vitamin D and CRP levels in ophiasis AA., Conclusion: CRP concentrations were found to be elevated in AA patients. The considerable accuracy of CRP in the diagnosis of AA is substantiated by a statistically significant al. A noteworthy inverse linear association was observed between serum vitamin D and CRP concentrations in ophiasis AA., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Alopecia areata (AA) is an autoimmune disease which results in non-scarring hair loss on the scalp or any surface with hair. Several genetic polymorphisms of the interleukin genes have been linked with this disease but the results are inconsistent. This systematic review and meta-analysis were done to find the association between rs3118470, rs2275913, rs3212227, and rs10889677 of the IL2RA, IL17A, IL12B, and IL23R genes, respectively, of the interleukin family with alopecia areata., Methods: A comprehensive search for relevant research articles was conducted in Pubmed, Google Scholar, and Embase databases. Our search yielded 8 relevant articles with 1940 cases and 1788 controls. The odds ratio with 95% confidence intervals was calculated using fixed effect and random effect models. Heterogeneity was determined using the Q-test and I2 test. Publication bias was determined and funnel plots were used to adjust the odds ratio., Results: We found a significant risk effect for rs3118470 of the IL2RA gene with alopecia areata in the dominant model (CC + CT vs TT; OR = 1.54, 95% confidence interval = 1.05-2.26, P < .05, I2 = 69.03%) and homozygous model (CC vs TT; OR = 2.00, 95% confidence interval = 1.07-3.71, P < .05, I2 = 72.84%). For the other single nucleotide polymorphisms, we could not find any statistically significant association with the disease., Conclusion: Our analysis showed that mutation of rs3118470 of IL2RA gene possesses a significant risk effect for alopecia areata. Future studies with larger sample sizes and ethnic backgrounds are warranted to confirm our findings., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Alopecia areata (AA) is a common non-scarring hair loss condition driven by the collapse of immune privilege and oxidative stress. The role of ferroptosis, a type of cell death linked to oxidative stress, in AA is yet to be explored, even though it's implicated in various diseases. Using transcriptome data from AA patients and controls from datasets GSE68801 and GSE80342, we aimed to identify AA diagnostic marker genes linked to ferroptosis. We employed Single-sample gene set enrichment analysis (ssGSEA) for immune cell infiltration evaluation. Correlations between ferroptosis-related differentially expressed genes (FRDEGs) and immune cells/functions were identified using Spearman analysis. Feature selection was done through Support vector machine-recursive feature elimination (SVM-RFE) and LASSO regression models. Validation was performed using the GSE80342 dataset, followed by hierarchical internal validation. We also constructed a nomogram to assess the predictive ability of FRDEGs in AA. Furthermore, the expression and distribution of these molecules were confirmed through immunofluorescence. Four genes, namely SLC40A1, LCN2, CREB5, and SLC7A11, were identified as markers for AA. A prediction model based on these genes showed high accuracy (AUC = 0.9052). Immunofluorescence revealed reduced expression of these molecules in AA patients compared to normal controls (NC), with SLC40A1 and CREB5 showing significant differences. Notably, they were primarily localized to the outer root sheath and in proximity to the sebaceous glands. Our study identified several ferroptosis-related genes associated with AA. These findings, emerging from the integration of immune cell infiltration analysis and machine learning, contribute to the evolving understanding of diagnostic and therapeutic strategies in AA. Importantly, this research lays a solid foundation for subsequent studies exploring the intricate relationship between AA and ferroptosis., (© 2024. The Author(s).)

Background: Although observational studies have found an association between hypothyroidism and alopecia areata, the causality of this relationship remains unclear., Objectives: This study aimed to investigate the genetic variants associated with hypothyroidism and their potential impact on the risk of developing alopecia areata., Methods: genome-wide association study summary statistics for hypothyroidism (30,155 cases and 379,986 controls) and alopecia areata (289 cases and 211,139 controls) were obtained from the IEU OpenGwas project. The inverse variance-weighted method was used as the primary analysis method to evaluate the causality between hypothyroidism and alopecia areata, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks., Result: Utilizing two-sample Mendelian randomization analysis, we found that the single-nucleotide polymorphisms (SNPs) of hypothyroidism (OR = 1.40, 95% CI: 1.12-1.75, p = 3.03×10 -3 ) significantly increased the risk of alopecia areata ( 289 cases and 211,139 controls ). KEGG pathway analysis showed that the candidate genes were mainly enriched in virion-herpesvirus, Th1 and Th2 cell differentiation, Th17 cell differentiation, T-cell receptor signaling pathway, PD-L1/PD-1 checkpoint pathway in cancer and Toll-like receptor signaling pathway. Protein-protein interaction networks results showed that CTLA4, STAT4, IL2RA, TYK2, IRF7, SH2B3, BACH2, TLR3, NOD2, and FLT3., Conclusion: This study provided compelling genetic evidence supporting a causative association between hypothyroidism and alopecia areata, which could potentially inform the development of more efficacious treatment strategies for patients afflicted by alopecia areata., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Ma, Zhang, Chen, Tang, Tai and Cao.)

