162 APPENDICES English summary Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical peripheral polyarthritis in the hands and/or feet, leading to long-term disability if not treated effectively. Genetic and immunological studies show that cells of the adaptive immune response are involved in the pathogenesis of RA. The specificity of this immune response is encoded by rearranged T- and B-cell receptors (TCR and BCR, respectively) expressed by clones of T- and B-lymphocytes, plasmablasts, and plasma cells. To investigate the adaptive immune response thoroughly and on a genomic level next-generation sequencing (NGS) technology was developed. This technique makes it able to analyze the repertoire of T- and B-cell receptors individually on the RNA level, in any given bodily compartment, at any given time. Substantial advances in the treatment of RA have been seen, such as the introduction of several new classes of drugs, including biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Targeting the adaptive immune response using these targeted therapies, for instance with abatacept or rituximab, have been proven to be of clinical benefit in RA patients. However, these new therapies are as yet not curative. Relapses may still occur after treatment, and joint destruction is unfortunately inevitable. Selective targeting of such disease-associated adaptive immune cell clones might be highly effective while having few side effects. However, such selective targeting may only be feasible if the same T- or B-cell clones dominate the immune response at different sites of inflammation. Before RA is fully established, it is preceded by a preclinical phase, in which genetically predisposed individuals accumulate environmental risk factors, and during which autoimmunity develops, followed by the emergence of non-specific signs and symptoms before arthritis becomes manifest. It has been shown that early treatment initiation in RA patients improves disease signs and symptoms, with lower disease scores and improved physical functioning as well as reduced structural damage detected by radiography. Early treatment in at-risk individuals has the theoretical potential to delay or prevent disease onset, with a positive impact on both patients’ life and society. We investigated the TCR and BCR repertoire using NGS to gain more knowledge on the adaptive immune response in different phases of RA and in various locations; ranging from the early at-risk phase to clinically apparent RA, from studies in blood-only to other bodily compartments, and from T-cells to B-cells. Part I - Adaptive immune responses at sites of inflammation Part I describes the behaviour of the adaptive immune responses at various sites of inflammation during RA. We used the earlier-mentioned NGS technology to quantitatively assess whether different T-cell clones dominate the inflammatory infiltrate
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