51 Inflamed joints share dominant B-cell clones tissue with peripheral blood (20% for T- cell and 2% for B-cell clones). This suggests that B-cell responses might be much more localized than T-cell responses. This might suggest localized proliferation and/or maturation with an increase in BCR expression, e.g. in the transformation of mature B-cells to plasma cells. Another explanation could be an antigen-driven influx of specific B-cell clones. Such a localized influx of B-cells into the joint on a stable TCR background might result in a clinical arthritis. It would be very interesting to further investigate this into more detail, e.g. in a prospective study in seropositive individuals at increased risk of RA while sampling paired synovial tissue, fluid and blood samples during the course of the disease. It is remarkable that in the BCR repertoire the observed ST- SF overlap (8%) is actually in the range of ST-ST overlap within and between different joints (resp 17% and 9%), while the earlier study for T-cell overlap demonstrated a significantly higher ST-ST overlap than SF-ST overlap (p < 0.01; 54% and 50% vs 26%, respectively). This might indicate that there is more circulation of B-cells than T-cells from the synovium to the synovial fluid in the B-cell compartment than in the T-cell compartment. Since intra-joint overlaps observed in the ST-SF and ST-ST comparisons are in the same (albeit low) range, our data suggest that B cells derived from synovial fluid or alternatively from synovial tissue are equally informative regarding antigen specificity of B-cells in the synovium. This indicates that for future B-cell studies in RA one might use SF from arthrocentesis as a substitute for ST obtained by arthroscopy or ultrasound- guided biopsy. The latter may have several advantages since arthrocentesis is a less invasive, patient-friendly procedure, which does not require theatre time. More studies are required to further characterize these overlapping TCR and BCR clones. This might entail functional characterization, including antigen specificity, in order to develop antigen receptor directed therapies. However, it might also concern genomic and proteomic analyses in order to identify more uniform cellular targets selectively present in the activated B- and/or T-cell clones. Although isolation of B-cells from synovium without modification of the expression of surface markers is challenging, it is important to commence these analyses in the near future in order to develop more selective immunotherapy. We wish to note that in our efforts to perform a UMI- standardized reproducible quantitative analysis of the BCR repertoire we based our analysis on mRNA of the heavy chain only. One might argue that different cell types from the B-cell lineage, such as B-cells and plasma cells, express different levels of BCR-heavy mRNA. Literature describes a 5-50 fold difference in the expression of BCR mRNA in plasma 3
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