Cμ→Cδ Class Switch Recombination and IgD Production Contribute to Mucosal Immunity

Abstract

IgD has remained an enigmatic isotype since its discovery in 1965. Although assumed to have evolved recently, its discovery in amphibians and bony fishes suggests that IgD arose much earlier and has evolutionarily important functions. IgD is usually expressed by B cells through alternative splicing of an RNA containing the VDJ exon and the Cu and C6 genes. Yet, some B cells express exclusively IgD after class switch recombination (CSR) from Cμ to Cδ. We detected abundant IgD+IgM− B cells in human respiratory mucosa. Mucosal IgD+IgM− B cells expressed virtually exclusively λ light chain, exhibited a partial plasmablastic phenotype and secreted IgD across the epithelium. They also expressed AID and contained extrachromosomal Sμ‐σδ switch circles, two hallmarks of ongoing IgD CSR. In vitro, IgD CSR and secretion occurred after exposure of B cells to either T cell‐dependent (CD40L) or ‐independent (BAFF or APRIL) signals. In vivo, IgD CSR did not require functional follicles and T cell help via CD40L. Together with prior studies showing the polyreactivity of IgD+IgM− B cells, our data suggest that IgD CSR takes place to provide the respiratory mucosa with additional extrafollicular and follicular layers of immune protection. Finally, by showing elevated numbers of circulating IgD+IgM− plasmablasts in children with diseases associated with hyper IgD production, our findings functionally link IgD with inflammation.