Autoantibody-Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity

作者：Slight Webb Samantha; Lu Rufei; Ritterhouse Lauren L; Munroe Melissa E; Maecker Holden T; Fathman Charles G; Utz Paul J; Merrill Joan T; Guthridge Joel M; James Judith A^*

来源：Arthritis & Rheumatology, 2016, 68(10): 2492-2502.

DOI：10.1002/art.39706

ObjectiveAntinuclear antibodies (ANAs) are detected in approximate to 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.
MethodsHealthy individuals (n=790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjogren'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.
ResultsOf 790 individuals screened, 57 (7%) were ANA-positive. The majority of proinflammatory cytokines, including interferon- (IFN), 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). IFN, IFN, 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 IFN stimulation compared with ANA-negative controls (P < 0.05).
ConclusionANA-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.

• 出版日期2016-10