The function and regulation of immunoglobulin D

Abstract

Recent discoveries of IgD in ancient vertebrates suggest that IgD has been preserved in evolution from fish to human for important immunological functions. A non-canonical form of class switching from IgM to IgD occurs in the human upper respiratory mucosa to generate IgD-secreting B cells that bind respiratory bacteria and their products. In addition to enhancing mucosal immunity, IgD class-switched B cells enter the circulation to 'arm' basophils and other innate immune cells with secreted IgD. Although the nature of the IgD receptor remains elusive, cross-linking of IgD on basophils stimulates release of immunoactivating, proinflammatory and antimicrobial mediators. This pathway is dysregulated in autoinflammatory disorders such as hyper-IgD syndrome, indicating that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.

Figure 1

Structural diversity of IgD. The heavy chain variable region and light chain of IgD are represented by gray ovals, whereas the Cδ domains of the heavy chain constant region of IgD are represented by colored ovals. Intragenic duplications of C_δ exons and alternative splicing generate structural diversity of IgD in fish. Transmembrane and secreted fish IgD molecules are shown to emphasize alternative splicing. No transmembrane forms have been described in lungfish. Xenopus has abundant transmembrane IgD as well as transcripts encoding secreted IgD. However, the structure of secreted IgD has not been clearly shown in xenopus. Presence of Ig light chain is predicted but not demonstrated in IgD from bony fish, xenopus, and lungfish. IgD of channel catfish and puffer fish, among other bony fishes, is shown. The red domain is encoded by a duplicated C_μ1 exon. IgD of leopard gecko and green anole lizard is shown. The blue domains denote C_α-like domains found in leopard gecko IgD. The red domains in cow, sheep, horse and pig IgD indicate the inclusion of a C_μ1 or C_μ1-like domain. Hinge regions of IgD are not shown.

Figure 2

Induction, regulation and function of mucosal IgD. Mucosal dendritic cells (DCs) present antigen to activate CD4⁺ T helper (TH) cells. These cells induce follicular IgM⁺IgD⁺ B cells to undergo IgM-to-IgD CSR through a TD pathway involving CD40L, IL-2 and IL-21. In addition, innate immune cells such as DCs, monocytes and epithelial cells produce BAFF, APRIL, IL-2 and IL-15 probably upon sensing microbial products. These mediators stimulate extrafollicular IgM⁺IgD⁺ B cells to undergo IgM-to-IgD CSR in a TI manner. The resulting IgD class-switched (IgM⁻IgD⁺) B cell differentiate into plasmablasts that secrete IgD molecules reactive against respiratory antigens. Secreted IgD also binds to an IgD receptor (IgDR) on circulating basophils. In the presence of IgD cross-linking antigens, basophils migrate to systemic or mucosal lymphoid tissues, where they enhance immunity by releasing immunoactivating, proinflammatory and antimicrobial factors such as BAFF, IL-4, IL-1β and TNF. These factors augment mucosal immune responses by promoting B and T cell activation, leukocyte recruitment and direct microbial killing.