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Abstract
Objective Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE.
Methods Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE.
Results ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles.
Conclusions ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.
- Autoimmunity
- Lupus Erythematosus, Systemic
- Risk Factors
- Autoantibodies
Data availability statement
Data are available on reasonable request. Data are available on reasonable request to the corresponding author.
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Data availability statement
Data are available on reasonable request. Data are available on reasonable request to the corresponding author.
Footnotes
Handling editor Josef S Smolen
X @Yuz6Yusof, @edvital
Collaborators Not applicable.
Contributors Study conception and design: LMC, EMV, MYMY, DP, SW and AP. Acquisition of data: LMC, AA, ZW, AP and MYMY. Analysis and interpretation of data: LMC, SW, DP and EMV. All authors have contributed to drafting the work or reviewing it critically for important intellectual content. All authors have approved the version submitted for publication. EV is responsible for the overall content as guarantor. He accepts full responsibility for the finished work and/or the conduct of the study, had access to the data and controlled the decision to publish.
Funding MYMY’s work was supported by NIHR Doctoral Research Fellowship DRF-2014-07-155 and Wellcome Trust Institutional Strategic Fund Fellowship 204825/Z/16/Z. EMV’s work was supported by NIHR Clinician Scientist award CS-2013-13-032 and UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee 101089173.MYMY’s work was supported by NIHR Doctoral Research Fellowship DRF-2014-07-155 and Wellcome Trust Institutional Strategic Fund Fellowship 204825/Z/16/Z. EMV’s work was supported by NIHR Clinician Scientist award CS-2013-13-032 and UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee 101089173.
Disclaimer The views expressed are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care.
Competing interests LMC has received consultancy fees from UCB and Alumis. MYMY has received consultancy fees from Aurinia Pharmaceuticals and UCB and speaker fees from Alumis, Roche and Novartis. EMV has received consultancy fees from Roche, GSK, AstraZeneca, Aurinia Pharmaceuticals, Lilly and Novartis. He has also received research grants paid to his employer from Roche, AstraZeneca and Sandoz. All other authors have declared no competing interests.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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