The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20060964
The Journal of Experimental Medicine, Vol. 204, No. 3, 645-655
The Rockefeller University Press, 0022-1007 $30.00
© van Zelm et al.
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ARTICLE

 Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

Menno C. van Zelm1,2, Tomasz Szczepanski1,3, Mirjam van der Burg1, and Jacques J.M. van Dongen1

1 Erasmus MC, Department of Immunology and 2 Department of Pediatrics, 3015 GE Rotterdam, Netherlands
3 Department of Pediatric Hematology and Oncology, Silesian Medical Academy, 41-800 Zabrze, Poland

CORRESPONDENCE J.J.M. van Dongen: j.j.m.vandongen{at}erasmusmc.nl

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.

Abbreviations used: CSR, class switch recombination; Ig{kappa}REHMA, Ig{kappa} restriction enzyme hot-spot mutation assay; KREC, kappa-deleting recombination excision circle; MZ, marginal zone; RQ-PCR real-time quantitative PCR; SHM, somatic hypermutation; TREC, T cell receptor excision circle.


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