12 CHAPTER 1 Figure 2 | 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA [18] RF: IgM-rheumatoid factor, ACPA: antibodies against citrullinated proteins, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate. Adaptive immune response Genetic and immunological studies show that cells of the adaptive immune response are involved in the pathogenesis of RA [19–26]. 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. In the time preceding disease manifestation (pre-RA) and in the early stages of clinically overt disease, T-cells shift towards a pro-inflammatory phenotype, with an accumulation of expanded T-cells in the synovium and increased levels of serum pro-inflammatory cytokines, including IL-2 [26–29]. B-lineage cells are also altered in pre-RA individuals, with high levels of IgA plasmablasts in the peripheral blood [30]. Moreover, besides ACPA, RA patients often display other AMPAs, for instance against acetylated and carbamylated proteins, closer to disease onset [31,32]. These findings suggest that the immune system is already derailed years before RA onset, which would potentially allow for targeted interventions to prevent or at least delay disease onset. 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. Since clones of activated T- and B-cells present identical TCRs and BCRs at their surface, expanded clones can be identified as a deviation in the repertoire, also known as dominant clones or
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