Introduction:

The human polymeric immunoglobulin receptor (PIGR) is expressed by mucosal epithelial cells, and is, as the name states, a receptor for polymeric immunoglobulins. Specifically, it binds polymeric IgM and dimeric IgA and transports these across the mucosal epithelial barrier and releases them as secretory antibodies in the mucosal secretions [1].

Disease relevance of PIGR

• To examine the mechanism by which PIGR expression is down-regulated in lung carcinoma, RNA was microdissected from formalin-fixed, paraffin-embedded lung carcinomas (14 adenocarcinomas and 8 squamous cell carcinomas) [2].
• PIGR mRNA levels were decreased in adenocarcinomas and squamous cell carcinomas relative to adjacent non-tumor tissue, and were inversely correlated with stage of differentiation [2].
• Genes that are down-regulated in colorectal cancer, including PIGR, frequently have non-canonical E-Boxes, while genes that are up-regulated in colorectal cancer generally have canonical E-Boxes [3].
• CONCLUSIONS: We present genetic evidence leading to hypothesize a possibility of PIGR to function as the EBV nasopharyngeal epithelium receptor via IgA-EBV complex transcytosis failure [4].
• Polymeric immunoglobulin receptor polymorphisms and risk of nasopharyngeal cancer [4].

High impact information on PIGR

• The best studied example of this is the transport of polymeric IgA and IgM by the polymeric immunoglobulin receptor (pIgR) across many types of epithelial cells [5].
• Phosphorylation of a cytoplasmic serine promotes transcytosis of the pIgR without ligand bound [5].
• The pIgR binds its ligand at the basolateral surface and is internalized into endosomes [5].
• The polymeric immunoglobulin receptor (pIgR) plays a crucial role in mucosal immunity against microbial infection by transporting polymeric immunoglobulins (pIg) across the mucosal epithelium [6].
• Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis [7].

Chemical compound and disease context of PIGR

• The cDNA encoding the NH2-terminal 589 amino acids of the extracellular domain of the human polymeric immunoglobulin receptor was inserted into transfer vectors to generate recombinant baculo- and vaccinia viruses [8].
• Contribution of polymeric immunoglobulin receptor to regulation of intestinal inflammation in dextran sulfate sodium-induced colitis [9].

Biological context of PIGR

• An E-Box motif, which binds transcription factors of the basic helix-loop-helix/leucine zipper (bHLH/zip) family, was identified as a major regulatory element in the PIGR gene promoter [3].
• Haplotype of the two missense PIGR SNPs, 1093G-->A and 1739C-->T, and sequence analyses have confirmed the role of the nucleotide PIGR1739 and excluded possibility of an additional significant nonsynonymous NPC susceptibility SNP [4].
• To prove the hypothesis, we evaluated two candidate genes, complement receptor 2 (CR2) and polymeric immunoglobulin receptor (PIGR) by using 4 SNPs, CR2IVS2-848C-->T, PIGRIVS3-156G-->T, PIGR1093G-->A and PIGR1739C-->T, to genotype 175 cases and 317 controls, divided into Thai, Chinese and Thai-Chinese based on their respective ethnic origins [4].
• Here we present a detailed analysis of the promoter of the PIGR gene by transient transfection of luciferase reporter plasmids into cultured cell lines [10].
• The gene encoding human transmembrane secretory component (locus PIGR) is linked to D1S58 on chromosome 1 [11].

Anatomical context of PIGR

• The level of expression of polymeric Ig receptor is controlled to a large extent by transcription of the PIGR gene in mucosal epithelial cells [10].
• Analysis of somatic cell hybrids and in situ chromosomal hybridization localized the human PIGR gene locus to 1q31----q41 [12].
• The identification of novel functions for SC and SIgA has expanded our view of the immunobiology of pIgR, a key component of the mucosal immune system that bridges innate and adaptive immune defense [13].
• The biosynthetic pathway of apically sorted polymeric immunoglobulin receptor mutants similarly traversed apical endosomes, raising the possibility that apical receptors are segregated from basolateral receptors in apical endosomes [14].
• We found that in the course of basolateral exocytosis, the wild-type polymeric immunoglobulin receptor is targeted from the trans-Golgi network to apical and basolateral endosomes [14].

