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Spontaneous Class Switch Recombination in B Cell Lymphopoiesis Generates Aberrant Switch Junctions and Is Increased after VDJ Rearrangement¹

Efrat Edry^*, Sergei B. Koralov, Klaus Rajewsky and Doron Melamed^2,*,

^* Department of Immunology, Bruce Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Technion–Israel Institute of Technology, Haifa, Israel; and Infectious Disease Institute, Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115

Mature B cells replace the µ constant region of the H chain with a downstream isotype in a process of class switch recombination (CSR). Studies suggest that CSR induction is limited to activated mature B cells in the periphery. Recently, we have shown that CSR spontaneously occur in B lymphopoiesis. However, the mechanism and regulation of it have not been defined. In this study, we show that spontaneous CSR occurs at all stages of B cell development and generates aberrant joining of the switch junctions as revealed by: 1) increased load of somatic mutations around the CSR break points, 2) reduced sequence overlaps at the junctions, and 3) excessive switch region deletion. In addition, we found that incidence of spontaneous CSR is increased in cells carrying VDJ rearrangements. Our results reveal major differences between spontaneous CSR in developing B cells and CSR induced in mature B cells upon activation. These differences can be explained by deregulated expression or function of activation-induced cytidine deaminase early in B cell development.

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 the Israel Science Foundation, United States–Israel Binational Science Foundation, Colleck Research Fund (to D.M.), and grants from the National Institutes of Health (to K.R.).

² Address correspondence and reprint requests to Dr. Doron Melamed, Department of Immunology, Technion, Faculty of Medicine, Haifa 31096, Israel. E-mail address: melamedd{at}tx.technion.ac.il

³ Abbreviations used in this paper: BM, bone marrow; CSR, class switch recombination; AID, activation-induced cytidine deaminase; SHM, somatic hypermutation; BM, bone marrow; GLT, germline transcript; PST, postswitch transcript; DIG, digoxigenin; Tg, transgenic; CT, circular transcript.

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