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Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction¹

Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107

We have described an Ig-transgenic, autoreactive B cell clonotype that undergoes a novel tolerance pathway. Early in development this clonotype expresses average BCR levels, but these levels are progressively down-regulated as development proceeds efficiently to the mature, follicular compartment. This clonotype does not display conventional features of anergy and can be induced to undergo apoptosis and receptor editing in in vitro bone marrow cultures, but these pathways are not taken in vivo. These data suggested that autoantigen-driven down-regulation of BCR levels and, hence, avidity for autoantigen allows this clonotype to bypass conventional tolerance mechanisms. To test this idea, we enforced elevated levels of expression of BCR in this clonotype by making the transgenic Igh locus homozygous. This resulted in retarded clonotype development and L chain receptor editing in vivo. These data support a pivotal role for adaptive, autoantigen-induced adjustment of BCR expression levels in the regulation of primary B cell development and tolerance.

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 The studies were supported by National Institutes of Health Grant AI038965 (to T.M.).

² X.L. and S.S. contributed equally to this work.

³ Current address: Renal Electrolyte & Hypertension Division, School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 115 Clinical Research Building, Philadelphia, PA 19104.

⁴ Address correspondence and reprint requests to Dr. Tim Manser, Department of Microbiology and Immunology, Jefferson Medical College, 469 JAH, 1020 Locust Street, Philadelphia, PA 19107. E-mail address: manser{at}mail.jci.tju.edu

⁵ Abbreviations used in this paper: Ars, p-azophenylarsonate; FO, follicular; s, surface; BM, bone marrow; ANA, antinuclear Ab; KLH, keyhole limpet hemocyanin; MZ, marginal zone.