Background: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown. Objective: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. Methods: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 103 Genomics. Results: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5 1 COL18A1 1 subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 1 dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A 1 FCER1A 1) and tissue-resident memory T cells (CD69 1 CD103 1). The frequencies of type 2 (IL13 1)/type 22 (IL22 1) T cells were higher than those of type 1 (IFNG 1) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. Conclusion: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN) response signatures in tubular cells and in keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous, and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histological differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

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The vertebrate-conserved RNA-binding protein (RBP) DND1 is required for survival of primordial germ cells (PGCs), as well as germ cell tumour (TGCT) suppression in mice1–5. Here we report that DND1 binds a UU[A/U] trinucleotide motif predominantly in messenger RNA (mRNA) 3′ untranslated regions (UTRs), and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase (CCR4) complex. Transcriptomic analysis revealed that the extent of suppression is dependent on the number of DND1 binding sites. The DND1-dependent mRNA destabilization is required for survival of murine PGCs and spermatogonial stem cells (SSCs) by suppressing apoptosis. The target RNA spectrum includes positive regulators of apoptosis, inflammation, and modulators of signalling pathways regulating stem cell pluripotency including the TGF-β super family, all of which are aberrantly elevated in Dnd1-deficient PGCs. We propose that the induction of the posttranscriptional suppressor DND1 synergizes with concurrent transcriptional changes to sharpen developmental transitions during cellular differentiation and maintenance of the germline.

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