IgE Abs are a common mediator of allergic responses and are generally produced in type 2 immune responses to allergens. Allergen stimulation of IgE-bound FcεRI on mast cells or basophils induces the production of chemical mediators and cytokines. In addition, IgE binding to FcεRI without allergen promotes the survival or proliferation of these and other cells. Thus, spontaneously produced natural IgE can increase an individual’s susceptibility to allergic diseases. Mice deficient in MyD88, a major TLR signaling molecule, have high serum levels of natural IgE, the mechanism for which remains unknown. In this study, we demonstrated that the high serum IgE levels were maintained from weaning by memory B cells (MBCs). IgE from plasma cells and sera from most Myd88−/− mice, but none of the Myd88+/− mice, recognized Streptococcus azizii, a commensal bacterium overrepresented in the lungs of Myd88−/− mice. IgG1+ MBCs from the spleen also recognized S. azizii. The serum IgE levels declined with the administration of antibiotics and were boosted by challenge with S. azizii in Myd88−/− mice, indicating the contribution of S. azizii–specific IgG1+ MBCs to the natural IgE production. Th2 cells were selectively increased in the lungs of Myd88−/− mice and were activated upon addition of S. azizii in the lung cells ex vivo. Finally, lung nonhematopoietic cells, and CSF1 overproduced therefrom, were responsible for natural IgE production in Myd88−/− mice. Thus, some commensal bacteria may prime the Th2 response and natural IgE production in the MyD88-defective lung environment in general.

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