142 CHAPTER 7 The therapeutic options for rheumatoid arthritis (RA) have increased immensely in the past two decades and resulted in improvements in outcome and quality of life. Especially, the arrival of biological (b) and targeted synthetic (ts) disease-modifying anti-rheumatic drugs (DMARDs), with therapeutic targets ranging from cytokines (e.g. tumor necrosis factor (TNF) to CD20 on B-cells, has dramatically improved the life of patients as exemplified by improved disease signs and symptoms together with less structural damage. However, these therapies have been proven not to be curative. Therefore, there is a clear need for a better understanding of the underlying pathophysiology, including the contribution of the adaptive immune system and its window of opportunity for treatment in RA patients and individuals at risk of developing RA. Thus, the aim of this thesis was to investigate the adaptive immune response in different phases of RA and in various physical locations. In this final chapter, we will summarize the main findings of each chapter, discuss implications, and share our vision of research challenges in the field for the coming years. Part I Adaptive immune responses at sites of inflammation The first part of this thesis describes characteristics of cells involved in the adaptive immune response in RA by investigating T- and B-cell responses in various bodily compartments. In Chapter 2 we use quantitative, T-cell receptor (TCR) repertoire analysis to characterize RA synovitis in different joints. We demonstrate that RA synovitis is dominated by uniform, systemic T-cell responses. Within a single patient, synovial inflammation in multiple joints was dominated by a limited number of expanded TCR clones, even when these clones were not dominantly present in PB. In Chapter 3 we show, using the same quantitative analysis, but now on the B-cell receptor (BCR) repertoire, that dominant B-cell responses are also shared: 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 shared B-cell clones between synovial tissue in different joints indicates that for future B-cell (clonality) 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. However, for functional assays certain differences between SF and ST may exist, which remains to be tested. Intriguingly, when comparing the B-cell receptor repertoire to the T-cell receptor repertoire, we see some striking differences. In the BCR repertoire the observed ST- SF overlap, mentioned above, is in the range of ST-ST overlap within and between different joints, while the TCR repertoire overlap demonstrated a significantly
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