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Whole transcriptome profile of citrulline-specific B cells from patients with rheumatoid arthritis

ABSTRACT: Although the contribution of B-cell derived autoreactive antibodies to rheumatoid arthritis (RA) has been studied extensively, the autoantibody-independent roles of B cells in the progression of the disease is not well-defined. By utilizing whole transcriptome profiling of human citrulline-specific B cells, we identified diverse inflammatory pathways, cytokines and transcriptional programs that define the biological role of B cells in RA and identify targets for drug intervention. Significantly, we identified the restricted expression of IL15Rα on citrulline-specific B cells and also demonstrated that B cells can express the epidermal growth factor amphiregulin (AREG) under inflammatory conditions. Mechanistically, we demonstrate that AREG has a direct impact on the cellular effectors of RA; it increases the proliferation and invasiveness of RA fibroblast-like synoviocytes (FLS) and synergizes with ACPA to enhance differentiation of osteoclasts. Overall, we present the first comprehensive transcriptome profile of autoreactive B-cell in an autoimmune disease, which can serve as a foundational dataset for studying the multi-faceted roles of B cells in autoimmune diseases

ORGANISM(S): Homo sapiens

PROVIDER: GSE99006 | GEO | 2018/11/16

REPOSITORIES: GEO

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Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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Whole transcriptome profile of citrulline-specific B cells from patients with rheumatoid arthritis

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