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Gene expression signatures in inflammatory and sclerotic morphea skin and blood distinguishes morphea from systemic sclerosis

ABSTRACT: Morphea is an inflammatory disorder of the skin and soft tissue characterized by fibrosis that has been likened to systemic sclerosis (SSc). We sought to capture the molecular heterogeneity of morphea by examining lesional skin gene expression and blood biomarkers, and compare the gene expression profiles with those from SSc lesional and site matched non lesional skin, as well as sera obtained from adult patients with untreated morphea. We found the morphea transcriptome is dominated by IFNg-mediated Th1 immune dysregulation, with relative paucity of pathways associated with fibrosis. These results were mirrored when morphea gene expression profiles were compared with SSc. Interestingly, expression profiles of morphea skin samples clustered with the SSc inflammatory subset and distinct from the SSc fibro-proliferative subset. Unaffected morphea skin also differed from unaffected SSc skin in that it did not exhibit pathological gene expression signatures. Examination of downstream IFNg-mediated chemokines, CXCL9 and CXCL10, revealed increased transcription in the skin but not in sera. While elevated serum CXCL9 proteins quantified by ELISA were associated with active disease and widespread cutaneous disease. Taken together, these results indicate that inflammatory and sclerotic morphea is a skin directed process characterized by Th1 immune mediated dysregulation, which contrasts with fibrotic signatures and systemic transcriptional changes associated with SSc. The association of circulating CXCL9 concentration with clinical activity and burden of skin disease supports its potential as a readily accessible biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201405 | GEO | 2025/04/13

REPOSITORIES: GEO

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Project description:Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being FDA-approved. Although vitiligo is primarily regarded as a Th1/IFN-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: To obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Results: Robust inflammatory dysregulation was captured not only in lesional, but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of Th1 (OASL, CXCL9, CXCL10), Th2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and Th17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of Th1 (CXCL9, OASL), Th2 (IL4R, IL10, CCL13, CCL17, CCL22), and Th17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (VASI and/or VIDA) significantly and positively correlated with multiple inflammatory mediators (i.e., CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. Conclusions: Our findings show that immune dysregulation in vitiligo involves immune axes beyond Th1/Tc1, with upregulation of particularly type 2 markers already in nonlesional skin, suggesting a role during early lesion formation. Capsule Summary: We suggest that the inflammatory dysregulation of vitiligo is more complex than previously appreciated, involving not only Th1, but also Th2 and some components of Th17/22 immune axes, even in clinically normal appearing skin. Clinical implications: The dysregulation of multiple inflammatory mediators in nonlesional vitiligo skin might have major implications for future targeted treatment approaches.

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Gene expression signatures in inflammatory and sclerotic morphea skin and blood distinguishes morphea from systemic sclerosis

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