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

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.

Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

“…Metabolism gene sets were created from literature mining. Hematopoietic gene sets were derived from Immune/Inflammatory-Scope (I-Scope), a tool developed to identify immune cell-specific genes in big data 72 . Non-hematopoietic cellular gene sets were derived from T-Scope 72 or literature mining.…”

“…Hematopoietic gene sets were derived from Immune/Inflammatory-Scope (I-Scope), a tool developed to identify immune cell-specific genes in big data 72 . Non-hematopoietic cellular gene sets were derived from T-Scope 72 or literature mining. Many gene sets in T-Scope were derived from The Human Protein Atlas ( https://www.proteinatlas.org ) 73 , 74 .…”

Arthritis in Systemic Lupus Erythematosus: From 2022 International GISEA/OEG Symposium

“…Damage was represented by fibrous thickening of the joint capsule and tendon sheaths and loss of cartilage with minimal bone loss (hook erosion) [ 24 , 25 ]. Compared with osteoarthritis and RA, the most recent gene expression analysis from synovial biopsies in SLE patients suggested myeloid cell-driven pathogenesis of lupus arthritis [ 26 ]. Evidence of a more robust immune infiltrate than initially reported was found by identifying M1 and M2 macrophages, neutrophils, granulocytes, activated T-cells, and dendritic cell (DC) transcriptomes [ 26 ].…”

“…Compared with osteoarthritis and RA, the most recent gene expression analysis from synovial biopsies in SLE patients suggested myeloid cell-driven pathogenesis of lupus arthritis [ 26 ]. Evidence of a more robust immune infiltrate than initially reported was found by identifying M1 and M2 macrophages, neutrophils, granulocytes, activated T-cells, and dendritic cell (DC) transcriptomes [ 26 ]. Moreover, a significant upregulation of proinflammatory interferon-inducible (IFI) genes and a significant downregulation of genes involved in extracellular matrix (ECM) homeostasis with low tissue repair/destruction activity were displayed [ 11 , 26 , 27 ].…”

“…Evidence of a more robust immune infiltrate than initially reported was found by identifying M1 and M2 macrophages, neutrophils, granulocytes, activated T-cells, and dendritic cell (DC) transcriptomes [ 26 ]. Moreover, a significant upregulation of proinflammatory interferon-inducible (IFI) genes and a significant downregulation of genes involved in extracellular matrix (ECM) homeostasis with low tissue repair/destruction activity were displayed [ 11 , 26 , 27 ]. The type I IFN signature is considered pivotal in maintaining inflammation in established disease, but a clear relationship between IFN activation and disease activity of lupus arthritis has not been established [ 28 ].…”