Human IgD + IgM − Memory B Cells and Their Possible Impact on Mucosal Homeostasis and Tolerance

ABSTRACT This review discusses evidence indicating that the human nasopharyngeal mucosa includes a heterogeneous subset of memory B cells expressing IgD but not IgM. Such IgD + IgM − memory (IgD‐ME) B cells differentiate from germinal center B cell precursors that have undergone class switching from IgM to IgD in tonsillar lymphoid follicles. This DNA recombination process is associated with a mutation‐intensive program aimed at generating broadly reactive IgD antibodies that target a vast array of microbial and non‐microbial antigens. We review data indicating that many IgD‐ME B cells express atypical‐like B cell properties, accumulate polyreactivity and some autoreactivity in a somatic hypermutation‐dependent manner, and include precursors of IgD‐secreting IgD + IgM − plasma cells (IgD‐PCs). We further discuss the complex innate and adaptive signaling networks underlying the induction of IgD‐ME B cells and their clonal differentiation into IgD‐PCs. Furthermore, we consider the broad reactivity and functional effects of the IgD antibodies expressed by IgD‐ME B cells and released by IgD‐PCs. Moreover, we delve into the mechanisms whereby secreted IgD antibodies may contribute to mucosal tolerance and homeostasis. Lastly, we examine human disorders associated with abnormalities of the IgD response.