Uncovering the early interactions and spatial distribution of dermal fibroblasts and immune cells in treatment-naive patients with diffuse cutaneous systemic sclerosis (SSc) is critical to understandi Show more
Uncovering the early interactions and spatial distribution of dermal fibroblasts and immune cells in treatment-naive patients with diffuse cutaneous systemic sclerosis (SSc) is critical to understanding the earliest events of skin fibrosis. We generated an integrated multiomic dataset of early-stage, treatment-naive diffuse cutaneous SSc skin. Skin biopsies were analyzed by single-nuclei multiome sequencing (snRNA-Seq and snATAC-Seq) and two spatial transcriptomic methods to comprehensively determine molecular changes. We identified an immunomodulatory niche within the papillary, hypodermis, and vascular regions enriched for activated myeloid cells and fibroblasts characterized by expression of genes such as CXCL12, APOE, and C7. Pathway analyses showed significant enrichment of PI3K/AKT/mTOR signaling pathway expression in these cellular niches, driven by profibrotic growth factor signaling networks. Macrophage subclustering showed SSc-specific macrophage activation of IL-6/JAK/STAT signaling and enrichment of oxidative phosphorylation pathways. Ligand-receptor analysis revealed that SSc macrophages secrete PDGF and TGF-β to activate SSc-dominant fibroblast subclusters. Spatial transcriptomic analyses showed monocyte-derived MRC1+ macrophages express PDGF near PDGFRhiTHY1hi fibroblasts. Multiomic data integration and spatial transcriptomic neighborhood analysis revealed the colocalization of fibroblasts, macrophages, and T cells around the vasculature. These data suggest that interactions between activated immune cells and immunomodulatory fibroblasts around vascular niches are an early event in scleroderma pathogenesis. Show less
Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has em Show more
Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations. Show less