A5090620591- T-cell and B-cell Immunology
- Rheumatoid Arthritis Research and Therapies
- Cancer-related molecular mechanisms research
- Immunotherapy and Immune Responses
- Lymphoma Diagnosis and Treatment
- Systemic Lupus Erythematosus Research
- Immune Cell Function and Interaction
- Musculoskeletal synovial abnormalities and treatments
- Osteoarthritis Treatment and Mechanisms
- Circular RNAs in diseases
- Extracellular vesicles in disease
- MicroRNA in disease regulation
- Salivary Gland Disorders and Functions
- RNA Research and Splicing
- RNA modifications and cancer
- Immune Response and Inflammation
- Inflammatory Myopathies and Dermatomyositis
- Systemic Sclerosis and Related Diseases
- Multiple Myeloma Research and Treatments
- Diabetes and associated disorders
- Protein Degradation and Inhibitors
- Single-cell and spatial transcriptomics
- Autoimmune and Inflammatory Disorders Research
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
University of Zurich
2020-2025
University Hospital of Zurich
2020-2025
Karolinska Institutet
2016-2023
Karolinska University Hospital
2016-2023
Center for Rheumatology
2022
Abstract Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, accessibility, and gene expression FLS, B T cells with genetic fine mapping RA loci. Results We identify...
We present an optimized dissociation protocol for preparing high-quality skin cell suspensions in-depth single-cell RNA-sequencing (scRNA-seq) analysis of fresh and cultured human skin. Our enabled the isolation a consistently high number highly viable cells from small freshly dissociated punch biopsies, which we use scRNA-seq studies. recapitulated not only main populations existing atlases, but also identified rare populations, such as mast cells. Furthermore, effectively isolated single
Abstract Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie progression depending on location. Here, we identify joint-specific changes RA synovium and synovial fibroblasts (SF) between knee hand joints. We show the long non-coding RNA HOTAIR, which is only expressed SF, regulates more than 50% of this site-specific gene...
Glucocorticoids (GCs) exert potent anti-inflammatory effects in immune cells through the glucocorticoid receptor (GR). Dendritic (DCs), central actors for coordinating responses, acquire tolerogenic properties response to GCs. Tolerogenic DCs (tolDCs) have emerged as a potential treatment various inflammatory diseases. To date, underlying cell type-specific regulatory mechanisms orchestrating GC-mediated acquisition of immunosuppressive remain poorly understood. In this study, we...
In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a atlas human synovium in inflammatory arthritis. The protocol allowed consistent isolation highly viable cells from tiny fresh biopsies, minimizing biopsy drop-out rate. scRNA-seq contained over 100,000 unsorted 25 tissues affected by arthritis, including 16 structural, 11 lymphoid, 15 myeloid cell clusters. This map expanded diversity types/states, detected neutrophils,...
Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, I diabetes, and inflammatory bowel disease. However, functional consequences of these are poorly characterized. Herein, we show blood cells that PTPN2 highly correlated DNA methylation levels at four CpG sites downstream expression long non-coding RNA (lncRNA) LINC01882 sites. We observed is mainly expressed T anti-CD3/CD28...
Abstract The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number studies exploring function in T cells, exact impact on T‐cell humans still unclear. In this study, using RNA sequencing, we show that, upon TCR‐activation, naïve human CD4 + cells homozygous for overexpress set genes CFLAR and 4‐1BB , which are important cytotoxic differentiation. Moreover, protein expression T‐box transcription factor...
Salivary gland dysfunction is a hallmark of Sjögren's disease (SjD). Here, we investigated the pro-inflammatory properties salivary gland-derived fibroblasts (SGF) that were cultured from minor (MSG) tissues patients with SjD and controls. SGF exhibited higher rates proliferation compared to RNA sequencing revealed pronounced in response stimulation IL1 polyI:C, an activation "interferon responses", "JAK STAT", "NF-kappa B" signaling, as well "complement" pathways. In addition encoding...
Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies, a chronic disorder clinically characterized by muscle weakness cell infiltrates in tissue. In PM, major component is CD8+ T cells, whereas DM, CD4+ plasmacytoid dendritic B cells predominate. this study, with the aim to differentiate involvement T-cell subpopulations myositis subgroups, we investigated transcriptomic profiles from peripheral blood patients myositis. Total RNA was...
HLA-DRB1 alleles have been associated with several autoimmune diseases. For anti-citrullinated protein antibody positive rheumatoid arthritis (RA), shared epitope (SE) are the major genetic risk factors. In order to study regulation of histocompatibility complex (MHC) Class II gene expression in immune cells, we investigated transcriptomic profiles a variety cells from healthy individuals carrying different alleles. Sequencing libraries peripheral blood mononuclear CD4+ T CD8+ and CD14+...
