Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Corrado, Alessia; Ramonell, Richard P.; Woodruff, Matthew C.; Tipton, Christopher; Wise, Sarah; Levy, Joshua; DelGaudio, John; Kuruvilla, Merin E.; Magliocca, Kelly R.; Tomar, Deepak; Garimalla, Swetha; Scharer, Christopher D.; Boss, Jeremy M.; Wu, Hao; Gumber, Sanjeev; Fucile, Chris; Gibson, Greg; Rosenberg, Alexander; Sanz, Iñaki; Lee, F. Eun-Hyung

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using V(H) next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.