Absence of surface IgD does not impair naive B cell homeostasis and memory B cell formation in humans

One Sentence Summary Human B cells with a genetic defect in IGHD develop normally in vivo , and do not have a competitive disadvantage to IgD-expressing B cells for developing into memory B cells. Abstract Surface immunoglobulin D (IgD) is co-expressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 years after its initial discovery. We here examined the in vivo role of surface IgD in human B-cell homeostasis and antibody responses in four individuals with heterozygous nonsense mutations in IGHD . All IGHD heterozygous individuals had normal numbers of B cells and serum immunoglobulins, and did not show signs of immunodeficiency or immune dysregulation. IgD + and IgD– naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD– subset. Furthermore, both IgD+ and IgD– naive mature B cells had normal replication histories, similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig switched memory B cells showed similar levels of somatic hypermutations. Thus human B cells lacking IgD expression develop normally and generate immunological memory in vivo , suggesting that surface IgD might function more restricted in regulating of B-cell activation to specific antigenic structures.