50 CHAPTER 3 Figure 3 | Comparing B-cell receptor repertoires in synovial tissue, synovial fluid and peripheral blood Bar charts of (A) the number of BCR-clones, (B) number of highly expanded BCR-clones (HECs) and (C) impact of HECs on total repertoire per compartment (bars show mean and SD; ** p<0.01, **** p<0.0001, using a Tukey’s multiple comparison test; ns=not significant). (D) Representative overlap-plots in one patient comparing the synovial tissue (ST) to synovial fluid (SF) and (E) comparing the SF to peripheral blood (PB) in one patient; for further details see legend Figure 1D. Scatter plot of (F) percentage of overlapping top-25 BCR-clones and (G) Chao-modified Sørensen indices of the total BCR-clones repertoire when comparing different compartments (n=6; lines at mean and SD; ** p<0.01, *** p<0.001 using a paired t test; ns=not significant). Discussion Using quantitative, B-cell receptor repertoire analysis we demonstrate that RA synovitis in different joints shares dominant B-cell responses. Within the same patient a limited number of expanded B-cell receptor clones were retrieved in the inflamed synovial tissue and fluid in different joints. The observed sharing between synovial tissue in different joints suggests that immunotherapy, selectively targeting a limited number of shared, expanded B-cell clones might be feasible and effective [23]. However, compared to the top-25 overlap observed in T-cell clones within and between synovial tissue samples taken in the same (54%) and in different joints (50%) in a previous study, the overlap in the B-cell compartment is much less pronounced (17% and 9%, respectively) [11]. This is even more clear in the comparison of synovial
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