1 Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China.
2 Department of Dermatology, Veterans Affairs Medical Center, San Francisco, CA, United States.
3 Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States.
4 Department of Statistics, University of California, Berkeley, Berkeley, CA, United States.
5 Clinical Research Centre, Medical University of Białystok, Białystok, Poland.
6 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
7 Department of Plastic Surgery, University of California, San Francisco, San Francisco, CA, United States.
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Identifying genetic variation underlying human diseases establishes targets for therapeutic development and helps tailor treatments to individual patients. Large-scale transcriptomic profiling has extended the study of such molecular heterogeneity between patients to somatic tissues. However, the lower resolution of bulk RNA profiling, especially in a complex, composite tissue such as the skin, has limited its success. Here we demonstrate approaches to interrogate patient-level molecular variance in a chronic skin inflammatory disease, psoriasis vulgaris, leveraging single-cell RNA-sequencing of CD45+ cells isolated from active lesions. Highly psoriasis-specific transcriptional abnormalities display greater than average inter-individual variance, nominating them as potential sources of clinical heterogeneity. We find that one of these chemokines, CXCL13, demonstrates significant correlation with severity of lesions within our patient series. Our analyses also establish that genes elevated in psoriatic skin-resident memory T cells are enriched for programs orchestrating chromatin and CDC42-dependent cytoskeleton remodeling, specific components of which are distinctly correlated with and against Th17 identity on a single-cell level. Collectively, these analyses describe systematic means to dissect cell type- and patient-level differences in cutaneous psoriasis using high-resolution transcriptional profiles of human inflammatory disease.
JC and RC receive support (research grants to their institution) from LEO Pharmaceuticals, Sanofi, and Pfizer. 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.
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