163 English summary at various sites of inflammation in RA, i.e. in blood, synovial tissue, and synovial fluid (Chapter 2). In addition, different joints and different locations within one joint are compared. Furthermore, we analyzed to what extent these different compartments share the same dominant T-cell clones. We showed that RA synovitis is dominated by uniform, systemic T-cell responses. Within a single patient, synovial inflammation in multiple joints is dominated by a limited number of expanded TCR clones, even when these clones were not dominantly present in peripheral blood. Since T- and B-cells closely interact in adaptive responses, we consequently started investigating to what extent different joints also share dominant B-cell clones, by investigating the same aforesaid compartments (Chapter 3). We demonstrated 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. We conclude that in RA BCR clonal responses may be more localized than TCR clonal responses, pointing to antigen-selective influx, proliferation and/or maturation of B-cells. B lineage cells in the synovial fluid may adequately represent the dominant BCR clones of the synovial tissue, which is in contrast to T-cells. Collectively, the presence of shared B- and especially T-cells in different joints from the same patient suggests that approaches might be feasible that aim to develop antigen-receptor specific targeting of lymphocyte clones in RA as an alternative to more generalized immunosuppressive strategies. Part II - Treatment options in early stages of rheumatoid arthritis The second part of this thesis (Part II), focuses on the earliest stages of RA (i.e. the at-risk phase, phase of clinically silent autoimmunity, clinically suspect arthralgia, and undifferentiated arthritis), as early intervention in at-risk individuals has the theoretical potential to delay or even prevent disease onset. This initiated, a comprehensive systematic literature review to obtain a complete overview of all preventive strategies applied to at-risk individuals, taking into account all studies that have hitherto been performed and ongoing clinical trials, as well as patient perspectives to understand the feasibility of these types of interventions (Chapter 4). Part III - Dynamics in the of B-cell repertoire after B-cell depletion in different phases of RA In Part III of this thesis, the behaviour of B-cells before and after B-cell depletion is investigated. Although B-cell depleting therapy in RA is clearly effective, response is variable and does not always correlate with B-cell depletion itself. We investigated the depletion and repopulation of B-cells after B-cell depletion with rituximab treatment in RA patients (Chapter 5). Time points of achieved depletion and repopulation were defined based on the percentage of unmutated BCR-clones in the repertoire. A
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