Polymeric immunoglobulin receptor

pIgR is produced among others by intestinal epithelial cells (IECs) and bronchial epithelial cells. pIgR belongs to the family of type I transmembrane proteins. The extracellular portion of the protein contains six domains: five evolutionary conserved immunoglobulin-like domains, and one non-homologous domain, which is involved in proteolytic cleavage of pIg-pIgR complex from the apical side of the IECs. The quite long intracellular domain of the receptor, along with the transmembrane region, is responsible for the transduction of highly conserved signals. During transcytosis, an essential part of pIgR, the secretory component, is attached to the ligand and later cleaved with the ligand to form fully functioning secreted IgA. == History ==

Per Brandtzaeg showed that secretory component acts as a plasma membrane receptor on epithelial cells for polymeric immunoglobulin A and immunoglobulin M. This was paradoxical, as secretory component is a soluble protein, whereas plasma membrane receptors are transmembrane proteins. Numerous models were proposed for how secretory component might work as a receptor, though none of these models resolved this paradox. == Function ==

Polymeric immunoglobulin receptor is responsible for transcytosis of soluble dimeric IgA, pentameric IgM, and immune complexes from the basolateral to the apical mucosal epithelial cell surface. pIgR has a strong specificity to polymeric immunoglobulins and is not responsive to monomeric immunoglobulin. The ligand’s J-chain is responsible for the binding of pIgR to its ligand. The accumulation of ICs on the basolateral side of mucous layers can have detrimental effects. Transcytosis of IgA ICs from the formation sites represents an important mechanism of eliminating circulating antigens and minimizing their negative effects. == Regulation ==

Cytokinetic regulation The expression of pIgR is critically regulated by the pro-inflammatory cytokines, such as IL-1, IL-4, TNF-α, and IFN-γ. The transcriptional regulation by different cytokines proceeds through similar pathways, involving the NF-kB feedback loop. Interaction of IL-1 and TNF-α with their receptors ultimately lead to transcriptional activation of PIGR gene due to nuclear translocation of NF-kB. NF-kB interacts with intron 1 of the PIGR gene to start pIgR mRNA synthesis. Hormonal regulation The level of pIgRs in the mucosal reproductive tract is highly dependent on the activity of sex hormones and correlates with estrous cycle phases. The peaks of pIgR expression at proestrus and estrus phases are due to the dominant activity of estrogen, which acts as a pIgR agonist. The low levels of pIgR during the diestrus are linked to the downregulating activity of progesterone, which peaks during this phase and is able to reverse the activity of estrogen. Androgens are the agonists of pIgR expression in both male and female reproductive tissues. Prolactin elevates the levels of IRF-1 via Jak-STAT pathway. IRF-1 is known to be a direct agonist of pIgR expression. Considering this linkage, prolactin is believed to exhibit indirect upregulation of pIgR levels during pregnancy and lactation. Pathogenic stimulation IECs express a variety of Toll-like receptors (TLRs), activation of which ultimately leads to the pIgR upregulation during the infection. The most prominent modulators of pIgR regulation consist of TLR4 and TLR3, which recognize bacterial lipopolysaccharide and viral dsRNA respectively. TLR4, like the majority of TLRs, transduce the signal though MyD88 adaptor and execute the function via NF-kB, which stimulates the expression of pIgR by binding to intron 1 of the gene. TLR3, on the other hand, involves the regulation by the means of IRF-1, which is able to promote the transcription of PIGR gene by binding to exon 1. == References ==