133 B-cells during preclinical phase of rheumatoid arthritis the detection of these cells. Another possibility could be that these clones, although dominant in our RNA analysis, are of low frequency in peripheral blood. Therefore, it could be possible that these cells are found in the blood tubes used for direct lysis and sequencing, but not in the blood tubes used for sorting. In summary, the current study reveals novel insights into the dynamics of B lineage cells in the pathophysiology and development of RA in the earliest stages of disease development. It shows that the BCRh repertoire is constantly changing over time in the preclinical phase of RA. This is expected, following B cell depleting therapy, but is also present in placebo treated or untreated RA-risk individuals. 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 in our analyses. This suggests continuous development of new dominant clonal responses, some of which might be involved in autoantibody production in at-risk patients. Such a continuously renewing response in this phase might explain the observation that new (sub)specificities in these autoimmune responses just before the onset of arthritis. More insight in these processes might help to develop novel prevention strategies and targeted therapies. 6
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