Immunoglobulin D enhances immune surveillance by activating antimicrobial, pro-inflammatory and B cell-stimulating programs in basophils

Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells co-express with IgM through alternative RNA splicing. We found active T cell-dependent and T cell-independent IgM-to-IgD class switching in human upper respiratory mucosa B cells. This process required activation-induced cytidine deaminase and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell-stimulating factors including cathelicidin, interleukin-1, interleukin-4 and B cell-activating factor BAFF upon IgD cross-linking. By showing dysregulation of IgD class-switched B cells and IgD-armed basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.