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BackgroundIn previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain.ObjectiveOur aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate ex vivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis.MethodsWe harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously.ResultsUnsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes.ConclusionWe propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases.

Introduction Pemphigus is a rare and life-threatening autoimmune disease that manifests as blisters and erosions on skin and/or mucosa. It is mediated by autoreactive B cells targeting desmoglein 1 (DSG1) [...], BACKGROUND. Pemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy. METHODS. Skin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed. RESULTS. We demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, [CD4.sup.+] T cells predominantly produced CXCL13. These clonally expanded [CXCL13.sup.+][CD4.sup.+] T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with [CXCL13.sup.+][CD4.sup.+] memory T cells and increased CXCL13 production of [CD4.sup.+] T cells through IL-2 consumption and TGF-p stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus. CONCLUSION. Through this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving [CXCL13.sup.+][CD4.sup.+] T cells and Tregs within these structures plays an important role in CXCL13 production. TRIAL REGISTRATION. ClinicalTrials.gov NCT04509570. FUNDING. This work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).

Background: Trials and real‐life studies demonstrated clinically meaningful improvements of disease activity in the majority of patients with moderate to severe atopic dermatitis (AD) treated with the anti‐IL‐4RA‐antibody dupilumab. However, misdiagnosis or confounding skin diseases in particular cutaneous T‐cell lymphoma (CTCL) may lead to inadequate response. Objective: To investigate the clinical and pathological features of patients with AD who showed insufficient response to dupilumab. Methods: We reviewed the medical records of 371 patients treated with dupilumab for severe AD. Insufficient response was defined as failure to achieve an improvement of the eczema area severity index (EASI) of at least 50% (EASI‐50) at Week 16 and of 75% (EASI‐75) at Week 52. Among 46 patients with insufficient response, 35 patients consented to a re‐evaluation including a full physical exam, biopsies and laboratory assessments including immunohistochemistry and T‐cell receptor gene rearrangement analysis to differentiate CTCL. Results: Of the 371 patients treated with dupilumab, 46 (12.3%) patients showed insufficient response to dupilumab. Of these, 35 underwent further evaluation, and 19 (54.2% of inadequate responders) were finally diagnosed with mycosis fungoides (MF). In these patients, transition to or addition of conventional MF treatment led to clinical improvements. Conclusions: Insufficient response to dupilumab treatment may help uncover early MF on an existing AD background. [ABSTRACT FROM AUTHOR]

This article discusses a study that used spatial transcriptomics to gain insights into the pathogenesis and therapy of pemphigus vulgaris (PV) and bullous pemphigoid (BP), which are autoimmune bullous skin diseases. The study compared the gene expression profiles of intact and blistered epidermis, as well as dermal immune cells, in PV and BP patients. The findings revealed distinct pathways and gene expression patterns associated with blister formation in each disease. The study provides a foundation for identifying potential therapeutic targets to regulate intracellular pathways involved in blister formation. [Extracted from the article]

Background: Efforts to profile atopic dermatitis (AD) tissues have intensified, yet comprehensive analysis of systemic immune landscapes in severe AD remains crucial. Methods: Employing single‐cell RNA sequencing, we analyzed over 300,000 peripheral blood mononuclear cells from 12 severe AD patients (Eczema area and severity index (EASI) > 21) and six healthy controls. Results: Results revealed significant immune cell shifts in AD patients, including increased Th2 cell abundance, reduced NK cell clusters with compromised cytotoxicity, and correlated Type 2 innate lymphoid cell proportions with disease severity. Moreover, unique monocyte clusters reflecting activated innate immunity emerged in very severe AD (EASI > 30). While overall dendritic cells (DCs) counts decreased, a distinct Th2‐priming subset termed "Th2_DC" correlated strongly with disease severity, validated across skin tissue data, and flow cytometry with additional independent severe AD samples. Beyond the recognized role of Th2 adaptive immunity, our findings highlight significant innate immune cell alterations in severe AD, implicating their roles in disease pathogenesis and therapeutic potentials. Conclusion: Apart from the widely recognized role of Th2 adaptive immunity in AD pathogenesis, alterations in innate immune cells and impaired cytotoxic cells have also been observed in severe AD. The impact of these alterations on disease pathogenesis and the effectiveness of potential therapeutic targets requires further investigation. [ABSTRACT FROM AUTHOR]

Here, we present a case of a 53-year-old female patient with chronic neck pain and systemic inflammation who was ultimately diagnosed with systemic lupus erythematosus. Notably, applying fat-suppressed T2-weighted MRI sequences was pivotal in detecting structural fascial changes commonly associated with systemic inflammatory diseases. PET-CT scans further revealed systemic inflammation around multiple joints, providing valuable insights into MRI signal alterations. This case underscores the importance of considering systemic autoimmune pathology as a potential underlying cause of chronic musculoskeletal pain. It also highlights the clinical utility of MRI with fat suppression sequences in identifying inflammation-related fascial changes. This case emphasizes the significance of a comprehensive evaluation, particularly in situations where clinical features overlap between autoimmune and degenerative skeletal pathologies. Fat-suppressed MRI can provide information about fascial pathology related to systemic inflammatory diseases. In this context, it is worth noting that PET-CT and fat suppression MRI complement each other by providing complementary information about inflammation and the underlying causes of a patient's pain. [ABSTRACT FROM AUTHOR]