The Journal of Experimental Medicine
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Published 15 March 2004. doi:10.1084/jem.20030955
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 843-853
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Positive Selection of B Cells Expressing Low Densities of Self-reactive BCRs

Emmanuelle Gaudin1, Yi Hao1, Maria Manuela Rosado1, Richard Chaby3, Robert Girard2, and António A. Freitas1

1 Lymphocyte Population Biology Unit and 2 Unité du Development des Lymphocytes, Institut Pasteur, 75015 Paris, France
3 Unité Associé de Recherche 1961 and Unité Mixte de Recherche 8619, Centre Nationale de la Recherche Scientifique, Université Paris-Sud, 91405 Orleans, France

Address correspondence to António A. Freitas, Lymphocyte Population Biology Unit, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015 Paris, France. Phone: 33-1-45688582; Fax: 33-1-45688921; email: afreitas{at}pasteur.fr

B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self-reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs.

Key Words: B lymphocytes • self-reactivity • avidity • selection • self-antigen

The present address of M.M. Rosado is Research Center Ospedale Bambino Gesù, 00165 Rome, Italy.

Abbreviations used in this paper: BCR, B cell receptor; BrdU, bromodeoxyuridine; HEL, hen egg lysozyme.


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