32 CHAPTER 2 Figure 3 | Comparing T-cell receptor repertoires in synovial tissue, synovial fluid and peripheral blood Bar charts of (A) the number of TCRβ-clones, (B) number of highly expanded TCRβ-clones (HECs) and (C) impact of HECs on total repertoire per compartment (bars show mean and SD; * p < 0.05, ** p < 0.01, *** p < 0.001, using a Tukey’s multiple comparison test). (D) Overlap-plot comparing synovial tissue (ST) to synovial fluid (SF) in one patient; (E) Overlap plot SF to peripheral blood (PB) in one patient. Scatter plot of (F) percentage of overlapping top-25 TCRβ-clones and (G) Chao-modified Sørensen indices of the total TCRβ-clones repertoire when comparing different compartments (n=8; lines at mean and SD; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, using a paired t test). Discussion This quantitative, comprehensive, whole-repertoire TCR analysis shows that RA synovitis is not dominated by variable, local T cell responses but rather by uniform, systemic T cell responses. Within a single patient, synovial inflammation in multiple joints was dominated by a limited number of expanded TCRβ clones, even when these clones were not dominantly present in PB. This observation suggests that immunotherapy, selectively targeting a limited number of shared, expanded T cell clones, might be effective and feasible [35]. Therefore, to develop this kind of targeted immunotherapy, further characterization of the overlapping “clones” is indicated (e.g., regarding phenotype, TCR α- and β-chain pairing, Ag specificity, and genomic profiles). This meets substantial challenges because it requires harvesting of (enough) cells from the synovium in a phe-
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