Gene Expression Meta‐Analysis Reveals Concordance in Gene Activation, Pathway, and Cell‐Type Enrichment in Dermatomyositis Target Tissues

Abstract

Objective. We conducted a comprehensive gene expression meta-analysis in dermatomyositis (DM) muscle and skin tissues to identify shared disease-relevant genes and pathways across tissues.Methods. Six publicly available data sets from DM muscle and two from skin were identified. Meta-analysis was performed by first processing data sets individually then cross-study normalization and merging creating tissue-specific gene expression matrices for subsequent analysis. Complementary single-gene and network analyses using Significance Analysis of Microarrays (SAM) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify genes significantly associated with DM. Cell-type enrichment was performed using xCell.Results. There were 544 differentially expressed genes (FC ≥ 1.3, q < 0.05) in muscle and 300 in skin. There were 94 shared upregulated genes across tissues enriched in type I and II interferon (IFN) signaling and major histocompatibility complex (MHC) class I antigen-processing pathways. In a network analysis, we identified eight significant gene modules in muscle and seven in skin. The most highly correlated modules were enriched in pathways consistent with the singlegene analysis. Additional pathways uncovered by WGCNA included T-cell activation and T-cell receptor signaling. In the cell-type enrichment analysis, both tissues were highly enriched in activated dendritic cells and M1 macrophages.Conclusion. There is striking similarity in gene expression across DM target tissues with enrichment of type I and II IFN pathways, MHC class I antigen-processing, T-cell activation, and antigen-presenting cells. These results suggest IFN-γ may contribute to the global IFN signature in DM, and altered auto-antigen presentation through the class I MHC pathway may be important in disease pathogenesis.

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

“…Three times the number of autoantibody targeted proteins were regulated by type I and II interferons in DM than in HC. This underscores the relevance of interferons in DM 27 , 28 and indicates the potential of interferon blockade as a therapy. Identification with high confidence of specific biological processes enriched in both DM and HC suggests an organisational structure within the targets of these accumulated autoantibodies.…”

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

“…Interestingly three times the number of autoantibody targeted proteins were regulated by type I and II interferons in DM than in HC. This underscores the relevance of interferons in this disease (Neely, 2019;Somani et al, 2008), and indicates the potential of interferon blockade as a therapy. The identification with high confidence of specific biological processes enriched in both DM and HC, suggests an organisational structure within the targets of these accumulated autoantibodies.…”

“…The finding that in myositis, autoantigen expression correlates with expression of muscle regeneration markers (Pinal-Fernandez et al, 2019) suggests that after initial viral presentation, the increased concentrations of muscle proteins may then be sufficient even in the absence of viral proteins to invoke periodic rises of autoantibodies. Moreover, the continuous activation of innate immunity observed in DM (Neely, 2019;Pinal-Fernandez et al, 2019;Walsh et al, 2007;Wong et al, 2012) can also potentiate autoimmunity through chronic immune-mediated tissue damage resulting in autoantigen release without the need for specific activation of auto-reactive T cells by a microbial mimic (Panoutsakopoulou et al, 2001). Therefore, following the initial viral exposure there is a high chance that this effect will spread amongst related proteins within specific signalling pathways (since protein homology is related to function) of the initial hit.…”

Investigating genetic drivers of dermatomyositis pathogenesis using meta-analysis

“…DM muscle samples were taken from series GSE1551, GSE 3307, and GSE48280 and DM skin samples were taken from series GSE32245 and GSE46239. As these studies do not define DM subtypes nor provide myositis-specific autoantibody presence, we combined samples across studies to elucidate general mechanisms of pathogenesis [14,16,37,38,39]. Meta-analysis was also conducted in rheumatoid arthritis (RA) blood (114 RA vs 90 healthy; samples taken from series GSE15573 and GSE17755) and synovial fluid (130 RA vs 68 healthy; samples taken from series GSE12021, GSE13026, GSE1919, GSE2053, GSE21959, GSE29746, GSE55235, GSE55457, and GSE77298), sarcoidosis (SD) bronchoalveolar lavage (21 SD vs 20 healthy; samples taken from series GSE75023 and GSE110779) and peripheral blood (216 SD vs 271 healthy; samples taken from GSE18781, GSE1907, GSE19314, GSE37912, GSE42825, GSE42826, GSE42830, GSE42832, and GSE83456), systemic sclerosis (SSc) skin (63 SSc vs 31 healthy; samples taken from GSE12493 and GSE9285), and Kawasaki (KA) peripheral blood (121 KA vs 40 healthy; samples taken from GSE18606, GSE68004, and GSE109351) for comparative TRIM activity analysis.…”