Associations of PIGR with chemical compounds

• Polymeric immunoglobulin receptor (PIGR) is a transmembrane glycoprotein which is expressed by epithelial cells and is involved in the transcellular transport of polymeric immunoglobulins into secretions [12].
• Surface pIgR on human bronchial epithelial cells was also cleaved by serine proteinases, as shown by immunofluorescence [15].
• The FcalphaRI-binding site on IgA1 overlaps the reported polymeric immunoglobulin receptor (pIgR)-binding site, which might explain why secretory IgA cannot initiate phagocytosis or bind to FcalphaRI-expressing cells in the absence of an integrin co-receptor [16].
• Each pair of alpha-helices is antiparallel and conserved residues in the loop between Helices 1 and 2 exhibit a novel 'tyrosine fork' structure that is involved in binding pIgR [17].
• The scFv was constructed from a monoclonal antibody directed against pIgR and a cysteine residue was added at the carboxyl end to facilitate its conjugation to polylysine (polyK) via the heterobifunctional cross-linker SPDP [18].

Physical interactions of PIGR

• Chromatin immunoprecipitation (ChIP) demonstrated that USF proteins bind the PIGR promoter in vivo, which is enriched in acetylated histones [3].

Regulatory relationships of PIGR

• Expression of pIgR is regulated by microbial products through Toll-like receptor signaling and by host factors such as cytokines and hormones [13].
• Transcription of pIgR is regulated both by promoter elements [19] as well as an intronic enhancer that is responsive to the cytokines IL4 [20] [21] and TNF [22][23]
• We studied the mechanism by which interferon-gamma (IFN-gamma) induces pIgR expression in HT-29.74 cells, a subclone of the HT-29 cell line selected for high concns of pIgR [24].
• Depletion of endogenous MAL2 drastically blocked transcytotic transport of exogenous polymeric immunoglobulin receptor and endogenous glycosylphosphatidylinositol-anchored protein CD59 to the apical membrane [25].
• Transcytosis experiments performed using human polymeric immunoglobulin receptor (pIgR) expressing Madine-Darby canine kidney (MDCK) cells showed that one of the recombinants showed a high degree of colocalization with PDC-E2 [26].

Other interactions of PIGR

• Multivariate regression analysis demonstrated that reduced USF2 mRNA and increased AP2-alpha mRNA levels were predictive of down-regulated PIGR mRNA expression in the majority of adenocarcinomas and in moderately differentiated squamous cell carcinomas [2].
• The structure of pIgR domain 1 reveals a folding topology similar to immunoglobulin variable domains, but with differences in the counterparts of the complementarity determining regions (CDRs), including a helical turn in CDR1 and a CDR3 loop that points away from the other CDRs [27].
• Here we present the first genetic linkage study of PIGR versus syntenic markers, including D1S58 and F13B, which have been previously regionalized to 1q31-q32 and 1q31-q32.1, respectively [11].
• We found that PIGR is closely linked to D1S58 (lods + 5.06 at theta max = 0.06, without sex difference) [11].
• In contrast, pIgR/SC production by cultured epithelial cells (quantified by enzyme-linked immunosorbent assay) was significantly increased by supernatants from interleukin-8/formylmethionylleucylphenylalanine-activated PMN (122.6 +/- 17.3 versus 70.9 +/- 9 ng/mg protein, P < 0.01) [15].

Analytical, diagnostic and therapeutic context of PIGR

• Several studies have utilized immunohistochemistry to demonstrate that PIGR expression varies in different types of lung carcinoma, and is down-regulated during tumor progression [2].
• This possibility agreed with Southern blot analysis performed on a separate sample of 32 other colonic carcinomas in which the diallelic loss of D1S58 (which exhibits a close linkage centromerically to PIGR) was calculated to be 6.4% [28].
• Molecular cloning and exon-intron mapping of the gene encoding human transmembrane secretory component (the poly-Ig receptor) [29].
• From 5 to 66% of the respiratory epithelial cells had beta-galactosidase activity after treatment, comparable to the percentage of cultured human tracheal epithelial cells that express polymeric immunoglobulin receptor (8-35%) [30].
• Gel electrophoresis mobility shift assays with nuclear extracts from different pIgR-expressing epithelial cell lines demonstrated proteins that bind independently to both the E-box and the IRS sequence of the pIgR promoter [31].

References