Psoriasis is a chronic, immune-mediated inflammatory skin disease associated with a polygenic mode of inheritance. There are few studies that explore the association of a psoriasis Polygenic Risk Score (PRS) with patient clinical characteristics, and to our knowledge there are no studies examining psoriasis PRS associations across different ethnicities. In this study, we used a multi-racial psoriasis cohort to investigate PRS associations with clinical phenotypes including age of onset, psoriatic arthritis, other comorbidities, psoriasis body location, psoriasis subtype, environmental triggers, and response to therapies. We collected patient data and Affymetrix genome-wide SNP data from a cohort of 607 psoriasis patients and calculated an 88-loci PRS (PRS-ALL), also partitioned between genetic loci within the HLA region (PRS-HLA; 11 SNPS) and loci outside the HLA region (PRS-NoHLA; 77 SNPS). We used t-test and logistic regression to analyze the association of PRS with clinical phenotypes. We found that PRS-HLA and PRS-noHLA had differing effects on psoriasis age of onset, psoriatic arthritis, psoriasis located on the ears, genitals, nails, soles of feet, skin folds, and palms, skin injury as an environmental trigger, cardiovascular comorbidities, and response to phototherapy. In some cases these PRS associations were ethnicity specific. Overall, these results show that the genetic basis for clinical manifestations of psoriasis are driven by distinct HLA and non-HLA effects, and that these PRS associations can be dependent on ethnicity.

Ankylosing spondylitis (AS) is an immune-mediated inflammatory disorder that primarily affects the axial skeleton, especially the sacroiliac joints and spine. This results in chronic back pain and, in extreme cases, ankylosis of the spine. Despite its debilitating effects, the pathogenesis of AS remains to be further elucidated. This study used single cell CITE-seq technology to analyze peripheral blood mononuclear cells (PBMCs) in AS and in healthy controls. We identified a number of molecular features associated with AS. CD52 was found to be overexpressed in both RNA and surface protein expression across several cell types in patients with AS. CD16⁺ monocytes overexpressed TNFSF10 and IL-18Rα in AS, while CD8⁺ T_EM cells and natural killer cells overexpressed genes linked with cytotoxicity, including GZMH, GZMB, and NKG7. Tregs underexpressed CD39 in AS, suggesting reduced functionality. We identified an overrepresented NK cell subset in AS that overexpressed CD16, CD161, and CD38, as well as cytotoxic genes and pathways. Finally, we developed machine learning models derived from CITE-seq data for the classification of AS and achieved an Area Under the Receiver Operating Characteristic (AUROC) curve of > 0.95. In summary, CITE-seq identification of AS-associated genes and surface proteins in specific cell subsets informs our understanding of pathogenesis and potential new therapeutic targets, while providing new approaches for diagnosis via machine learning.

It has long been recognized that anatomic location is an important feature for defining distinct subtypes of plaque psoriasis. However, little is known about the molecular differences between scalp, palmoplantar, and conventional plaque psoriasis. To investigate the molecular heterogeneity of these psoriasis subtypes, we performed RNA-seq and flow cytometry on skin samples from individuals with scalp, palmoplantar, and conventional plaque psoriasis, along with samples from healthy control patients. We performed differential expression analysis and network analysis using weighted gene coexpression network analysis (WGCNA). Our analysis revealed a core set of 763 differentially expressed genes common to all sub-types of psoriasis. In contrast, we identified 605, 632, and 262 genes uniquely differentially expressed in conventional, scalp, and palmoplantar psoriasis, respectively. WGCNA and pathway analysis revealed biological processes for the core genes as well as subtype-specific genes. Flow cytometry analysis revealed a shared increase in the percentage of CD4+ T regulatory cells in all psoriasis subtypes relative to controls, whereas distinct psoriasis subtypes displayed differences in IL-17A, IFN-gamma, and IL-22 production. This work reveals the molecular heterogeneity of plaque psoriasis and identifies subtype-specific signaling pathways that will aid in the development of therapy that is appropriate for each subtype of plaque psoriasis.

Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.

Early diagnosis of psoriatic arthritis (PSA) is important for successful therapeutic intervention but currently remains challenging due, in part, to the scarcity of non-invasive biomarkers. In this study, we performed single cell profiling of transcriptome and cell surface protein expression to compare the peripheral blood immunocyte populations of individuals with PSA, individuals with cutaneous psoriasis (PSO) alone, and healthy individuals. We identified genes and proteins differentially expressed between PSA, PSO, and healthy subjects across 30 immune cell types and observed that some cell types, as well as specific phenotypic subsets of cells, differed in abundance between these cohorts. Cell type-specific gene and protein expression differences between PSA, PSO, and healthy groups, along with 200 previously published genetic risk factors for PSA, were further used to perform machine learning classification, with the best models achieving AUROC ≥ 0.87 when either classifying subjects among the three groups or specifically distinguishing PSA from PSO. Our findings thus expand the repertoire of gene, protein, and cellular biomarkers relevant to PSA and demonstrate the utility of machine learning-based diagnostics for this disease.

The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4⁺ and CD8⁺ T effector cells and CD4⁺ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A , IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8⁺ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.

Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.

Background

Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8⁺ T cells have been identified as pathogenic drivers.

Objective

Our study focused on comprehensively characterizing the phenotypic variation of CD8⁺ T cells in psoriatic lesions.

Methods

We used single-cell RNA sequencing to compare CD8⁺ T-cell transcriptomic heterogeneity between psoriatic and healthy skin.

Results

We identified 11 transcriptionally diverse CD8⁺ T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8⁺ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program.

Conclusion

Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8⁺ T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.