The enigmatic function of IgD: some answers at last

Abstract

IgD emerged soon after IgM at the time of inception of the adaptive immune system. Despite its evolutionary conservation from fish to humans, the specific functions of IgD have only recently begun to be elucidated. Mature B cells undergo alternative mRNA splicing to express IgD and IgM receptors with identical antigenic specificity. The enigma of dual IgD and IgM expression has been tackled by several recent studies showing that IgD helps peripheral accumulation of physiologically autoreactive B cells through its functional unresponsiveness to self-antigens but prompt readiness against foreign antigens. IgD achieves this balance by attenuating IgM-mediated anergy while promoting specific responses to multimeric non-self-antigens. Additional research has clarified how and why certain mucosal B cells become plasmablasts or plasma cells specializing in IgD secretion. In particular, the microbiota has been shown to play an important role in driving class switch-mediated replacement of IgM with IgD. Secreted IgD appears to enhance mucosal homeostasis and immune surveillance by "arming" myeloid effector cells such as basophils and mast cells with IgD antibodies reactive against mucosal antigens, including commensal and pathogenic microbes. Here we will review these advances and discuss their implications in humoral immunity in human and mice.

Landscape of Non-canonical Cysteines in Human VH Repertoire Revealed by Immunogenetic Analysis

“…The existence of IgD could not be reliably determined using the current dataset. However, because IgD is a spliced variant of the pre-mRNA that produces IgM (Gutzeit et al, 2018), and cysteine-containing CDR-H3s are quite abundant in IgM, it is reasonable to presume that cysteinecontaining CDR-H3s are likely to be present in IgDs. However, this assumption, if validated, will imply that cysteine-containing CDR-H3s are prevalent across all Ig classes and IGHV germline families.…”

Pten controls B‐cell responsiveness and germinal center reaction by regulating the expression of IgD BCR

“…While early developmental stages almost exclusively show IgM BCR expression, mature Fo.B cells exhibit a characteristic upregulation of IgD BCR accompanied by downregulation of IgM. Although this regulation is evolutionary conserved, the role of IgD BCR in B‐cell function remains unclear (Chen & Cerutti, , ; Ubelhart & Jumaa, ; Gutzeit et al , ). Together with previous data (Kim et al , ), we recently proposed that IgD is specialized for recognition of antigen encountered in the form of immune complexes (Ubelhart et al , ) and that this optimizes IgD BCR for T‐cell‐dependent immune reactions (Roes & Rajewsky, ).…”

Absence of Surface IgD Does Not Impair Naive B Cell Homeostasis or Memory B Cell Formation inIGHDHaploinsufficient Humans

“…In addition to IgM, circulating naive B cells coexpress a receptor with the IgD isotype, resulting from alternative splicing of the exons encoding the variable domain to Cd constant regions encoding exons (4)(5)(6). IgM function has been extensively studied, and even though IgD coexpression is highly conserved in jawed vertebrates (7), the biological role of surface IgD remains enigmatic even 50 y after its initial discovery (8,9).…”