Abstract
ObjectiveType I interferon (IFN) responses are broadly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Given the cardinal role of autoantibodies in SLE, this study was undertaken to investigate whether the findings of a B cell–specific IFN assay correlate with SLE activity.MethodsB cells and peripheral blood mononuclear cells (PBMCs) were stimulated with type I IFN and type II IFN. Gene expression was analyzed, and the expression of pathway‐related membrane proteins was determined. A flow cytometry assay for tetherin (CD317), an IFN‐induced protein ubiquitously expressed on leukocytes, was validated in vitro and then clinically against SLE diagnosis, plasmablast expansion, and the British Isles Lupus Assessment Group (BILAG) 2004 score in a discovery cohort (n = 156 SLE patients, 30 rheumatoid arthritis [RA] patients, and 25 healthy controls). A second, longitudinal validation cohort of 80 SLE patients was also evaluated for flare prediction.ResultsIn vitro, a close cell‐specific and dose‐response relationship between type I IFN–responsive genes and cell surface tetherin was observed in all immune cell subsets. Tetherin expression on multiple cell subsets was selectively responsive to stimulation with type I IFN compared to types II and III IFNs. In patient samples from the discovery cohort, memory B cell tetherin showed the strongest associations with diagnosis (SLE:healthy control effect size 0.11 [P = 0.003]; SLE:RA effect size 0.17 [P < 0.001]), plasmablast numbers in rituximab‐treated patients (R = 0.38, P = 0.047), and BILAG 2004. These associations were equivalent to or stronger than those for IFN score or monocyte tetherin. Memory B cell tetherin was found to be predictive of future clinical flares in the validation cohort (hazard ratio 2.29 [95% confidence interval 1.01–4.64]; P = 0.022).ConclusionOur findings indicate that memory B cell surface tetherin, a B cell–specific IFN assay, is associated with SLE diagnosis and disease activity, and predicts flares better than tetherin on other cell subsets or whole blood assays, as determined in an independent validation cohort.
Highlights
Type I interferons (IFNs) are a highly pleiotropic group of cytokines that link the innate and adaptive immune systems and play a pivotal role in autoimmune disease [1,2,3]
A flow cytometry assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leukocytes, was validated in vitro and clinically against systemic lupus erythematosus (SLE) diagnosis, plasmablast expansion, and the British Isles Lupus Assessment Group (BILAG) 2004 score in a discovery cohort (n = 156 SLE patients, 30 rheumatoid arthritis [RA] patients, and 25 healthy controls)
In patient samples from the discovery cohort, memory B cell tetherin showed the strongest associations with diagnosis (SLE:healthy control effect size 0.11 [P = 0.003]; SLE:RA effect size 0.17 [P < 0.001]), plasmablast numbers in rituximab-treated patients (R = 0.38, P = 0.047), and BILAG 2004
Summary
Type I interferons (IFNs) are a highly pleiotropic group of cytokines that link the innate and adaptive immune systems and play a pivotal role in autoimmune disease [1,2,3]. All nucleated cells express type I IFN receptors and express a set of IFN-s timulated genes (ISGs) after exposure to type I IFN [4,5]. A challenge in the assessment of type I IFN response in an individual disease is ensuring that the appropriate cellular response can be detected within this complex system. Type I IFN proteins are unstable in blood and not detected even in monogenic interferonopathies with known high type I IFN production, possibly due to their efficient binding to the abundant IFN receptor [6]. We previously analyzed ISG expression in sorted cells from patients with systemic lupus erythematosus (SLE), a prototypic IFN-mediated disease, and healthy individuals and showed that in both groups, ISG expression was markedly higher in monocytes than in other circulating immune cells. ISG expression in monocytes dominates ISG assays that use unsorted blood [7]
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