Background: Although there have been indications that periodontitis (PD) may be susceptible to alopecia areata (AA), the underlying mechanism of its pathogenesis remains poorly understood. The objective of our study is to conduct further research into the occurrence of this complication., Methods: The gene expression omnibus (GEO) database was the source of acquisition for both PD and AA datasets. Various methods, including the differentially expressed genes (DEGs) analysis, functional enrichment analysis, protein-protein interaction (PPI) network construction, Cytohubba algorithms, and RandomForest algorithms, were utilized to identify candidate hub immuno-related genes (IRGs) for diagnosing AA with PD. The diagnostic efficacy was assessed by constructing receiver operating characteristic (ROC) curves. To further deepen our understanding, immune cell infiltration, flow cytometry assay, and immunofluorescence techniques were employed to uncover immune cell dysregulation in PD and AA., Results: 899 and 803 DEGs were detected in AA and PD, respectively, with an intersection of 150 common DEGs enriched in immune regulation. Further analysis of the junction of shared DEGs and IRGs was analyzed using the PPI network, Mcode, and Cytohubba algorithms. Three hub genes (CTSS, IL2RG, and ITGAL) were subsequently selected by Cytohubba and RandomForest algorithms and were found to be promising candidate hub genes with high diagnostic values (AUC ranging from 0.776 to 0.909) for diagnosing AA with PD. Additionally, various dysregulated immune cells were observed, with mast cells potentially serving as markers for AA and plasma for PD., Conclusion: Three candidate hub IRGs (CTSS, IL2RG, and ITGAL) were identified with considerable diagnostic values. Besides, mast cells could serve as markers for AA, while plasma may indicate PD. Our research has the potential to identify shared diagnostic candidate genes and immune cells for AA and PD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although numerous observational studies have indicated a potential association between autoimmune diseases, such as rheumatoid arthritis (RA) and alopecia areata (AA), the research reports lack a clear causal relationship. In this study, our objective is to utilize the Mendelian randomization (MR) design to examine the potential causal association between RA and AA., Methods: To investigate the causal relationship between RA and AA, we utilized large-scale gene aggregation data from genome-wide association studies (GWAS), including RA (n=58,284) and AA (n=361,822) based on previous observational studies. In our analysis, we mainly employed the inverse variance-weighted (IVW) method of the random effects model, supplemented by the weighted median (WM) method and the MR Egger method., Results: The findings from the IVW methods revealed a significant association between genetically predicted RA and an increased likelihood of AA, as evidenced by an odds ratio of 1.21 (95%CI = 1.11-1.32; P < 0.001. Both the WM method and MR-Egger regression consistently showed significant directional outcomes (Both P < 0.05), indicating a robust association between RA and AA. Additionally, both the funnel plot and the MR-Egger intercepts provided evidence of the absence of directional pleiotropy, suggesting that the observed association is not influenced by other common genetic factors., Conclusions: The results of the study suggest a possible link between genetically predicted RA and AA. This finding highlights the importance for individuals diagnosed with RA to remain vigilant and aware of the potential development of AA. Regular monitoring and early detection can be crucial in managing and addressing this potential complication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhong, Lan, Zheng, Zhang and Wen.)

Competing Interests: Conflicts of interest Dr Guttman-Yassky has received institutional grants from AbbVie, Celgene, Eli Lilly, Janssen, Dermavant, DS Biopharma, Novartis, Pfizer, Regeneron, Glenmark, Galderma, Asana Biosciences, Innovaderm, Dermira, LEO Pharma, Novan, Kyowa Kirin, Concert, Union Therapeutics, and Ralexar; and is a consultant for Sanofi, Regeneron, Celgene, Dermira, Galderma, Glenmark, Novartis, Pfizer, LEO Pharma, AbbVie, Eli Lilly, Kyowa Kirin, Mitsubishi Tanabe, Asana Biosciences, Union Therapeutics, Allergan, Amgen, Concert, DS Biopharma, EMD Serono, Escalier, and Flx Bio. Dr Ungar is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Incyte, Rapt Therapeutics, and Pfizer. He is also a consultant for Arcutis Biotherapeutics, Castle Biosciences, Pfizer, and Sanofi. Authors O’Hagan, Caldas and Dr Correa da Rossa have no conflicts of interest to declare.

