Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by immune dysregulation, cutaneous and visceral fibrosis, and vasculopathy. It disproportionately affects African ancestry (AA) individuals who, despite the higher disease severity, are dramatically underrepresented in research. Monocytes show heightened activation in SSc, and in AA relative to European ancestry individuals. Monocytes are thus a good target tissue for elucidating disease mechanisms. In this study, we sought to characterize differential gene expression of classical monocytes in SSc patients and unaffected controls of African ancestry.
Methods: Classical monocytes (CD14++CD16-) were FACS-isolated from 17 female AA SSc cases and 18 female AA controls. All patients met the 2013 ACR/EULAR classification criteria for SSc, most (72%) presenting with diffuse cutaneous SSc. Total RNA was used to prepare RNA-Seq libraries using Illumina’s TruSeq RNA Exome kit. Upon sequencing on an Illumina HiSeq2500 instrument, data was analyzed by Rosalind, with a HyperScale architecture developed by OnRamp BioInformatics. Specifically, individual sample reads were aligned to the hg19 reference genome using STAR and quantified using HTseq. Differential expression analysis was implemented using DESeq2 and functional enrichment analysis was performed using Advaita iPathway Guide.
Results: A total of 743 genes showed differential expression (FDR P-value < 0.4). The top differentially expressed genes (P < E-04) include the collagen COL9A2 gene, the protein phosphatase PPP1R14B, the tubulin TUBB4B, the kinase-binding AKAP1, the ubiquitin ligase RNF146, the heparanase HPSE, the nuclear factor NF-Kappa-B activator TRAF3IP2, and the chromatin regulator SMARCA4. The SSc monocyte transcriptome showed an enrichment of genes in the AMPK signaling pathway, genes involved in chromatin organization, transcription factor binding, and glycogen storage diseases. The top upstream regulator is the MAPK11 kinase.
Conclusion: Unlike what has been reported in different peripheral blood subsets in EA patients, our results show a weaker upregulation of genes involved in immune and inflammatory processes in monocytes from AA patients. Instead, our study reveals an upregulation of genes involved in cellular processes associated with transcription and energy regulation in SSc patients, consistent with an increased metabolic rate of these myeloid cells in SSc. These results support the increasing awareness that metabolic reprogramming has important roles in mediating immune and vascular responses. Collectively, these results support the need to understand the regulatory architecture of SSc in different cell types and in individuals of different ancestries.
To cite this abstract in AMA style:Ramos P, da Silveira W, Wirth J, Wilson N, Wilson R, Nam J, Hazard E, Oates J, Cunningham M, Chung D, Hardiman G. Classical Monocytes from African Ancestry Patients with Systemic Sclerosis Show Transcription and Energy Regulation Gene Expression Signatures [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/classical-monocytes-from-african-ancestry-patients-with-systemic-sclerosis-show-transcription-and-energy-regulation-gene-expression-signatures/. Accessed May 29, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/classical-monocytes-from-african-ancestry-patients-with-systemic-sclerosis-show-transcription-and-energy-regulation-gene-expression-signatures/