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Title: CD19+ B cells in early rheumatoid arthritis
Authors: Thalayasingam, Nishanthi
Issue Date: 2020
Publisher: Newcastle University
Abstract: Background Rheumatoid Arthritis (RA) is a genetically complex disease which causes inflammation primarily affecting synovial joints. The therapeutic success of B cell depletion in RA has confirmed the clinical relevance of B cells in disease, but their specific role in pathogenesis remains unclear. Aims 1. Identify differences in the transcriptome of CD19+ B cells between RA samples and disease controls 2. Carry out an expression quantitative trait locus (eQTL) analysis of confirmed RA genetic risk loci 3. Identify RA disease-specific eQTLs 4. Immunophenotype peripheral blood B cells Method 242 patients were recruited, RNA and DNA was extracted for subsequent analyses and parallel flow cytometry data obtained. Results A list of differentially expressed genes, without multiple test correction (MTC), was identified between the transcriptome in RA and disease controls. Web-based analysis tools identified downregulation of B cell receptor (BCR) signalling and pathways involved in transcription and RNA processing in the RA group. A list of differentially expressed genes (with MTC) was identified when samples were divided based on chronological age and inflammatory status, not diagnosis. The eQTL analysis at RA risk loci identified 10 cis eQTLs in B cells and a further 21 potential RA-specific eQTLs which lay outside the known RA risk loci. The RA group had an increased frequency of CD19+CD24hiCD38hi cells, a postulated regulatory subset Conclusions Age and inflammatory status have a greater influence on the CD19+ B cell transcriptome than RA in this cohort. The genetic component to gene expression is highlighted by the eQTL findings and will aid the prioritisation of genes for downstream functional work. The disease-specific eQTLs identified may indicate novel mechanisms of disease. The absence of a robust diagnostic gene signature between the disease groups examined may relate to the heterogeneity of the B cells examined, as highlighted by differences in the frequency of CD19+CD24hiCD38hi cells.
Description: PhD Thesis
Appears in Collections:Translational and Clinical Research Institute

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