Commensal bacteria and the lung environment are responsible for Th2-mediated memory yielding natural IgE in MyD88-deficient mice

IgE antibody is known as a common mediator of allergic responses, generally produced in type 2 immune responses to allergens. It is known that IgE binding to FcεRI without allergen binding promotes survival or proliferation of mast cells, basophils and other cells. Thus, spontaneously produced IgE, namely natural IgE, can increase an individual’s susceptibility to allergic diseases. Mice with a genetic defect in MyD88, a major signaling molecule downstream of Toll-like receptors, have a high level of serum natural IgE, the mechanism for which remains unknown. Here, we demonstrated that the maintenance of high serum IgE levels depends on memory B cells (MBCs). IgE from plasma cells and the sera from most of Myd88–/– mice, but none of Myd88+/– mice, recognized Streptococcus azizii (S. azizii), a commensal bacterium over-represented in the lung of Myd88–/– mice. IgG1+ MBCs from spleen also recognized S. azizii. The serum IgE levels declined by administration of antibiotics and were boosted by challenge with S. azizii in Myd88–/– mice. Moreover, bulk IgH repertoire analysis revealed that CDR3 sequences were highly shared between IgE+ PCs and IgG1+ or IgG2+ MBCs, indicating the contribution of S. azizii-specific IgG1+ MBCs to the natural IgE production. IgD- IgM- CD138- GL7- CD38+ CD19+ class-switched memory B cells or CD19- CD98+ CD138+ plasma cells (PCs) were sorted from spleen, mediastinal LN (medLN) or lung of unimmunized MyD88-deficient mice. Bulk IgH sequencing was performed for IgE, IgG1/2b/2c and IgG3 isotypes in these samples, and pairwise distances of the sequences were calculated based on the Morisita-Horn similarity index.