Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity

Abstract

Secretory IgA (SIgA) antibodies represent the first line of antigen-specific immune defense protecting the mucosal surfaces against environmental pathogens and antigens, and maintaining homeostasis with the commensal microbiota. The polymeric immunoglobulin receptor (pIgR) has the dual role of transporting locally produced dimeric IgA across mucosal epithelia, and serving as the precursor of secretory component, a glycoprotein that enhances the immune functions of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimize the role of SIgA in mucosal immunity. Disruption of this regulatory network in disease states similar to inflammatory bowel disease can result in profound consequences for mucosal homeostasis and systemic sequelae. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of infectious and inflammatory diseases that originate at mucosal surfaces.

Figure 1

Regulation of production of SIgA and free SC in mucosal epithelia. The single-layered epithelium is covered with a thick mucus layer that physically excludes members of the resident microbiota. (1) Stimulation of epithelial Toll-like receptors (TLRs) with microbial-associated molecular patterns activates MyD88-dependent signaling pathways that trigger up-regulation of PIGR gene transcription. Activation of TLRs may also stimulate pIgR transcytosis (2) Newly synthesized pIgR molecules are sorted to the basolateral surface of epithelial cells. (3) Dimeric IgA secreted by lamina propria plasma cells binds to pIgR on the epithelial membrane and stimulates transcytosis. (4) IgA-bound and unoccupied pIgR are transcytosed through epithelial cells. (5) Proteolytic cleavage of pIgR at the apical surface releases SIgA and free SC. (6) Binding of SIgA and SC to luminal bacteria promotes association with the mucin layer and biofilm formation, and prevents direct access of bacteria to the epithelial surface.

Figure 2

Regulation of PIGR gene transcription by microbial products and host cytokines. Ligation of Toll-like receptors (TLRs) and cytokine receptors results in translocation of activated transcription factors to the nucleus and de novo synthesis of additional transcription factors. The PIGR gene contains binding sites for members of the Interferon Regulatory Factor (IRF), Signal Transducer and Activator of Transcription (STAT) and Nuclear Factor-κB (NF-κB) families of transcription factors. The complex signaling pathways that regulate PIGR gene transcription are described in the text.