title: Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies.
abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (±5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (±1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials.
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.|Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
authors.forename: Rufei
authors.initials: R
authors.lastname: Lu
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Munroe
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Bean
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Fife
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Slight-Webb
authors.affiliation: Rheumatology Service, Walter Reed National Military Medical Center, Bethesda, MD 20889.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keith
authors.affiliation: Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, OH 45229.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.|Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
mesh_terms: D056704:Adaptive Immunity; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology*; D015415:Biomarkers; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood*; D018450:Disease Progression; D006801:Humans; D007113:Immunity, Innate; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis / Q000276:immunology*; D011379:Prognosis; D015398:Signal Transduction; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000097:blood
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D016207:Cytokines; D048069:Tumor Necrosis Factors
keywords: Autoantibodies; Biomarkers; Cytokines; Disease progression; Forecasting; Systemic lupus erythematosus