Signals from a self-antigen induce positive selection in early B cell ontogeny but are tolerogenic in adults.
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.
Ferry
Helen
H
Henry Wellcome Building of Molecular Physiology, University of Oxford, UK.
Crockford
Tanya L
TL
Leung
Janson C H
JC
Cornall
Richard J
RJ
D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D017951:Antigen Presentation / Q000235:genetics; D001202:Ascitic Fluid / Q000166:cytology / Q000276:immunology; D001323:Autoantibodies / Q000502:physiology; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D017637:Clonal Deletion / Q000235:genetics; D005333:Fetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011828:Radiation Chimera; D017634:Self Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; C421864:hen egg lysozyme; D009113:Muramidase