●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●Skin gene module●●●●●●●●●●●●●●●●●●●●●●●●●●7IMS researchers provide proof-of-concept that pa-tients can be stratified based on disease phenotype and trajectory to enable a more personalized ap-proach to treatment.Heterogeneity in skin manifestationsCross-sectional, cross-tissue analysisPapulationDifferential molecular signatures linked totwo differential skin manifestationsErythemaY, Amagai M, Koseki H. Multifaceted analysis of cross-tissue tran-scriptomes reveals phenotype-endotype associations in atopic dermatitis. Nat Commun 14, 6133 (2023)SkinPBMCPBMC gene moduleClinical data●●Heterogeneity in disease trajectoriesLongitudinal analysisDisease severityPBMC gene expressionTreatmentTimePatient clusters with differential patternsof longitudinal features・・・・・・●●●●●●●●Atopic dermatitis is characterized by inflamed and often intensely itchy skin that can occur on and off over a patient’s lifetime. The disease is highly heterogeneous, with the initiation of the disease, the location of skin rashes, the disease course, and its severity all varying widely from per-son to person – making it both difficult to study and treat.Historically, researchers have simplified atopic der-matitis studies by omitting the disease’s heterogeneous, systemic, and chronic aspects. According to Aiko Sekita, a Research Scientist from the Laboratory for Developmental Genetics led by Haruhiko Koseki at IMS, studies to date have mostly opted for the straightforward strategy of ex-amining either skin samples or blood samples taken from patients at a single time point.Up to the challenge of exploring the neglected hetero-geneity of atopic dermatitis, Sekita and the team led by Koseki collaborated with researchers at Keio University to tackle the problem from multiple angles.In the first part of their study published in Nature Com-munications, the team conducted cross-sectional transcrip-tome analysis. This approach accounted for both the local and systemic aspects of atopic dermatitis by examining skin and blood samples from 115 patients and 14 healthy controls. It also highlighted the heterogeneity of symptoms by grouping patients based on two clinically distinct skin manifestations: erythema or skin redness, and papulation or the development of small bumps on the skin.“This is the first study to integrate the different tis-sue types, especially in terms of the transcriptome,” noted Sekita, adding that the detailed analysis of the two skin manifestations is likewise unique.According to Sekita, it is difficult to combine the tran-scriptomes of different tissues due to their tissue depen-dency. The team overcame this hurdle by conducting co-expression analysis to identify modules of functionally-related genes expressed in both skin and blood. Based on the resulting 21 skin and 15 blood modules, they then de-veloped a model to extract factors that contribute to either an erythema- or papulation-dominant phenotype.Despite some overlap, patients with these phenotypes tended to have different immunological signatures, sug-gesting the possibility of stratifying patients by skin mani-festations to inform treatment decisions.“Currently we don’t know which drug is suitable to which patient subset, but, in the future, patients and physi-cians might be able to choose treatments based on each patient’s molecular signature,” Sekita explained.In the second part of their study, the team accounted for the chronic nature of atopic dermatitis by following 30 pa-tients for up to one year – analyzing their transcriptomes, conducting relevant laboratory tests, and assessing severity. Through application of the transcriptomic modules identi-fied in their cross-sectional analysis, the researchers out-lined three patient clusters with distinct patterns of innate immune activity that are associated with disease course and medication history.These findings provide proof-of-concept that it is also possible to stratify patients on the basis of disease trajec-tory for more personalized treatment. However, Sekita notes that due to the limited sample size of the longitudinal analysis, the results should be verified in wider popula-tions. Including racially and ethnically diverse datasets would also be important to account for disease heterogene-ity, she concluded.Figure: Cross-sectional and longitudinal analyses help unravel the heterogeneous nature of atopic dermatitisCross-sectional analyses of the transcriptomes of both skin and peripheral blood mononuclear cells (PBMC) led to the identification of molecular factors that contribute to either an erythema- or papulation-dominant phe-notype. Subsequently, longitudinal analysis of patients for up to one year identified three patient clusters with distinct immune signatures that correlated with disease course and treatment history. These findings provide novel ways to stratify patients for more personalized treatment.Original paper:Sekita A*, Kawasaki H, Fukushima-Nomura A, Yashiro K, Tanese K, Toshima S, Ashizaki K, Miyai T, Yazaki J, Kobayashi A, Namba S, Naito T, Wang Q, Kawakami E, Seita J, Ohara O, Sakurada K, Okada ●●●●●●●●●●Blood tests●●●●Haruhiko KosekiHighlighting heterogeneity in atopic dermatitis
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