Transcriptomic profiling of vitiligo patients shows polar immune dysregulation in involved and uninvolved skin.

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.

Methods: We performed bulk RNA-sequencing combined with real-time PCR and immunohistochemistry of skin biopsies from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing.

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.