Introduction: Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work has demonstrated pIgR to be upregulated in hepatocellular carcinoma, even though it is not expressed in normal liver cells. High pIgR levels are associated with poor survival and distant metastases for a number of cancers such as nasopharyngeal cancers, lung and oesophageal cancers. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). My aim was to assess pIgR's role in PDAC by interrogating human PDAC tissue samples as well using cell biology experimental tools. Methods: pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. Results: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies using colorectal and nasopharyngeal cancer cell lines. Downregulation in pIgR expression in Capan1 cell line resulted in reduction of cellular proliferation (n= 3, P < 0.05, Friedman test), adhesion (n= 3, P < 0.05, Kruskal-Wallis) and migration (n= 3, P < 0.05, Kruskal-Wallis). In 3D organotypic models, pIgR downregulation resulted in reduced cancer cell invasion (n= 9, P < 0.05, Kruskal- Wallis) and diminished contraction of gels (n= 9, P < 0.05, Kruskal-Wallis). In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. There was no IgA expression in PDAC. pIgR expression had no clinical correlation with routine prognostic measures such as differentiation, lymph node metastasis (n= 88, P=0.5012, Kruskal-Wallis). Even in combination with stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had no statistically significant impact on prognosis but had a trend towards better survival (n= 88, P=0.2791, Mann-Whitney U test). Conclusion: pIgR may be involved in progression from pre-neoplastic lesions such as PanIN to PDAC. pIgR may have a biological impact on cellular motility and invasion due to yet to be deciphered signalling cascades with marked effect on cellular phenotype. Careful analysis is required to study the impact of pIgR on prognostic impact bearing in mind the histological sub-types of pancreatic cancer.

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The mammalian intestine harbors an estimated 100 trillion microorganisms, which normally maintain a mutually beneficial relationship with the host. The intestinal epithelium consists of a single layer of intestinal epithelial cells (IECs) that provides a physical barrier as well as innate immune defense, preventing this vast community of microbes from entering host tissues. Secretory immunoglobulin A (SIgA) acts as the first line of antigen-specific immunity at the interface between the gut microbiota and the intestinal epithelium. Polymeric IgA secreted by plasma cells in the intestinal lamina propria is transported across IECs by the polymeric immunoglobulin receptor (pIgR). Defects in epithelial barrier and immune functions can lead to infections with opportunistic and pathogenic microbes and contribute to the etiology of inflammatory bowel disease (IBD). Here we investigate the ability of IEC biomarkers to define the mechanism and severity of intestinal inflammation, as well as provide insight into the function of IEC in regulating intestinal homeostasis and inflammation. Importantly, down-regulation of pIgR expression was a common feature in human IBD and mouse models of experimental colitis. One molecule of pIgR is consumed for every molecule of SIgA transported, thus high expression of pIgR is required to maintain sufficient supply of SIgA. Accordingly, we investigate the mechanisms by which IECs regulate pIgR expression in response to colonic bacteria. Cross-talk between the microbiota and IECs is mediated by pattern recognition receptors, including Toll-like receptors (TLR), leading to expression of gene products that enhance epithelial barrier function and innate immunity. The cytoplasmic adaptor protein MyD88 transduces signals from TLRs that recognize bacterial products. We show that pIgR induction by colonic bacteria is dependent on TLR4-MyD88 activation of NF-κB signaling. We examined the role of epithelial-specific MyD88 signaling in antibacterial immunity and epithelial expression of key gene products that participate in innate immunity in the gut by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88ΔIEC). MyD88ΔIEC mice display immunological and antimicrobial defects resulting in increased susceptibility to experimental colitis. We conclude that cross-talk between bacteria and IECs via MyD88-dependent signaling is crucial for maintenance of gut homeostasis.

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