Alopecia areata (AA) is among the most prevalent autoimmune diseases, but the development of innovative therapeutic strategies has lagged due to an incomplete understanding of the immunological underpinnings of disease. Here, we performed single-cell RNA sequencing (scRNAseq) of skin-infiltrating immune cells from the graft-induced C3H/HeJ mouse model of AA, coupled with antibody-based depletion to interrogate the functional role of specific cell types in AA in vivo. Since AA is predominantly T cell-mediated, we focused on dissecting lymphocyte function in AA. Both our scRNAseq and functional studies established CD8+ T cells as the primary disease-driving cell type in AA. Only the depletion of CD8+ T cells, but not CD4+ T cells, NK, B, or γδ T cells, was sufficient to prevent and reverse AA. Selective depletion of regulatory T cells (T reg ) showed that T reg are protective against AA in C3H/HeJ mice, suggesting that failure of T reg -mediated immunosuppression is not a major disease mechanism in AA. Focused analyses of CD8+ T cells revealed five subsets, whose heterogeneity is defined by an "effectorness gradient" of interrelated transcriptional states that culminate in increased effector function and tissue residency. scRNAseq of human AA skin showed that CD8+ T cells in human AA follow a similar trajectory, underscoring that shared mechanisms drive disease in both murine and human AA. Our study represents a comprehensive, systematic interrogation of lymphocyte heterogeneity in AA and uncovers a novel framework for AA-associated CD8+ T cells with implications for the design of future therapeutics.

Alopecia areata (AA) is a chronic, non-scarring, immune-mediated skin disease that affects approximately 0.5-2% of the global population. The etiology of AA is complex and involves genetic and environmental factors, with significant advancements in genetic research occurring in recent years. In addition to well-known genes such as PTPN22 , CTLA4 , and IL2 , which have been widely supported as being associated with AA, an increasing number of specific gene-related loci have been discovered through advances in genetic research. For instance, gene analysis of microRNAs can reveal the critical role of miRNAs in regulating gene expression, aiding in the understanding of cellular and organismal functional regulatory mechanisms. Furthermore, numerous studies have confirmed the existence of correlations between AA and other immune-related diseases. Examples include hyperthyroidism and rheumatoid arthritis. By understanding the interrelationships between AA and other immune diseases, we can further comprehend potential shared genetic foundations or pathogenic mechanisms among different diseases. Genetic research plays a crucial role in unraveling the pathogenesis of AA, as the identification of genetic variations associated with AA can assist in formulating more effective and targeted treatment strategies.

Alopecia areata (AA) is a disorder with several etiologies. The evidence suggests that the absolute copy number of mitochondrial deoxyribonucleic acid (mtDNA), as well as proportion of mutated mtDNA copies, determines disease onset. This study aims to quantify the relative index of the mtDNA copy number in patients with AA and healthy controls and correlate the results with the existing clinical ‎information. This case-control study included 50 patients with AA and 50 age- and sex-coordinated healthy persons as controls. The severity of AA was weighed using the Severity of Alopecia Tool and Kavak's classification. The relative index of the mtDNA copy number was measured by real-time qPCR. Significant statistical difference was observed between cases and controls regarding mean mtDNA copy number, p  < .001. There was significant positive correlation with SALT score ( p =  0.001). A cutoff value of >1.619 N/µL could significantly diagnose AA cases ( p  < .001), and a cutoff value of > 1.36 N/µL could discriminate mild AA cases from those with moderate AA ( p =  0.007). The relative index of mtDNA copy number is significantly elevated in AA cases and could be helpful in diagnosing and evaluating AA severity.

Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. Autoreactive CD8 T cells are key pathogenic effectors in the skin, and AA has been associated both with atopy and with perturbations in intestinal homeostasis. This study aimed to investigate mechanisms driving AA by characterizing the circulating immunophenotype and faecal microbiome, and by stratifying AA to understand how identified signatures associated with heterogeneous clinical features of the condition. Flow cytometric analyses identified alterations in circulating B cells and CD4 T cells, while 16S sequencing identified changes in alpha and beta diversity in the faecal microbiome in AA. The proportions of transitional and naïve B cells were found to be elevated in AA, particularly in AA samples from individuals with >50% hair loss and those with comorbid atopy, which is commonly associated with extensive hair loss. Although significant changes in circulating CD8 T cells were not observed, we found significant changes in CD4+ populations. In individuals with <50% hair loss higher frequencies of CCR6+CD4 ("Th17") and CCR6+CXCR3+CD4 ("Th1/17") T cells were found. While microbial species richness was not altered, AA was associated with reduced evenness and Shannon diversity of the intestinal microbiota, again particularly in those with <50% hair loss. We have identified novel immunological and microbial signatures in individuals with alopecia areata. Surprisingly, these are associated with lower levels of hair loss, and may therefore provide a rationale for improved targeting of molecular therapeutics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Leptin, produced by adipocytes, regulates metabolism, hunger, and immune response. The inflammatory role of leptin has been linked to autoimmune diseases. To assess leptin gene polymorphism and serum level in alopecia areata and their relation to metabolic syndrome (MS). This case-control study was conducted on 100 alopecia areata patients (50 with MS and 50 without MS) and 50 age- and gender-matched controls. Leptin gene polymorphism and serum level were assessed through the use of PCR and ELISA, respectively. GG genotype was the highest in AA with MS (54%), lower in AA without MS (42%), and the lowest in controls (20%). G allele was more expressed in cases, than in controls ( P < .001). The serum leptin level was the highest in AA with MS, lower in AA without MS, and the lowest in controls ( P value  = 0.001). Leptin level was significantly higher in GG polymorphism than AG and AA. Leptin gene polymorphism (GG genotype) and serum level appear to play a significant role in AA. Absent difference regarding leptin gene polymorphism and MS might indicate a separate inflammatory role of leptin or the future risk of MS development in AA patients.

Alopecia areata is a multifactorial autoimmune-based disease with a complex pathogenesis. As in all autoimmune diseases, genetic predisposition is key. The collapse of the immune privilege of the hair follicle leading to scalp loss is a major pathogenic event in alopecia areata. The microbiota considered a bacterial ecosystem located in a specific area of the human body could somehow influence the pathogenesis of alopecia areata, as it occurs in other autoimmune diseases. Moreover, the Next Generation Sequencing of the 16S rRNA bacterial gene and the metagenomic methodology have provided an excellent characterization of the microbiota. The aim of this narrative review is to examine the published literature on the cutaneous and intestinal microbiota in alopecia areata to be able to establish a pathogenic link. In this review, we summarize the influence of the microbiota on the development of alopecia areata. We first introduce the general pathogenic mechanisms that cause alopecia areata to understand the influence that the microbiota may exert and then we summarize the studies that have been carried out on what type of gut and skin microbiota is found in patients with this disease.

Alopecia Areata (AA) is characterised by an autoimmune response to hair follicles (HFs) and its exact pathobiology remains unclear. The current study aims to look into the molecular changes in the skin of AA patients as well as the potential underlying molecular mechanisms of AA in order to identify potential candidates for early detection and treatment of AA. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules, hub genes, and mRNA-miRNA regulatory networks associated with AA. Furthermore, Chi2 as a machine-learning algorithm was used to compute the gene importance in AA. Finally, drug-target construction revealed the potential of repositioning drugs for the treatment of AA. Our analysis using four AA data sets established a network strongly correlated to AA pathogenicity based on GZMA, OXCT2, HOXC13, KRT40, COMP, CHAC1, and KRT83 hub genes. Interestingly, machine learning introduced these genes as important in AA pathogenicity. Besides that, using another ten data sets, we showed that CHAC1 could clearly distinguish AA from similar clinical phenotypes, such as scarring alopecia due to psoriasis. Also, two FDA-approved drug candidates and 30 experimentally validated miRNAs were identified that affected the co-expression network. Using transcriptome analysis, suggested CHAC1 as a potential diagnostic predictor to diagnose AA., (© 2022 The Authors. IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

Introduction: Alopecia areata (AA) is a non-scarring, hair loss disorder and a common autoimmune-mediated disease with an estimated lifetime risk of about 2%. To date, the treatment of AA is mainly based on suppression or stimulation of the immune response. Genomics and transcriptomics studies generated important insights into the underlying pathophysiology, enabled discovery of molecular disease signatures, which were used in some of the recent clinical trials to monitor drug response and substantiated the consideration of new therapeutic modalities for the treatment of AA such as abatacept, dupilumab, ustekinumab, and Janus Kinase (JAK) inhibitors., Areas Covered: In this review, genomics and transcriptomics studies in AA are discussed in detail with particular emphasis on their past and prospective translational impacts. Microbiome studies are also briefly introduced., Expert Opinion: The generation of large datasets using the new high-throughput technologies has revolutionized medical research and AA has also benefited from the wave of omics studies. However, the limitations associated with JAK inhibitors and clinical heterogeneity in AA patients underscore the necessity for continuing omics research in AA for discovery of novel therapeutic modalities and development of clinical tools for precision medicine.

