Large-scale analysis of longitudinal skin gene expression in systemic sclerosis reveals relationships of immune cell and fibroblast activity with skin thickness and a trend towards normalisation over time

2021 ◽  
pp. annrheumdis-2021-221352
Author(s):  
Brian Skaug ◽  
Marka A Lyons ◽  
William R Swindell ◽  
Gloria A Salazar ◽  
Minghua Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Immunohistochemical Staining ◽  
Large Scale ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Principal Component ◽  
Skin Thickness ◽  
High Baseline ◽  
Over Time

ObjectivesDetermine relationships between skin gene expression and systemic sclerosis (SSc) clinical disease features, and changes in skin gene expression over time.MethodsA total of 339 forearm skin biopsies were obtained from 113 SSc patients and 44 matched healthy controls. 105 SSc patients had a second biopsy, and 76 had a third biopsy. Global gene expression profiling was performed, and differentially expressed genes and cell type-specific signatures in SSc were evaluated for relationships to modified Rodnan Skin Score (mRSS) and other clinical variables. Changes in skin gene expression over time were analysed by mixed effects models and principal component analysis. Immunohistochemical staining was performed to validate conclusions.ResultsGene expression dysregulation was greater in SSc patients with affected skin than in those with unaffected skin. Immune cell and fibroblast signatures positively correlated with mRSS. High baseline immune cell and fibroblast signatures predicted higher mRSS over time, but were not independently predictive of longitudinal mRSS after adjustment for baseline mRSS. In early diffuse cutaneous SSc, immune cell and fibroblast signatures declined over time, and overall skin gene expression trended towards normalisation. On immunohistochemical staining, most early diffuse cutaneous SSc patients with high baseline T cell and macrophage numbers had declines in these numbers at follow-up.ConclusionsSkin thickness in SSc is related to dysregulated immune cell and fibroblast gene expression. Skin gene expression changes over time in early diffuse SSc, with a tendency towards normalisation. These observations are relevant for understanding SSc pathogenesis and could inform treatment strategies and clinical trial design.

scholarly journals Enabling out-of-clinic human immunity studies via single-cell profiling of capillary blood

2020 ◽  
Author(s):  
Tatyana Dobreva ◽  
David Brown ◽  
Jong Hwee Park ◽  
Matt Thomson
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Environmental Factors ◽  
Single Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Capillary Blood ◽  
Specific Gene ◽  
Human Immune ◽  
Over Time

AbstractAn individual’s immune system is driven by both genetic and environmental factors that vary over time. To better understand the temporal and inter-individual variability of gene expression within distinct immune cell types, we developed a platform that leverages multiplexed single-cell sequencing and out-of-clinic capillary blood extraction to enable simplified, cost-effective profiling of the human immune system across people and time at single-cell resolution. Using the platform, we detect widespread differences in cell type-specific gene expression between subjects that are stable over multiple days.SummaryIncreasing evidence implicates the immune system in an overwhelming number of diseases, and distinct cell types play specific roles in their pathogenesis.1,2 Studies of peripheral blood have uncovered a wealth of associations between gene expression, environmental factors, disease risk, and therapeutic efficacy.4 For example, in rheumatoid arthritis, multiple mechanistic paths have been found that lead to disease, and gene expression of specific immune cell types can be used as a predictor of therapeutic non-response.12 Furthermore, vaccines, drugs, and chemotherapy have been shown to yield different efficacy based on time of administration, and such findings have been linked to the time-dependence of gene expression in downstream pathways.21,22,23 However, human immune studies of gene expression between individuals and across time remain limited to a few cell types or time points per subject, constraining our understanding of how networks of heterogeneous cells making up each individual’s immune system respond to adverse events and change over time.

scholarly journals P152 Skin score trajectory associates with survival and pulmonary outcome in diffuse cutaneous systemic sclerosis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Svetlana I Nihtyanova ◽  
Emma C Derrett-Smith ◽  
Carmen Fonseca ◽  
Voon H Ong ◽  
Christopher P Denton
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Complications ◽  
Rate Of Change ◽  
Skin Thickness ◽  
Group Level ◽  
Skin Score ◽  
Risk Of Death ◽  
Increased Risk ◽  
Diffuse Cutaneous Systemic Sclerosis ◽  
Over Time

