Analysis of Gene Expression from Systemic Lupus Erythematosus Synovium Reveals a Profile of Activated Immune Cells and Inflammatory Pathways

ABSTRACTArthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, whereas OA was characteristic of fibroblasts and RA of T- and B-cells. Upstream regulator analysis identified CD40L and inflammatory cytokines as drivers of the LA gene expression profile. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers. GSVA confirmed activation of specific myeloid and lymphoid cell types in LA. Numerous therapies were predicted to target LA, including TNF, NFκB, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.

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Analysis of gene expression from systemic lupus erythematosus synovium reveals myeloid cell-driven pathogenesis of lupus arthritis

Scientific Reports ◽

10.1038/s41598-020-74391-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Erika L. Hubbard ◽

Michelle D. Catalina ◽

Sarah Heuer ◽

Prathyusha Bachali ◽

Robert Robl ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Myeloid Cell ◽

Inflammatory Cells ◽

Systemic Lupus ◽

Common Manifestation

Abstract Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, in which pathogenic macrophages, myeloid-lineage cells, and their secreted products perpetuate inflammation, whereas OA was characterized by fibroblasts and RA of lymphocytes. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers (GCs). Gene Set Variation Analysis (GSVA) confirmed activation of specific immune cell types in LA. Numerous therapies were predicted to target LA, including TNF, NFκB, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.

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Meta-analysis of gene expression profiles of peripheral blood cells in systemic lupus erythematosus

Cellular and Molecular Biology ◽

10.14715/cmb/2018.64.10.7 ◽

2018 ◽

Vol 64 (10) ◽

pp. 40 ◽

Cited By ~ 2

Author(s):

Sang-Cheol Bae ◽

Young Ho Lee

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Blood Cells ◽

Expression Profiles ◽

Meta Analysis ◽

Gene Expression Profiles ◽

Peripheral Blood Cells ◽

Systemic Lupus

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Gene expression profiles of systemic lupus erythematosus and rheumatoid arthritis

Expert Review of Clinical Immunology ◽

10.1586/1744666x.3.5.797 ◽

2007 ◽

Vol 3 (5) ◽

pp. 797-806 ◽

Cited By ~ 4

Author(s):

Michael Centola ◽

Zoltan Szekanecz ◽

Emese Kiss ◽

Margit Zeher ◽

Gyula Szegedi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Systemic Lupus

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Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray

Genes and Immunity ◽

10.1038/sj.gene.6363966 ◽

2003 ◽

Vol 4 (3) ◽

pp. 177-186 ◽

Cited By ~ 184

Author(s):

G-M Han ◽

S-L Chen ◽

N Shen ◽

S Ye ◽

C-D Bao ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Oligonucleotide Microarray ◽

Human Systemic Lupus Erythematosus ◽

Systemic Lupus

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Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus

Arthritis & Rheumatism ◽

10.1002/art.22578 ◽

2007 ◽

Vol 56 (5) ◽

pp. 1579-1588 ◽

Cited By ~ 121

Author(s):

A. Nzeusseu Toukap ◽

C. Galant ◽

I. Theate ◽

A. L. Maudoux ◽

R. J. U. Lories ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Systemic Lupus ◽

Distinct Gene

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Gene Expression Profiles in a Rabbit Model of Systemic Lupus Erythematosus Autoantibody Production

The Journal of Immunology ◽

10.4049/jimmunol.1001254 ◽

2010 ◽

Vol 185 (7) ◽

pp. 4446-4456 ◽

Cited By ~ 7

Author(s):

Geeta Rai ◽

Satyajit Ray ◽

Jacqueline Milton ◽

Jun Yang ◽

Ping Ren ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Rabbit Model ◽

Gene Expression Profiles ◽

Systemic Lupus ◽

Autoantibody Production

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Unique monocyte transcriptomic profiles are associated with preclinical atherosclerosis in women with systemic lupus erythematosus (SLE)

10.1101/2020.08.05.20169136 ◽

2020 ◽

Author(s):

Laurel Woodridge ◽

Paul Ashford ◽

Elvira Chocano ◽

George Robinson ◽

Kirsty Waddington ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Risk ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Bioinformatic Analysis ◽