Autoimmunity, the reaction of the host against self, is a complex pattern of immunologic response that allows the immune system to react to "normal" tissue. Many such diseases exist in the skin, but in particular, two stand out as visible manifestations of autoimmune cutaneous attack. These are vitiligo, the immune attack on the melanocyte, and alopecia areata, the immune attack of the hair unit. These two illnesses include the prototypes of "simple" attacks on specific components of the skin. Other such illnesses are psoriasis-a complex series of immunologic responses resulting in a characteristic pattern of keratinocyte hyperproliferation-and lichen planus, which is similarly associated with a typical cutaneous skin disease pattern, but these will not be included in this review. In comparison, autoimmune polyendocrinopathies have defined pathways of disease based on single-gene mutations that can result in a variety of autoimmune skin features including vitiligo and alopecia areata. This contribution reviews known patterns of autoimmunity in childhood skin disease with a particular focus on single-gene disorders where they exist, and the more common multifactorial genes that contribute to this breach of the immune system's regulatory checks and balances. Genetic mechanisms that will be covered include innate and adaptive immunity, major histocompatibility complex II class associations, genetic polymorphisms, and major histocompatibility complex I class associations that bridge autoinflammatory and autoimmunity states, as well as alterations in oxidative metabolism promoting tissue destruction. End-organ tissue destruction appears to occur via interferon gamma and cytotoxic mediated activity and is a promising new therapeutic target. Janus kinase inhibitors also have the benefit clinically of both affecting the immune cascade at the cytotoxic T cell level and allowing triggering of melanocyte and hair follicular activity through the signal transducer and activator of transcription pathway, representing an attractive therapeutic with dial activity, among other cytokines implicated in end-organ destruction. Transplacental autoimmunity will not be covered herein. Greater insight into mechanisms of pediatric cutaneous autoimmunity in vitiligo and alopecia areata has yielded better therapeutic options and interventions. Understanding the basis of autoimmune triggering in our patients, that is, personalized medicine, may allow for targeted therapeutics with a goal of induction of remission, regeneration, or rejuvenation of the end-organ with the least toxic side effect profile., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To provide evidence of the association between CLTA-4 gene polymorphisms and alopecia areata (AA)., Methods: PubMed, EMBASE, Web of Science, Cochrane, Wanfang, and CNKI databases were searched until 30 April 2021. The selection was completed according to the inclusion and exclusion criteria. The study quality assessment was based on Newcastle-Ottawa Scale. The assessment of the association was measured by ORs and 95%CIs., Results: Nine studies, containing 2858 AA cases and 5444 disease-free control subjects were included. For rs231775 polymorphism, no significant association with AA was found, which was A vs. a, OR = 1.02 [0.81, 1.30], p  = 0.85; AA vs. aa, OR = 1.26 [0.81, 1.97], p  = 0.31; Aa vs. aa, OR = 1.04 [0.54, 2.01], p  = 0.91; AA + Aa vs. aa, OR = 1.04 [0.71, 1.53], p  = 0.82; AA vs. Aa + aa, OR = 1.31 [0.97, 1.78], p  = 0.08. For rs3087243 polymorphism, also no significant association was found, which was A vs. a, OR = 0.93 [0.78, 1.11]; p  = 0.40, AA vs. aa, OR = 0.68 [0.44, 1.06]; p  = 0.09; Aa vs. aa, OR = 0.87 [0.45, 1.68], p  = 0.68; AA + Aa vs. aa, OR = 0.93 [0.68, 1.28], p  = 0.66; AA vs. Aa + aa, OR = 0.78 [0.34, 1.81], p  = 0.57. For rs231726 polymorphism, a significant correlation was found, which was A vs. a, OR = 0.76 [0.70, 0.82], p  < 0.05., Conclusions: A significant correlation between CTLA-4 rs231726 polymorphism and AA susceptibility was found, but no significant association of CTLA-4 gene rs231775 and rs3087243 polymorphisms and AA susceptibility was found.