Sequential class switching is required for the generation of high affinity IgE antibodies
Open Access
- 16 January 2012
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (2), 353-364
- https://doi.org/10.1084/jem.20111941
Abstract
IgE antibodies with high affinity for their antigens can be stably cross-linked at low concentrations by trace amounts of antigen, whereas IgE antibodies with low affinity bind their antigens weakly. In this study, we find that there are two distinct pathways to generate high and low affinity IgE. High affinity IgE is generated through sequential class switching (μ→γ→ε) in which an intermediary IgG phase is necessary for the affinity maturation of the IgE response, where the IgE inherits somatic hypermutations and high affinity from the IgG1 phase. In contrast, low affinity IgE is generated through direct class switching (μ→ε) and is much less mutated. Mice deficient in IgG1 production cannot produce high affinity IgE, even after repeated immunizations. We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fcε receptors and prevents anaphylaxis and is thus beneficial.This publication has 80 references indexed in Scilit:
- Overlapping activation-induced cytidine deaminase hotspot motifs in Ig class-switch recombinationProceedings of the National Academy of Sciences of the United States of America, 2011
- IgE, mast cells, basophils, and eosinophilsJournal of Allergy and Clinical Immunology, 2010
- Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regionsProceedings of the National Academy of Sciences of the United States of America, 2010
- Controlling somatic hypermutation in immunoglobulin variable and switch regionsImmunologic Research, 2010
- Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndromeJournal of Allergy and Clinical Immunology, 2009
- Combined Immunodeficiency Associated withDOCK8MutationsThe New England Journal of Medicine, 2009
- Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody productionNature Immunology, 2009
- Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgEAdvances in Immunology, 2008
- Unique Maturation Program of the IgE Response In VivoImmunity, 2007
- Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory diseaseProceedings of the National Academy of Sciences of the United States of America, 2007