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Antibodies in a Heavy Chain Knock-In Mouse Exhibit Characteristics of Early Heavy Chain Rearrangement¹

Lenka Yunk^*, Wenzhao Meng^*, Philip L. Cohen, Robert A. Eisenberg and Eline T. Luning Prak^2,*

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine; Department of Medicine, Temple University School of Medicine; and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Studies in autoantibody transgenic mice have demonstrated receptor editing rearrangements at Ab H and L chain loci. However, the physiologic role of H chain editing (V_H replacement and rearrangement on the second allele) has been called into question. It is unclear if additional rounds of H chain rearrangement are driven by BCR specificity. In this study, we analyze the manner in which B cells undergo additional H chain rearrangements in an anti-DNA H chain knock-in mouse, B6.56R. We find that rearrangements in 56R⁺ B cells tend to involve the D gene locus on both alleles and the most J_H-proximal V_H gene segments on the endogenous allele. As a result, some B cells exhibit V(D)J rearrangements on both H chain alleles, yet allelic exclusion is tightly maintained in mature 56R B cells. As B cells mature, a higher proportion expresses the nontransgenic H chain allele. Rearrangements on both H chain alleles exhibit junctional diversity consistent with TdT-mediated N-addition, and TdT RNA is expressed exclusively at the pro-B cell stage in B6.56R. Collectively, these findings favor a single, early window of H chain rearrangement in B6.56R that precedes the expression of a functional BCR. B cells that happen to successfully rearrange another H chain may be favored in the periphery.

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 National Institutes of Health (Grants U01 DK070430, AR34156, and R01 DE017590) and the Alliance for Lupus Research.

² Address correspondence and reprint requests to Dr. Eline T. Luning Prak, University of Pennsylvania, 405B Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail address: luning{at}mail.med.upenn.edu

³ The online version of this article contains supplemental material.

⁴ Abbreviations used in this paper: QM, quasimonoclonal; AID, activation-induced cytidine deaminase.