ABSTRACT Background Alopecia areata (AA) frequently co‐occurs with atopic dermatitis (AD; AA‐AD); however, AA‐AD's features remain unclear. Objective To elucidate the clinical and immunological features of AA‐AD. Methods Retrospective analysis of data from 123 AA‐AD patients, 119 non‐atopic AA patients, and 126 AD patients (2011–2024). Peripheral blood mononuclear cells (PBMCs), plasma, and scalp tissues from patients and healthy controls (HC) were examined by flow cytometry, multiplex cytokine assays, and immunofluorescence. Results Clinically, AA‐AD patients were younger than non‐atopic AA and AD‐only patients, showed more severe alopecia and longer duration, but milder eczema, and exhibited higher dust‐mite allergy, total IgE (tIgE), and Eos counts/percentages than non‐atopic AA, while showing more intrinsic AD and lower tIgE and Eos counts/percentages than AD‐only patients. AA severity and duration were positively correlated with those of AD. Compared with AA‐AD patients with AA‐first onset and AA with intrinsic AD (AA‐IAD) patients, AA‐AD patients with AD‐first onset and AA with extrinsic AD (AA‐EAD) patients were younger, had more severe eczema, higher tIgE levels, and dust‐mite allergy. Compared with the non‐atopic AA group and HC, the AA‐AD group showed elevated plasma IL‐4/6/10/13 levels and increased Th2 cells and ILC2s (group 2 innate lymphoid cells) proportions in PBMCs, along with their IL‐13 production, all of which were positively correlated with AA course. AA‐AD scalp also showed that Th2 cells and ILC2s were most abundant. Conclusion AA‐AD defines a distinct clinical‐immunologic endotype of AA. AA and AD exhibit an asymmetric but bilateral interaction driven by Th2/ILC2s‐IL‐13‐centered pathways, representing key mechanisms and targets for precision therapy.
ABSTRACT Introduction While eosinophils are established pathogenic drivers and therapeutic targets in asthma, their role in chronic obstructive pulmonary disease (COPD) remains conflicting. This study aimed to investigate the bidirectional associations of eosinophils with COPD and asthma, and to elucidate the potential distinct underlying mechanisms. Methods In 302,370 UK Biobank participants, multivariable‐adjusted Cox proportional hazards models assessed associations between blood eosinophil counts and incident COPD, asthma, and asthma COPD overlap (ACO). Bidirectional two‐sample Mendelian randomization (MR) tested causality. Among 32,121 participants with available baseline Olink proteomic data, proteomic profiling characterized eosinophil‐associated plasma protein signatures and their associations with disease risk. Results During approximately 13.5 years of follow‐up, elevated blood eosinophils were associated with increased risks of COPD, asthma, and ACO. Unlike asthma, pre‐existing COPD did not predict subsequent eosinophil elevation. MR indicated a unidirectional effect of eosinophils on COPD but bidirectional causality for asthma. Proteomics revealed a broader protein interaction network in COPD (378 proteins) than in asthma (70 proteins). Exploratory mediation analyses, assuming an eosinophil‐to‐protein direction, estimated that the eosinophil‐associated proteomic signature statistically accounted for 87.8% of the association with COPD ( p = 0.076) and 59.1% of the association with asthma ( p < 0.001). Among these proteins, COPD‐associated mediators were linked to a broad and intricately woven inflammatory network, in contrast to the more streamlined network that is mainly confined to Type 2 inflammation seen in asthma. Conclusion Although elevated eosinophil levels are associated with increased COPD risk, their pathogenic role—embedded within a complex inflammatory network—differs fundamentally from the Th2‐centric inflammatory pathway characteristic of asthma. This observational study suggests that eosinophilic COPD is not simply a surrogate for asthma‐like Type 2 inflammation.
