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B Cell Tetherin: A Flow Cytometric Cell‐Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus
Author(s) -
ElSherbiny Yasser M.,
Md Yusof Md Yuzaiful,
Psarras Antonios,
Hensor Elizabeth M. A.,
Kabba Kumba Z.,
Dutton Katherine,
Mohamed Alaa A. A.,
Elewaut Dirk,
McGonagle Dennis,
Tooze Reuben,
Doody Gina,
Wittmann Miriam,
Emery Paul,
Vital Edward M.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41187
Subject(s) - tetherin , immunology , systemic lupus erythematosus , flow cytometry , peripheral blood mononuclear cell , autoantibody , medicine , b cell , lupus nephritis , immune system , t cell , memory b cell , interferon , lupus erythematosus , antibody , in vitro , biology , disease , biochemistry , viral envelope
Objective Type 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. Methods B cells and peripheral blood mononuclear cells ( PBMC s) 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 ( CD 317), 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. Results In 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 IFN s. 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). Conclusion Our 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.