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

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.