Signals from a Self-Antigen Induce Positive Selection in Early B Cell Ontogeny but Are Tolerogenic in Adults

• Published in: Journal of Immunology 2006-06, Vol.176 (12), p.7402-7411
• Main Authors: Ferry, Helen, Crockford, Tanya L, Leung, Janson C. H, Cornall, Richard J
• Format: Article
• Language: English
• Subjects: Aging - genetics; Aging - immunology; Animals; Animals, Newborn; Antigen Presentation - genetics; Ascitic Fluid - cytology; Ascitic Fluid - immunology; Autoantibodies - physiology; Autoantigens - immunology; Autoantigens - metabolism; Autoantigens - physiology; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Clonal Deletion - genetics; Fetus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase - immunology; Muramidase - metabolism; Muramidase - physiology; Radiation Chimera; Self Tolerance - genetics; Signal Transduction - genetics; Signal Transduction - immunology; Spleen - cytology; Spleen - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.12.7402

Positive and negative signals from self-Ags shape the B cell repertoire and the development of distinct B cell subsets, but little is known about what distinguishes these signals. To address this question, we have studied the development of anti-hen egg lysozyme MD4 Ig transgene B cells while systematically varying the level, distribution, and timing of exposure to different forms of hen egg lysozyme as a self-Ag. This process has allowed us to explore the effects of Ag independent of BCR specificity. Our findings show how the selection of autoreactive B cells is a competitive process involving immunogenic and tolerogenic forms of self-Ags. Due to a developmental switch during B cell ontogeny, autoreactive anti-hen egg lysozyme MD4 Ig transgene B cells are negatively selected by self-Ags in adult bone marrow but susceptible to positive selection by some of the same self-Ags in fetal and neonatal life. However, the persistence of B1 cells and IgM autoantibodies from early ontogeny enables autoreactive B cells from the adult bone marrow to escape negative selection. Our data suggest that this rescue may be due to the clearance or masking of self-Ag by IgM autoantibody. We discuss the implications of these findings in terms of B cell selection and the maintenance of self-tolerance during early and adult life.