Abstract Background Skin thickness improves over time in most diffuse cutaneous systemic sclerosis (dcSSc) patients and the use of group level skin score (mRss) as an endpoint is clinical trials can be challenging. We explore the association between individual mRss trajectories and outcome in early dcSSc patients. Methods Subjects with at least one mRss assessment within the first 5 years from onset were included. Random effects models were fitted to evaluate changes in mRss over time and model-predicted individual patient intercepts and slopes were included in Cox regression to assess associations with outcome. Results Of the 467 patients, 22.7% were male and mean age of disease onset was 45.5 years. Most frequent autoantibodies were anti-Scl70 in 30.2% and anti-RNA polymerase (ARA) in 30.0% of subjects. Average mRss at 12 months from onset was 25 and this declined over time, slowing down with longer disease duration (3.4, 2.7, 1.9 and 1.2 units at years 2, 3, 4 and 5). Higher initial mRss associated with greater subsequent decline (correlation coefficient -0.3). Both higher baseline mRSS (intercept) and slower decline (higher slope) predicted increased risk of death with 8% increase in hazard for every unit higher baseline mRss and 4% increase for every unit higher slope (Table 1). Adjusting for autoantibodies did not change the estimates. ANA+ENA- subjects had the highest risk of death, followed by ATA + (HR 0.91, p = 0.677 v ANA+ENA-), while risk was lowest among ARA+ subjects (HR 0.47, p = 0.002 v ANA+ENA-). Risk of pulmonary complications was associated with rate of change in mRss but not with baseline absolute value. A unit slower yearly decline in mRss increased the hazard of pulmonary fibrosis (PF) by 3.5% and pulmonary hypertension (PH) by 7% (Table 1). The association between mRss and PF disappeared after adjusting for antibody specificities, while the association between skin and PH did not change. Autoantibodies did not show significant association with PH development within this dcSSc cohort. Conclusion Although at a group level there is an improvement in skin over the initial 5 years, for individual patients, poor outcome for skin predicts increased risk of pulmonary complications and higher mortality. Disclosures S.I. Nihtyanova None. E.C. Derrett-Smith None. C. Fonseca None. V.H. Ong None. C.P. Denton None.

scholarly journals Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

2019 ◽  
Vol 79 (3) ◽  
pp. 379-386 ◽  
Author(s):  
Brian Skaug ◽  
Dinesh Khanna ◽  
William R Swindell ◽  
Monique E Hinchcliff ◽  
Tracy M Frech ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
T Cell ◽  
Disease Duration ◽  
Immune Cell ◽  
Study Cohort ◽  
Progression Rate ◽  
Cell Type ◽  
Adaptive Immune ◽  
Adaptive Immune Cell

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

RNA-sequencing indicates age-dependent shifts in the cardiac fibroblast transcriptome between fetal, neonatal, and adult developmental ages

2021 ◽  
Author(s):  
Luke R Perreault ◽  
Thanh T Le ◽  
Madeleine J Oudin ◽  
Lauren Deems Black
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Cardiac Fibroblasts ◽  
Principal Component ◽  
Phenotypic Heterogeneity ◽  
Gene Set Enrichment Analysis ◽  
Rna Seq ◽  
Adult Rats ◽  
Chemokine Production ◽  
Developmental Age

Background: Cardiac fibroblasts are responsible for extracellular matrix turnover and repair in the cardiac environment and serve to help facilitate immune responses. However, it is well established that they have significant phenotypic heterogeneity with respect to location, physiological conditions, and developmental age. The goal of this study was to provide an in-depth transcriptomic profile of cardiac fibroblasts derived from rat hearts at fetal, neonatal, and adult developmental ages to ascertain variations in gene expression that may drive functional differences in these cells at these specific stages of development. Results: We performed RNA-seq of cardiac fibroblasts isolated from fetal, neonatal, and adult rats and compared to the rat genome. Principal component analysis of RNA-seq data suggested data variance was predominantly due to developmental age. Differential expression and Gene set enrichment analysis against Gene Ontology and Kyoto Encyclopedia of Genes and Genomes datasets indicated an array of differences across developmental ages, including significant decreases in cardiac development and cardiac function-associated genes with age, and a significant increase in immune and inflammatory-associated functions - particularly immune cell signaling, and cytokine and chemokine production - with respect to increasing developmental age. Conclusion: These results reinforce established evidence of diverse phenotypic heterogeneity of fibroblasts with respect to developmental age. Further, based on our analysis of gene expression, age-specific alterations in cardiac fibroblasts may play a crucial role in observed differences in cardiac inflammation and immune response observed across developmental ages.

