Autoantibody‐Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity
Open Access
- 5 April 2016
- journal article
- systemic lupus-erythematosus
- Published by Wiley in Arthritis & Rheumatology
- Vol. 68 (10), 2492-2502
- https://doi.org/10.1002/art.39706
Abstract
Objective Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5–8%. Immunologic differences between ANA-positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA-positive individuals avoid transition to clinical autoimmune disease. Methods Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjögren's syndrome. From this screening, 31 European American ANA-positive healthy individuals were selected and demographically matched to ANA-negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry. Results Of 790 individuals screened, 57 (7%) were ANA-positive. The majority of proinflammatory cytokines, including interferon-γ (IFNγ), tumor necrosis factor, interleukin-17 (IL-17), and granulocyte colony-stimulating factor, exhibited a stepwise increase in serum levels from ANA-negative controls to ANA-positive healthy individuals to SLE patients (P < 0.0001). IFNα, IFNβ, IL-12p40, and stem cell factor/c-Kit ligand were increased in SLE patients only (P < 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA-positive individuals (P < 0.001). Further, IL-1 receptor antagonist (IL-1Ra) was down-regulated in SLE patients only (P < 0.0001). ANA-positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT-1 and pSTAT-3 following IFNα stimulation compared with ANA-negative controls (P < 0.05). Conclusion ANA-positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL-12p40, and stem cell factor/c-Kit ligand. Further, severely decreased levels of IL-1Ra in SLE patients compared with ANA-positive individuals may contribute to disease development. These results highlight the importance of IFN-related pathways and regulatory elements in SLE pathogenesis.Keywords
Funding Information
- NIH (National Institute of Allergy and Infectious Diseases) (U19-AI-082714, U19-AI-082719, U01-AI-101934, and U19-AI-110491)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (RC1-AR-058554 and P30-AR-053483)
- National Institute of General Medical Sciences (U54-GM-104938 and P30-GM-103510)
- National Center for Research Resources (S10-RR-026735)
- Oklahoma Medical Research Foundation J. Donald and Patricia Capra Fellowship Program
- NIH through a University of Oklahoma Health Sciences Center Microbiology and Immunology Training grant (National Institute of Allergy and Infectious Diseases) (T32-AI-007633-12)
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