Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology

• Published in: Annals of the rheumatic diseases Vol. 83; no. 10; pp. 1322 - 1334
• Main Authors: Carter, Lucy Marie, Md Yusof, Md Yuzaiful, Wigston, Zoe, Plant, Darren, Wenlock, Stephanie, Alase, Adewonuola, Psarras, Antonios, Vital, Edward M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.10.2024; Elsevier Limited
• Subjects: Adult; Antibodies, Antinuclear - blood; Antibodies, Antinuclear - immunology; Antigens; Antinuclear antibodies; Autoantibodies; Autoimmune diseases; Autoimmunity; B-Lymphocytes - immunology; Case-Control Studies; CD4 antigen; Cytokines; Dendritic cells; Disease Progression; Electron transport chain; Female; Gene expression; Genomics; Humans; Immune response; Immunology; Interferon; Interferon Type I - genetics; Interferon Type I - immunology; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lupus; Lupus Erythematosus, Systemic; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocytes B; Lymphocytes T; Lymphopenia; Male; Metabolic rate; Middle Aged; Oxidative phosphorylation; Peripheral blood mononuclear cells; Phosphorylation; Proteins; Risk Factors; Sequence Analysis, RNA; Systemic lupus erythematosus; Transcriptome; Transcriptomics; United Kingdom > UK; Autoimmunity; Autoantibodies; Lupus Erythematosus, Systemic; Risk Factors
• DOI: 10.1136/ard-2023-225349
• ISSN: 0003-4967; 1468-2060

ObjectiveMechanisms 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.MethodsBulk 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.ResultsANA+ 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.ConclusionsANA 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.