scholarly journals Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2639-2649 ◽  
Author(s):  
Han-Yu Chuang ◽  
Laura Rassenti ◽  
Michelle Salcedo ◽  
Kate Licon ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Lymphocytic Leukemia ◽  
Cancer Evolution ◽  
Sample Collection ◽  
Over Time

Abstract The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on 2 other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points before therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL.

scholarly journals Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation

2021 ◽  
Vol 22 (24) ◽  
pp. 13328
Author(s):  
Artur Wnorowski ◽  
Jakub Wójcik ◽  
Maciej Maj
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Immune Cell ◽  
Cell Lineage ◽  
Expression Data ◽  
Experimental Conditions ◽  
Pathological Conditions ◽  
Pituitary Adenylate Cyclase ◽  
G Protein Coupled

G protein-coupled receptor 55 (GPR55) is a recently deorphanized lipid- and peptide-sensing receptor. Its lipidic endogenous agonists belong to lysoglycerophospholipids, with lysophosphatidylinositol (LPI) being the most studied. Peptide agonists derive from fragmentation of pituitary adenylate cyclase-activating polypeptide (PACAP). Although GPR55 and its ligands were implicated in several physiological and pathological conditions, their biological function remains unclear. Thus, the aim of the study was to conduct a large-scale re-analysis of publicly available gene expression datasets to identify physiological and pathological conditions affecting the expression of GPR55 and the production of its ligands. The study revealed that regulation of GPR55 occurs predominantly in the context of immune activation pointing towards the role of the receptor in response to pathogens and in immune cell lineage determination. Additionally, it was revealed that there is almost no overlap between the experimental conditions affecting the expression of GPR55 and those modulating agonist production. The capacity to synthesize LPI was enhanced in various types of tumors, indicating that cancer cells can hijack the motility-related activity of GPR55 to increase aggressiveness. Conditions favoring accumulation of PACAP-derived peptides were different than those for LPI and were mainly related to differentiation. This indicates a different function of the two agonist classes and possibly the existence of a signaling bias.

scholarly journals Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC

2021 ◽  
Author(s):  
Yang Hu ◽  
Yudai Xu ◽  
Lipeng Mao ◽  
Wen Lei ◽  
Jan Jian Xiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Human Immune System ◽  
Immune Systems ◽  
Network Analyses ◽  
Age Related ◽  
Human Immune

Abstract Background: Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Therefore, the aim of this study is to exploit a large-scale population-based strategy to systematically identify genes and pathways differentially expressed as a function of chronological age. Despite the importance of age and race in shaping immune cell numbers and functions, it is unclear whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated variations are shared among ethnicities. Results: Here, we characterize peripheral blood mononuclear cells transcriptome from 19 healthy adults of RNA-seq data and 153 healthy subjects of micoarray data with 21~90 years of age using the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Conclusion: Overall, our findings reveal how age and race differentially affect the immune systems between Asian and Caucasian, as well as discovered a common genetic variant that greatly impacts normal PBMC aging between Asian and Caucasian.

scholarly journals AB0095 EXPRESSION AND PATHOGENIC ROLES OF INTEGRIN FAMILY GENE IN SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1076.2-1076
Author(s):  
D. Xu ◽  
T. Li ◽  
R. Mu
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pathway Analysis ◽  
Expression Patterns ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Skin Thickness ◽  
Endothelial Cell Function ◽  
Family Gene ◽  
Integrin Family

