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Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

ABSTRACT: Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction¹. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity^1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

SUBMITTER: Zhang F

PROVIDER: S-EPMC10651487 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Zhang Fan F Jonsson Anna Helena AH Nathan Aparna A Millard Nghia N Curtis Michelle M Xiao Qian Q Gutierrez-Arcelus Maria M Apruzzese William W Watts Gerald F M GFM Weisenfeld Dana D Nayar Saba S Rangel-Moreno Javier J Meednu Nida N Marks Kathryne E KE Mantel Ian I Kang Joyce B JB Rumker Laurie L Mears Joseph J Slowikowski Kamil K Weinand Kathryn K Orange Dana E DE Geraldino-Pardilla Laura L Deane Kevin D KD Tabechian Darren D Ceponis Arnoldas A Firestein Gary S GS Maybury Mark M Sahbudin Ilfita I Ben-Artzi Ami A Mandelin Arthur M AM Nerviani Alessandra A Lewis Myles J MJ Rivellese Felice F Pitzalis Costantino C Hughes Laura B LB Horowitz Diane D DiCarlo Edward E Gravallese Ellen M EM Boyce Brendan F BF Moreland Larry W LW Goodman Susan M SM Perlman Harris H Holers V Michael VM Liao Katherine P KP Filer Andrew A Bykerk Vivian P VP Wei Kevin K Rao Deepak A DA Donlin Laura T LT Anolik Jennifer H JH Brenner Michael B MB Raychaudhuri Soumya S

Nature 20231108 7987

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction<sup>1</sup>. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity<sup>1,2</sup>. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used m ...[more]

PMID: 37938773

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Project description:IntroductionAngiogenesis is an early event in the pathogenesis of both psoriatic arthritis (PsA) and rheumatoid arthritis (RA); however, there are striking differences in blood vessel morphology and activation between the two arthropathies. The aim of this study was to assess if the PsA and RA joint microenvironments differentially regulate endothelial cell function.MethodsPsA and RA primary synovial fibroblasts (SFC) were isolated from synovial biopsies, grown to confluence, and supernatants harvested and termed 'conditioned media' (CM). Human umbilical vein endothelial cells (HUVEC) were cultured with PsA SFC or RA SFC-CM (20%). HUVEC tube formation, migration, and PBMC adhesion were assessed by matrigel tube formation, wound repair, and PBMC adhesion assays. HUVEC cell surface expression of ICAM, VCAM, and E-Selectin was assessed by flow cytometry. Transcriptome analysis of genes promoting angiogenesis was performed by real-time PCR. Finally, a MSD multiplex angiogenic assay was performed on PsA SFC and RA SFC supernatants.ResultsMacroscopic synovitis and vascularity were similar in PsA and RA patients; however, significant differences in vascular morphological pattern were recorded with tortuous, elongated vessels observed in PsA compared to straight regular branching vessels observed in RA. Transcriptome analysis showed strong upregulation of the pro-angiogenic signature in HUVEC primed with PsA SFC-CM compared to RA SFC-CM and basal control. In parallel, paired PsA SFC-CM significantly induced HUVEC tube formation compared to that of RA SFC-CM. Furthermore, PsA SFC-CM induced HUVEC migration was paralleled by a significant induction in VEGFA, PFKFB3, ICAM-1, and MMP3 mRNA expression. A significant increase in PBMC adhesion and cell surface expression of VCAM-1, ICAM-1, and E-Selectin expression was also demonstrated in PsA SFC-CM-primed HUVEC compared to RA SFC-CM. Finally, VEGF, TSLP, Flt-1, and Tie-2 expression was elevated in PsA SFC-CM compared to RA SFC-CM, with no significant difference in other pro-angiogenic mediators including MIP-3, bFGF, PIGF, and MCP-1.ConclusionPsA SFC and RA SFC secreted factors differentially regulate endothelial cell function, with soluble mediators in the PsA joint microenvironment inducing a more pro-angiogenic phenotype compared to the RA.

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Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

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Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

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