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* Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138;
Department of Dermatology, Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, MA 02115; and
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
The terminal stage of B cell differentiation culminates in the formation of plasma cells (PC), which secrete large quantities of Igs. Despite recent progress in understanding the molecular aspect of PC differentiation and maintenance, the requirement for the synthesis of secretory Igs as a contributing factor has not been explored. To address this issue, we generated activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-knockout mice, in which a normally diverse repertoire of B cell receptors is retained, yet B cells are unable to synthesize secretory Igs. These mice possess polyclonal B cells but have no serum Igs. Following immunization in vivo, PCs, identified by CD138 expression and loss of the B220 marker, were starkly reduced in number in spleen and bone marrow of AID–/–µs–/– agammaglobulinemic mice compared with wild-type mice. Upon mitogenic stimulation in vitro, AID–/–µs–/– B cells differentiated into plasmablasts to some extent, but showed reduced survival compared with wild-type B cells. We found no evidence that this reduced survival was attributable to accumulation of membrane IgM. Our results indicate that the synthesis of secretory Igs is a requirement for maintenance of B220–CD138+ PCs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grant from the National Institutes of Health (to H.L.P.). B.T. was supported by a Dorot Foundation fellowship.
2 Address correspondence and reprint requests to Dr. Hidde L. Ploegh, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. E-mail address: ploegh{at}wi.mit.edu
3 Abbreviations used in this paper: PC, plasma cell; GC, germinal center; CSR, class switch recombination; SHM, somatic hypermutation; ER, endoplasmic reticulum; NP-CG, nitrophenyl-conjugated chicken gammaglobulin; UPR, unfolded protein response; AID, activation-induced cytidine deaminase; µs, secretory µ; µm, membrane µ; XBP-1, X-box binding protein 1; IRE, inositol-requiring enzyme; PNA, peanut agglutinin; MZ, marginal zone.
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