High-affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High-affinity Abs are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC); however, several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the “indirect switching pathway” for IgE, has been described whereby Ag-specific B cells initially switch to the IgGl isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high-affinity IgE develops in the GC, but we did not test the indirect switching model. In this study, we analyzed the importance of the indirect switching pathway by constructing IgGl-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgGl, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgGl-cre Bcl6-fl/fl mice with our food allergy model, we found that, as expected, IgGl Abs had decreased affinity, but unexpectedly, the affinity of IgE for allergen was unchanged. IgGl-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high-affinity IgE. Thus, in a food allergy response, high-affinity IgE can be efficiently formed in the absence of indirect switching to IgGl, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.
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