192 Disparities of B-cell type I interferon production and responses in SLE. (April 2019)

• Record Type: Journal Article
• Authors: Winn Chatham, W; Hsu, Hui-Chen; Mountz, John; Wu, Qi; Essman, Alex; Ojo, Oluwagbemiga; Liu, Shanrun; Yang, PingAr; Luo, Bao; Hamilton, Jennie
• Is Part Of: Lupus science & medicine. Volume 6(2019)supplement 1
• Page Start: A144
• Page End: A145
• Publication Date: 2019-04
• Subjects: Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1136/lupus-2019-lsm.192
• Languages: English
• ISSNs: 2398-8851

Abstract

Abstract : Background: Dysregulated responses to type I interferons (IFNs) is a hallmark of autoreactive B-cell development in SLE. This study investigated the source of IFN, the major type I IFN responsive B cells, and the disparities associated with B-cell IFN production and type I IFN responses. Methods: IFN expression in B, CD4 T and plasmacytoid dendritic cells (pDCs) in PBMCs were analyzed by flow cytometry. Single cell gene expression analysis was carried out using the Fluidigm/BioMark system for targeted expression of low abundance genes, and the 10x Chromium platform for unbiased transcriptome and BCR V(D)J analysis of approximately 2, 000 B cells per subject. Autoantigen epitope targets were analyzed using a 4287 high-throughput PEPperPrint Autoimmune Epitope Microarray and a conventional ELISA analysis. Results: IFN was analyzed in B cells, CD4 T cells and pDCs in PBMCs of SLE patients and healthy controls (HCs). Endogenous IFN was significantly increased in transitional (Tr), mature naïve, and memory B cells of SLE patients compared to HCs. Endogenous IFN in B cells was equivalent to that in pDCs. B-cell endogenous IFN was highly correlated with renal disease, anti-dsDNA, anti-Sm and anti-SSA. Strikingly, the highest correlation of IFN with clinical manifestations was observed in African-American (AA) patients with IgG autoAbs against snRNP323-339, U1snRNP-C97-113. At the single cell transcriptome levels, Tr B cells could be divided into type I IFN expressing (IFN+) or type I IFN stimulated gene (ISG+) subpopulations. TLR7 and TLR3 were mainly expressed by IFN +cells whereas TLR9 was mainly expressed by ISG +B cells. Unbiased single cells analysis of B cells indicated highly expressed ISG gene set in IGHM+, IGHD+, and IGHG +B cells in AA patients with autoantibodies and renal disease. Further, ISG highly expressing SLE B cells exhibited unique heavy- and light-chain repertoires including expression of the autoreactive IGHV4-34 gene, targeted with the 9 G4 anti-idiotype antibody that recognizes DNA- and RBP-autoreactive B cells. Conclusions: (i) B cells are an important source of type I IFNs in modulating TLR and BCR responses in SLE; (ii) there are well-orchestrated distinct programs in type I IFN expression and response genes in subsets of B cells, (iii) distinct pathways of autoreactive B cell survival and activation are effected by combined signaling through BCR, TLR, and IFNAR with resultant distinct BCR heavy- and light-chain repertoire. Funding Source(s): R01-AI-071110, R01 AI134023, LRA Distinguished Innovator Award and Novel Research Award, VA Merit Review Award I01B × 004049, Immunology T32 Training Grant 2T32AI007051-39, the LFA Finzi Summer Fellowship.