118 CHAPTER 6 Abstract Background B cells play a key role in the development of rheumatoid arthritis (RA), again illustrated by the fact that a single dose of rituximab administered during the RA-risk phase delays onset of arthritis. However, it is not clear whether rituximab (RTX) influences the B cell receptor (BCR) repertoire in this phase, and how this correlates with onset of arthritis. Objectives To study the effect of rituximab influences on the BCR repertoire during the preclinical phase of RA, and how this correlates with onset of arthritis. Methods Adaptive immune receptor sequencing (AIRR-seq) of the BCR-heavy (BCRh) chain was performed on peripheral blood samples obtained from RA-risk individuals that were treated with RTX or placebo (PRAIRI study). In a second cohort of untreated RA-risk individuals (DOMINO study), AIRR-seq was performed on sequential peripheral blood samples and FACS-sorted phenotyped subpopulations. Results In the preclinical phase of RA Rituximab induces clonal BCR depletion in sequential peripheral blood samples, followed by a gradual re-establishment of the normal BCRh repertoire from 6 months onwards up to 12 months after treatment. Phenotypic analyses in the DOMINO cohort show that plasmablasts/plasma cells carry most of the dominant BCRh signatures. Interestingly, the clonal BCR signatures that initially are dominant at baseline are encoded by memory B cells after 6 and 12 months in peripheral blood. Conclusion Our results show that the BCRh repertoire constantly changes over time in the preclinical phase of RA. These changes were seen not only after B cell depletion therapy, but also in placebo treated or untreated RA-risk individuals. During the preclinical phase, the most dominant BCRh clones appear to be of the plasmablast or plasma cell phenotype and intriguingly, disappear over time from the plasmablast/plasma cell compartment and reappear as low frequency memory B cell clones.
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