Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody.
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.
Department of Medicine II, Rheumatology and Clinical Immunology, University of Wuerzburg, Germany. asr4r@clinmed.gla.ac.uk
Anne-Sophie
AS
Rouzière
Christian
C
Kneitz
Arumugam
A
Palanichamy
Thomas
T
Dörner
Hans-Peter
HP
Tony
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology* / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012038:Regeneration / Q000187:drug effects / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D018951:Antigens, CD20; D007143:Immunoglobulin Heavy Chains