The Polymeric Immunoglobulin Receptor

Abstract

Secretory Immunoglobulin A (SIgA) antibodies represent the first line of antigen‐specific immune defence protecting the mucosal surfaces against environmental pathogens and antigens and maintaining homoeostasis with the commensal microbiota. The polymeric Ig receptor (pIgR) plays the dual role of transporting locally produced dimeric IgA across mucosal epithelia and serving as the precursor of the secretory component moiety of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimise the role of SIgA in mucosal immunity. Recent discoveries highlight the dynamic cross‐talk between pIgR, SIgA and the commensal microbiota that populate our mucosal surfaces. Dysregulation of pIgR expression and/or function can result in profound consequences for the pathogenesis of infectious, inflammatory and neoplastic diseases. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of diseases that originate at mucosal surfaces.

Key Concepts:

  • Secretory IgA (SIgA) antibodies represent the first line of antigen‐specific immune defence at mucosal surfaces.

  • The polymeric immunoglobulin receptor (pIgR) transports dimeric IgA across mucosal epithelial cells and serves as the precursor for the secretory component of SIgA.

  • Transcription of the PIGR gene in mucosal epithelial cells is regulated by signalling pathways initiated by host cytokines and microbial factors, involving the cytoplasmic adapter protein, myeloid differentiation primary response protein 88 (MyD88).

  • SIgA mediates immune protection by immune exclusion, intracellular neutralisation of antigens and pathogens and excretion of IgA‐containing immune complexes by pIgR‐mediated epithelial transcytosis.

  • Cross‐talk between pIgR, SIgA and commensal bacteria regulates the composition of the gut microbiota and promotes intestinal homoeostasis.

  • Dysregulated expression or function of pIgR can contribute to the pathology of infectious, inflammatory and neoplastic diseases.

Keywords: polymeric immunoglobulin receptor; secretory IgA; mucosal immunity; epithelial transcytosis; microbiota; cytokines; Toll‐like receptors; NF‐κB; infectious diseases; inflammatory bowel disease; cancer

Figure 1.

Schematic diagram of SIgA structure. The basic monomeric unit of IgA comprises two identical α heavy chains and two light chains (κ or λ) connected by disulphide bonds. The antigen‐binding sites are formed by interactions between the N‐terminal domains of the IgA heavy and light chains. Dimeric IgA is formed within the endoplasmic reticulum of IgA‐producing plasma cells when two IgA monomers are disulphide‐linked via a 12 kD joining (J) chain. The 80 kD secretory component associates with dimeric IgA during epithelial transcytosis (see Figure ).

Figure 2.

Transcytosis of the pIgR through a polarised epithelial cell and formation of SIgA. A polarised columnar epithelial cell is illustrated, with the apical surface at the top and the basolateral surface at the bottom. Transcription of the PIGR gene is regulated by signals received from host and microbial factors. Newly synthesised pIgR is targeted to the basolateral surface where it binds dIgA and dIgA‐containing immune complexes. Following receptor‐mediated endocytosis, dIgA‐bound or unoccupied pIgR is transported through a series of intracellular vesicles, in which neutralisation of pathogens and antigens (Ag) can take place. At the apical surface, pIgR is proteolytically cleaved to release free SC and SIgA. At mucosal surfaces and in external secretions, free SC and SIgA contribute to innate and adaptive immune defence. Modified from Kaetzel , with permission from Blackwell Publishing Group.

Figure 3.

Regulation of PIGR gene transcription by cytokines and microbial factors. Ligation of cytokine receptors and Toll‐like receptors (TLRs), results in translocation of activated transcription factors to the nucleus and de novo synthesis of additional transcription factors. The cytoplasmic adapter protein MyD88 is critical for transducing signals from cytokine receptors in the IL1R superfamily as well as many TLRs. The PIGR gene contains binding sites for members of the Interferon Regulatory Factor (IRF), signal transducer and activator of transcription (STAT) and nuclear factor kappa B (NF‐κB) families of transcription factors. The complex signalling pathways that regulate PIGR gene transcription are described in the text. Modified from Johansen and Kaetzel , with permission from Nature Publishing Group.

Figure 4.

Schematic structure of the human polymeric immunoglobulin receptor (pIgR). The pIgR is a type I transmembrane protein, with an N‐terminal extracellular region comprising five domains with homology to immunoglobulin variable regions. The three CDRs in domain 1 form a noncovalent binding surface for polymeric IgA and IgM. Unique motifs in CDR2 contribute to species‐specific binding of pIgR to IgM. Peptide motifs in domains 3 and 4 cooperate to form a binding surface for the SpsA/CbpA protein of S. pneumoniae. Seven N‐glycan residues on domains 1, 2, 4 and 5 contribute to innate immune functions of SC and may facilitate transcytosis of pIgR. During transcytosis, a disulphide bridge is formed between domain 5 of pIgR and the α heavy chain of dimeric IgA. An unstructured peptide, which is poorly conserved across species, links domain 5 to the membrane‐spanning region and contains site(s) for proteolytic cleavage of pIgR to secretory component (SC). The cytoplasmic domain of pIgR contains highly conserved signals for intracellular sorting, endocytosis and transcytosis. Modified from Kaetzel , with permission from Blackwell Publishing Group.

Figure 5.

Cross‐talk between pIgR, SIgA and the gut microbiota. The single‐layered epithelium that lines the gastrointestinal tract is covered with a thick mucus layer, which physically excludes members of the resident microbiota. Stimulation of epithelial toll‐like receptors (TLRs) with MAMPs activates MyD88‐dependent signalling pathways that trigger PIGR gene transcription. Activation of TLRs may also stimulate pIgR transcytosis. dIgA secreted by lamina propria plasma cells binds to pIgR on the basolateral surface of epithelial cells and is transcytosed to the apical surface. Four IgA‐bound and unoccupied pIgR are transcytosed through epithelial cells along with unoccupied pIgR. Proteolytic cleavage of pIgR at the apical surface releases SIgA and free SC. Binding of SIgA and SC to luminal bacteria promotes association with the mucus layer and prevents direct access of bacteria to the epithelial surface. Over time, the continuous cross‐talk with SIgA shapes the composition of the gut microbiota. Modified from Johansen and Kaetzel , with permission from Nature Publishing Group.

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Kaetzel, Charlotte S(Jan 2013) The Polymeric Immunoglobulin Receptor. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024237]