Systemic Lupus ◽

Cvd Risk ◽

Increased Risk ◽

Preclinical Atherosclerosis

Women with Systemic Lupus Erythematosus (SLE) show significantly increased cardiovascular risk compared to the general population. However, despite CVD being a major cause of morbidity and mortality for these women, this increased risk is not managed clinically and tools to dissect and predict their cardiovascular risk are lacking. Notably, this elevated CVD risk is not captured by traditional risk factors. To explore molecular programs underlying asymptomatic atherosclerosis in SLE we used a well-characterised cohort of CVD-free women with SLE, scanned for asymptomatic atherosclerotic plaques using non-invasive ultrasound imaging of the carotid and femoral arteries. We investigated the transcriptomic profiles of CD14+ circulating monocytes in women with SLE with or without preclinical atherosclerosis. We identified unique monocytic gene expression profiles that distinguished the presence of preclinical plaques in women with SLE. In addition, advanced bioinformatic analysis revealed functional pathways and interactions between the genes identified that could explain mechanistic differences in plaque formation. We propose that these molecular signatures could help understand why a subset of women with SLE are predisposed to develop atherosclerosis and at higher risk of developing clinical CVD. Collectively with other efforts, these molecular insights will help to better define atherosclerosis in the context of SLE which will be critical for future patient stratification and identification of anti-atherosclerotic therapies.

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Abstract P214: Isolevuglandins Mediate Inflammatory Gene Expression And Immune Activation In Hypertension And Systemic Lupus Erythematosus

Hypertension ◽

10.1161/hyp.78.suppl_1.p214 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Nestor de la Visitacion ◽

Charles D Smart ◽

Jaya Krishnan ◽

David G Harrison ◽

David M Patrick

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Ang Ii ◽

Systemic Lupus ◽

Inflammatory Gene Expression

Justification: Hypertension and systemic lupus erythematosus (SLE) share similarities including elevations of blood pressure, proteinuria, inflammation and renal dysfunction and both involve formation of isoLG adducts. We hypothesized that isoLG scavenging would modulate overlapping gene pathways in inflammatory cells in these two conditions. Methods: We performed 10 X genomics single cell sequencing on splenocytes of C57Bl/6 mice with angiotensin II (Ang II)-induced hypertension, Ang II co-treatment with the isoLG scavenger 2HOBA, and 24-week-old B6.SLE123 mice with or without 6-weeks of 2HOBA. Matched C57Bl/6 females were used as controls for the B6.SLE123 mice. Results: Both models exhibited myeloid expansion and genes associated with neutrophil infiltration compared to their respective controls and 2HOBA attenuated this ( Table 1 ). Hypertension was associated with neutrophil expansion whereas SLE was associated an expansion of neutrophils, monocytes, and dendritic cells. In SLE, 2HOBA predominantly modulated gene expression in dendritic cells. Gene ontology revealed 2HOBA downregulated genes governing inflammation including Il1 β (Avglog2(fold change) = -1.6, P adj = 0.002) in both hypertension and SLE. Conclusions: In a mouse model of SLE, scavenging of isoLGs with 2HOBA downregulates inflammatory genes specifically in DCs. In models of both hypertension and SLE, scavenging of isoLG prevents neutrophil expansion. Combined these data describe a shared role of isoLGs in hypertension and SLE and suggest a specific role of DCs and neutrophil activation in the pathogenesis of both conditions. Table 1. Percentage of myeloid derived cells in all groups.

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Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes

Nature Communications ◽

10.1038/s41467-021-22331-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Bing He ◽

Ping Chen ◽

Sonia Zambrano ◽

Dina Dabaghie ◽

Yizhou Hu ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Human Kidney ◽

Cell Types ◽

Model Organisms ◽

Mural Cell ◽

Glomerular Cell ◽

Individual Gene ◽

The Individual

AbstractMolecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney. The analysis reveals genetic programs for all four glomerular cell types (podocytes, glomerular endothelial cells, MCs and PECs) as well as rare glomerulus-associated macula densa cells. Importantly, we detect heterogeneity in glomerulus-associated Pdgfrb-expressing cells, including bona fide intraglomerular MCs with the functionally active phagocytic molecular machinery, as well as a unique mural cell type located in the central stalk region of the glomerulus tuft. Furthermore, we observe remarkable species differences in the individual gene expression profiles of defined glomerular cell types that highlight translational challenges in the field and provide a guide to design translational studies.

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