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

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

10.1101/2020.06.19.123307 ◽

2020 ◽

Author(s):

Erika L. Hubbard ◽

Michelle D. Catalina ◽

Sarah Heuer ◽

Prathyusha Bachali ◽

Robert Robl ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Immune Cells ◽

Lupus Erythematosus ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Inflammatory Cells ◽

Cell Types ◽

Systemic Lupus ◽

Common Manifestation

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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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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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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Stratification of Systemic Lupus Erythematosus Patients Using Gene Expression Data to Reveal Expression of Distinct Immune Pathways

10.1101/2020.08.25.20181578 ◽

2020 ◽

Author(s):

Aditi Deokar

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Gene Expression Data ◽

Lupus Erythematosus ◽

Mitochondrial Apoptosis ◽

Expression Data ◽

Systemic Lupus ◽

Autoantibody Production ◽

Apoptosis Pathway ◽

Immune Pathways

AbstractSystemic lupus erythematosus (SLE) is the tenth leading cause of death in females 15-24 years old in the US. The diversity of symptoms and immune pathways expressed in SLE patients causes difficulties in treating SLE as well as in new clinical trials. This study used unsupervised learning on gene expression data from adult SLE patients to separate patients into clusters. The dimensionality of the gene expression data was reduced by three separate methods (PCA, UMAP, and a simple linear autoencoder) and the results from each of these methods were used to separate patients into six clusters with k-means clustering.The clusters revealed three separate immune pathways in the SLE patients that caused SLE. These pathways were: (1) high interferon levels, (2) high autoantibody levels, and (3) dysregulation of the mitochondrial apoptosis pathway. The first two pathways have been extensively studied in SLE. However, mitochondrial apoptosis has not been investigated before to the best of our knowledge as a standalone cause of SLE, independent of autoantibody production, indicating that mitochondrial proteins could lead to a new set of therapeutic targets for SLE in future research.

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The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus

Rheumatology ◽

10.1093/rheumatology/kep255 ◽

2009 ◽

Vol 48 (12) ◽

pp. 1491-1497 ◽

Cited By ~ 62

Author(s):

B. C.-H. Kwan ◽

L.-S. Tam ◽

K.-B. Lai ◽

F. M.-M. Lai ◽

E. K.-M. Li ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Systemic Lupus ◽

Urinary Sediment

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Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607101113 ◽

2016 ◽

Vol 113 (38) ◽

pp. 10637-10642 ◽

Cited By ~ 45

Author(s):

Elaine V. Lourenço ◽

Aijing Liu ◽

Giuseppe Matarese ◽

Antonio La Cava

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

New Zealand ◽

Renal Disease ◽

Lupus Erythematosus ◽

Cellular Level ◽

Presentation Of Self ◽

Systemic Lupus ◽

Autoantibody Production

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

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