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B Cell Receptor Affinity and B Cell Subset Identity Integrate to Define the Effectiveness, Affinity Threshold, and Mechanism of Anergy¹

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

In this study we show that BCR affinity and subset identity make unique contributions to anergy. Analysis of anti-Smith (Sm) B cells of different affinities indicates that increasing affinity improves anergy’s effectiveness while paradoxically increasing the likelihood of marginal zone (MZ) and B-1 B cell differentiation rather than just follicular (FO) B cell differentiation. Subset identity in turn determines the affinity threshold and mechanism of anergy. Subset-specific affinity thresholds for anergy induction allow discordant regulation of low-affinity anti-Sm FO and MZ B cells and could account for the higher frequency of autoreactive MZ B cells than that of FO B cells in normal mice. The mechanism of anergy changes during differentiation and differs between subsets. This is strikingly illustrated by the observation that blockade of BCR-mediated activation of FO and MZ B cells occurs at different levels in the signaling cascade. Thus, attributes unique to B cells of each subset integrate with signals from the BCR to determine the effectiveness, affinity threshold, and mechanism of anergy.

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 National Institutes of Health Grants AI29576 and AI43587 and a grant from the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Stephen H. Clarke, Department of Microbiology and Immunology, CB 7290, 804 MEJ Building, University of North Carolina, Chapel Hill, NC 27599. E-mail address: shl{at}med.unc.edu

³ Abbreviations used in this paper: PC, plasma cell; FO, follicular; HEL, hen egg lysozyme; IRF-4, interferon response factor 4; MFI, mean fluorescence intensity; MZ, marginal zone; Sm, Smith; Tg, transgenic; Tr, transitional; XBP-1, X box-binding protein 1.