Abstract
B-cell depletive therapies have beneficial effects in patients suffering from rheumatoid arthritis. Nevertheless, the role of B cells in the pathogenesis of the disease is not clear. In particular, it is not known how the regeneration of the B-cell repertoire takes place. Two patients with active rheumatoid arthritis were treated with rituximab, and the rearranged immunoglobulin heavy-chain genes (Ig-VH) were analysed to follow the B-cell regeneration. Patient A was treated with two courses of rituximab, and B-cell regeneration was followed over 27 months by analysing more than 680 Ig-VH sequences. Peripheral B-cell depletion lasted 7 months and 10 months, respectively, and each time was accompanied by a clinical improvement. Patient B received one treatment course. B-cell depletion lasted 5 months and was accompanied by a good clinical response. B cells regenerated well in both patients, and the repopulated B-cell repertoire was characterised by a polyclonal and diverse use of Ig-VH genes, as expected in adult individuals. During the early phase of B-cell regeneration we observed the expansion and recirculation of a highly mutated B-cell population. These cells expressed very different Ig-VH genes. They were class-switched and could be detected for a short period only. Patient A was followed long term, whereby some characteristic changes in the VH2 family as well as in specific mini-genes like VH3–23, VH 4–34 or VH 1–69 were observed. In addition, rituximab therapy resulted in the loss of clonal B cells for the whole period.Our data show that therapeutic transient B-cell depletion by anti-CD20 antibodies results in the regeneration of a diverse and polyclonal heavy-chain repertoire. During the early phase of B-cell regeneration, highly mutated B cells recirculate for a short time period in both the patients analysed. The longitudinal observation of a single patient up to 27 months shows subtle intraindividual changes, which may indicate repertoire modulation.
Highlights
The role of B cells in autoimmunity is not completely understood, their importance in the pathogenesis of autoimmune diseases has been further appreciated in the past few years
B cells accounted for 10.1% of peripheral lymphocytes at the beginning of the study
The time points of 7 months and 27 months were the first times where B cells were detectable in peripheral blood, either by flow cytometry or by PCR
Summary
The role of B cells in autoimmunity is not completely understood, their importance in the pathogenesis of autoimmune diseases has been further appreciated in the past few years. It is well known that B cells are more than just the precursors of (auto)antibody-secreting cells [1,2,3,4] They are involved in the regulation of T-cell-mediated autoimmune diseases by different mechanisms. Activated B cells express co-stimulatory molecules, such as CD154, and in this way contribute to the evolution of T effector cells. They can produce chemokines and cytokines, like lymphotoxin α/β, that are essential for the differentiation of follicular dendritic cells in secondary lymphoid organs and for the organisation of effective lymphoid architecture
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