Background:Emerging evidence have shown that some integrin members are associated with inflammation and fibrosis in systemic sclerosis (SSc) patients[1-2]. However, the expression patterns and pathogenic significance of the whole integrin family in SSc are still unclear.Objectives:This study aimed at evaluating the integrin family gene expression in skin lesion from SSc patients and exploring its potential pathogenic mechanism.Methods:We utilized the public datasets of SSc skin tissue from Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. In addition, functional enrichment and pathway analysis were also conducted.Results:Compared with healthy controls, ITGA5, ITGA7, ITGA8, ITGB2, ITGB5, ITGAE and ITGB3BP were abnormally overexpressed in the skin of SSc. Further analysis indicated that ITGA5, ITGA7, ITGA8, ITGB2 and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS), while ITGAE and ITGB3BP were negatively correlated with mRSS in SSc. Increased ITGB5 expression was associated with positive of anti-centromere antibody (ACA). Functional enrichment and pathway analysis showed that integrin members had multiple functions in SSc. Among them, ITGA5, ITGB2 and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turn over, ECM-receptor interaction, focal adhesion and leukocyte trans-endothelial migration. ITGA5 and ITGB5 also affected angiogenesis and endothelial cell function. In addition, ITGA5 was uniquely enriched for actin organization, ITGB5 was uniquely enriched for TGF-β signaling, and ITGB2 was uniquely associated with immune cells activation.Conclusion:Our results implied that integrins, especially ITGA5, ITGB5, ITGB2 participated in the process of inflammation, vasculopathy and fibrosis in SSc. Together, they might render important therapeutic targets for SSc.References:[1]Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310-321.[2]Gerber, E.E., et al., Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature, 2013. 503(7474): p. 126-30.Disclosure of Interests:None declared

scholarly journals 4D chromosome reconstruction elucidates the spatial reorganization of the mammalian X-chromosome

2021 ◽  
Author(s):  
Anna Lappala ◽  
Chen-Yu Wang ◽  
Andrea Kriz ◽  
Hunter Michalk ◽  
Kevin Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Principal Component ◽  
Reaction Diffusion ◽  
Chromosome Architecture ◽  
3D Space ◽  
Xist Rna ◽  
Spatial Reorganization ◽  
Chromosome Reconstruction ◽  
Scale Structures

AbstractChromosomes are segmented into domains and compartments; yet, how these structures are spatially related in 3D is unclear. Here, by directly integrating Hi-C capture experiments and 3D modeling, we use X-inactivation as a model to examine the time evolution of 3D chromosome architecture during substantial changes in gene expression. First, we show that gene expression A/B compartments are consistent with phase separation in 3D space. Second, we show that residuals of smaller scale structures persist through transitions, despite further large-scale reorganization into the final inactive configuration, comprising two “megadomains”. Interestingly, these previously hidden residual structures were not detectable in 2D Hi-C maps or principal component analyses. Third, time-dependent reaction-diffusion simulations reveal how Xist RNA particles diffuse across the 3D X-superstructure as it reorganizes. Our 4DHiC pipeline helps satisfy the growing demand for methodologies that produce 3D chromosome reconstructions directly from 2D datasets, which are consistent with the empirical data.

scholarly journals ImmuCellDB: An Indicative Database of Immune Cell Composition From Different Tissues and Disease Conditions in Mouse and Human

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziyi Chen ◽  
Han Na ◽  
Aiping Wu
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Expression Data ◽  
Computational Tools ◽  
Cell Composition ◽  
Cell Abundance ◽  
Different Tissues

Immune cell composition is highly divergent across different tissues and diseases. A comprehensive resource of tissue immune cells across different conditions in mouse and human will thus provide great understanding of the immune microenvironment of many diseases. Recently, computational methods for estimating immune cell abundance from tissue transcriptome data have been developed and are now widely used. Using these computational tools, large-scale estimation of immune cell composition across tissues and conditions should be possible using gene expression data collected from public databases. In total, 266 tissue types and 706 disease types in humans, as well as 143 tissue types and 61 disease types, and 206 genotypes in mouse had been included in a database we have named ImmuCellDB (http://wap-lab.org:3200/ImmuCellDB/). In ImmuCellDB, users can search and browse immune cell proportions based on tissues, disease or genotype in mouse or humans. Additionally, the variation and correlation of immune cell abundance and gene expression level between different conditions can be compared and viewed in this database. We believe that ImmuCellDB provides not only an indicative view of tissue-dependent or disease-dependent immune cell profiles, but also represents an easy way to pre-determine immune cell abundance and gene expression profiles for specific situations.

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