Significance The role of the MHC region has been a long-standing issue in chronic inflammatory diseases, such as rheumatoid arthritis, and it not possible to identify underlying specific polymorphism. Here, we provide evidence that some association must be explained by how closely linked genes operate together haplotype blocks. We identified conserved haplotype, Ltab-Ncr3, comprising five ( lymphotoxin α β, Tnf , leukocyte-specific transcript 1 natural cytotoxicity-triggering receptor 3 )...
Objective We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extraterminal motif (BET) proteins translate changes into transcription. Here, we used a BET inhibitor (I‐BET151) to target inflammatory tissue reduce flare severity in murine experimental model. Methods BALB/c mice were treated intraperitoneal injection or local the paw with I‐BET151, which blocks interaction...
Bromodomain- and extra-terminal domain (BET) proteins are epigenetic reader that regulate transcription of their target genes by binding to acetylated histone side chains. Small molecule inhibitors, such as I-BET151, have anti-inflammatory properties in fibroblast-like synoviocytes (FLS) animal models arthritis. Here, we investigated whether BET inhibition can also affect the levels modifications, a novel mechanism underlying protein inhibition. On one hand, FLSs were treated with I-BET151...
Abstract The microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and direct downstream target of TP53 with roles in several pathways associated oncogenesis, such as proliferation, cellular growth, differentiation. Due to its broad suppressive activity, it not surprising that miR34a expression altered wide variety solid tumors hematological malignancies. However, the mechanisms by which regulated these cancers largely unknown. In this study, we find long noncoding RNA transcribed...
Background Articular involvement is underestimated in systemic sclerosis (SSc), but represents a major cause of disability and marker disease severity. There no approved effective therapy for arthritis SSc immunosuppressive treatments are given to patients by analogy with rheumatoid (RA), limited effect. The last few years have revolutionized the understanding pathogenesis RA deciphering heterogeneity synovium at both cellular molecular levels. Nevertheless, joint remains largely unknown....
<h3>Background:</h3> The pathogenesis of synovitis in systemic sclerosis (SSc) is unknown. Due to the lack evidence-based therapies, SSc patients with are treated as rheumatoid arthritis (RA) patients, however unknown effect. Previously, we showed that differs from RA a prevalent pauci-immune pathotype. <h3>Objectives:</h3> To decipher histological, cellular, and transcriptional differences between synovitis, specifically synovial fibroblasts (SF). <h3>Methods:</h3> We collected...
ABSTRACT We previously demonstrated that Homeobox (HOX) transcription factors are differentially expressed between joint locations and can accurately assign synovial fibroblasts (SFs) to their correct location. show here the expression of 5’HOXD HOXD10, HOXD11, HOXD13 in SFs strikingly overlaps with predilection sites for development rheumatoid arthritis (RA). Changes gene after silencing 5’HOXDs aligned joint-specific differences RA SFs. In particular, we identify as regulator or primary...
Abstract Single-cell RNA-sequencing is advancing our understanding of synovial pathobiology in inflammatory arthritis. Here, we optimized the protocol for dissociation biopsies and created a comprehensive reference single-cell atlas fresh human synovium We derived from published method cryopreserved (Donlin L. et al. Arthritis Res. Ther. 2019) with modifications to enrich cells minimize cell loss. These enabled consistently high yield viability, thereby minimizing rate tissue sample dropout....
Abstract Genome-wide association studies have reported >100 risk loci for rheumatoid arthritis (RA). These been shown to be enriched in immune cell-specific enhancers, but analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement the pathogenesis of RA. Here we integrated DNA architecture (ChIP-seq), 3D chromatin interactions (HiC, capture HiC), accessibility (ATAC-seq) and gene expression (RNA-seq) FLS, B cells T with genetic fine...
Background: Over the past decade, genome wide association studies (GWAS) have identified JAZF1 locus as a risk for several autoimmune diseases, including rheumatoid arthritis (RA) 1 . However, exact causal variants in and their underlying regulatory events contributing to RA are still not known. Here, we focus on effect of these gene expression synovial fibroblasts (SF). Objectives: To characterize functional consequences RA-causal SF. Methods: Genetic fine-mapping loci was conducted by...
<h3>Background</h3> Cell type- and stimulus-specific enhancers are key regulatory elements in chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) Sjögren`s syndrome (SjS). Recent transcriptome profiling of synovial fibroblasts (SF) from patients with RA minor salivary gland-derived fibroblast (SGF) SjS point to similarities populations derived these two diseases. Enhancer RNAs (eRNAs) short-lived non-coding transcribed cell type-specific that facilitate the...
Abstract Most forms of arthritis, have a distinctive topographical pattern joint involvement. Beyond these differences among diseases, there are also in phenotype and response to treatment between joints the same type suggesting that molecular mechanisms may differ depending on location. Here we show joint-specific tissue changes synovium local stromal cells (synovial fibroblasts;SF). The long non-coding RNA HOTAIR, expressed only lower extremities SF, regulates much this site-specific gene...