B cell tetherin: a flow-cytometric cell-specific assay for response to Type-I interferon predicts clinical features and flares in SLE

Objective: Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B lineage cell-specific IFN assay might correlate with SLE activity. Methods: B cells and PBMCs were stimulated wit...

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Published inbioRxiv
Main Authors El-Sherbiny, Yasser M, Md Yuzaiful Md Yusof, Psarras, Antonios, Elizabeth Ma Hensor, Kabba, Kumba Z, Dutton, Katherine, Alaa Aa Mohamed, Elewaut, Dirk, Mcgonagle, Dennis, Tooze, Reuben, Doody, Gina, Wittmann, Miriam, Emery, Paul, Vital, Edward
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.02.2019
Subjects
Autoantibodies
Autoimmune diseases
Cell surface
Diagnosis
Flow cytometry
Gene expression
Immunological memory
Interferon
Learning
Leukocytes
Lymphocytes B
Membrane proteins
Monocytes
Rituximab
Systemic lupus erythematosus
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Summary:Objective: Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B lineage cell-specific IFN assay might correlate with SLE activity. Methods: B cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinised for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validated in vitro then clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction. Results: In vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression was selectively responsive to the IFN-I compared to IFN-II and -III. In the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003; SLE/RA: effect size=0.17, p<0.001); plasmablast numbers in rituximab-treated patients (Rho=0.38, p=0.047) and BILAG-2004. Association were equivalent or stronger than interferon score or monocyte tetherin. The validation cohort confirmed this relationship with memory B-cell tetherin predictive of future clinical flares (Hazard Ratio=2.29 (1.01-4.64), p=0.022). Conclusion: Memory B cell surface tetherin, a reflection of cell-specific IFN response in a convenient flow cytometric assay, was associated with SLE diagnosis, disease activity and predicted flares better than other cell subsets or whole blood assays in independent validation cohorts.
DOI:10.1101/554352