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The aim of this study was to determine a genetic basis for IgA concentration in milk of Bos taurus. We used a Holstein-Friesian x Jersey F2 crossbred pedigree to undertake a genome-wide search for QTL influencing IgA concentration and yield in colostrum and milk. We identified a single genome-wide significant QTL on chromosome 16, maximising at 4.8 Mbp. The polymeric immunoglobulin receptor gene (PIGR) was within the confidence interval of the QTL. In addition, mRNA expression analysis revealed a liver PIGR expression QTL mapping to the same locus as the IgA quantitative trait locus. Sequencing and subsequent genotyping of the PIGR gene revealed three divergent haplotypes that explained the variance of both the IgA QTL and the PIGR expression QTL. Genetic selection based on these markers will facilitate the production of bovine herds producing milk with higher concentrations of IgA.

Background The polymeric immunoglobulin receptor (pIgR) is a transmembrane transporter of polymeric IgA through the intestinal epithelium. Its overexpression has been reported in several cancers, but its role as a diagnostic and prognostic biomarker of oncogenesis is currently unclear. Method A literature search was conducted to summarize the functions of pIgR, its expression levels, and its clinical implications. Results pIgR expression has previously been investigated by proteomic analysis, RNA sequencing, and tissue microarray at the level of both RNA and protein in various cancers including pancreatic, esophageal, gastric, lung, and liver. However, studies have reported inconsistent results on how pIgR levels affect clinical outcomes such as survival rate and chemotherapy resistance. Possible explanations include pIgR mRNA levels being minimally correlated with the rate of downstream pIgR protein synthesis, and the diversity of antibodies used in immunohistochemistry studies further magnifying this ambiguity. In ovarian cancer cells, the transcytosis of IgA accompanied a series of transcriptional changes in intracellular inflammatory pathways that inhibit the progression of cancer, including the upregulation of IFN-gamma and downregulation of tumor-promoting ephrins. These findings suggest that both the levels of pIgR and secreted IgA from tumor-infiltrating B cells affect clinical outcomes. Conclusion Overall, no direct correlation was observed between the levels of pIgR inside tumor tissue and the clinical features in cancer patients. Measuring pIgR protein levels with a more specific and possibly chemically defined antibody, along with tumoral IgA, is a potential solution to better understand the pathways and consequences of pIgR overexpression in cancer cells.

Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein widely expressed in mucosal epithelial cells that is involved in the transcytosis of the polymeric immunoglobulins IgA and IgM. Recent findings revealed increased plasma PIGR levels in subjects with subclinical atherosclerosis, although its function remains uncertain. To assess the role of PIGR in atherosclerosis. We analyzed PIGR levels in human atherosclerotic plaques compared to healthy aortic samples, as well as in the serum of subjects with peripheral arterial disease (PAD) and controls. Next, we studied the effect of germline deficiency in experimental atherosclerosis ( mice fed a western-diet for 10 weeks). Circulating IgA and IgM levels, as well as B and T cell numbers in spleen and Peyer's patches (PP), were analyzed by ELISA and flow cytometry, respectively. PIGR levels were increased in the intima of early human atherosclerotic lesions and in patients with PAD, compared to controls. mice showed elevated serum IgA and IgM levels, along with an increased number of germinal center B cells in both the spleen and PP. Moreover, mice displayed a significantly reduced plaque size in the aortic sinus and a strong decrease in foam cells (CD68 ), while no changes were observed in contractile smooth muscle cells (α-actin ) and collagen content compared to control mice. Global deficiency decreases atherosclerosis, suggesting that PIGR blockade may have beneficial effects in vascular pathologies.

Maintenance of intestinal homeostasis requires a healthy relationship between the commensal gut microbiota and the host immune system. Breast milk supplies the first source of antigen-specific immune protection in the gastrointestinal tract of suckling mammals, in the form of secretory IgA (SIgA). SIgA is transported across glandular and mucosal epithelial cells into external secretions by the polymeric Ig receptor (pIgR). Here, a breeding scheme with polymeric Ig receptor-sufficient and -deficient mice was used to study the effects of breast milk-derived SIgA on development of the gut microbiota and host intestinal immunity. Early exposure to maternal SIgA prevented the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes, including the opportunistic pathogen Ochrobactrum anthropi. By the age of weaning, mice that received maternal SIgA in breast milk had a significantly different gut microbiota from mice that did not receive SIgA, and these differences were magnified when the mice reached adulthood. Early exposure to SIgA in breast milk resulted in a pattern of intestinal epithelial cell gene expression in adult mice that differed from that of mice that were not exposed to passive SIgA, including genes associated with intestinal inflammatory diseases in humans. Maternal SIgA was also found to ameliorate colonic damage caused by the epithelial-disrupting agent dextran sulfate sodium. These findings reveal unique mechanisms through which SIgA in breast milk may promote lifelong intestinal homeostasis, and provide additional evidence for the benefits of breastfeeding.

This research was intended to investigate the kinetics of polymeric immunoglobulin receptor (pIgR) and its ligand immunoglobulins (Ig) in snakehead ( Channa argus ) through different vaccine delivery methods. First, we employed Oxford Nanopore Technologies (ONT) sequencing technology to acquire the snakehead fish’s complete transcriptome, and the full coding sequence (CDS) of pIgR was identified and isolated through transcriptome sequencing named Ch pIgR. The CDS sequence spanned 1251 base pairs, translating into a protein that consists of 416 amino acids and has a molecular weight of around 45.80 kDa. The Ch pIgR had a pair of immunoglobulin-like domains in addition to a transmembrane region and an intracellular region. Furthermore, a polyclonal antibody targeting the snakehead recombinant Ch pIgR was constructed. Ch pIgR and IgM responses were analyzed after immunization with Aeromonas hydrophila . Although Ch pIgR and IgM displayed a comparable transcription level, Ch pIgR exhibited a more rapid increase and reached its peak earlier than IgM . Both vaccinated groups experienced an elevation in ChpIgR mRNA levels in the gill and spleen. On the other hand, the bath immersion group manifested that the skin, gills, and intestines had an elevated IgM mRNA expression, whereas the intraperitoneal vaccination group reported that the spleen and head kidney possessed a greater expression. The ELISA results indicated that the IgM and Ch pIgR levels reached their highest peak more rapidly in the skin and gill mucus in the bathing group, whereas they reached a greater peak in intestinal mucus in the injection group. The outcomes indicated that both bath and intraperitoneal vaccinations increased Ch pIgR and secretory Ig levels in mucus and bile, shedding light on the function of pIgR in immune response and laying the foundation for future studies on pIgR-linked immune defenses in teleosts.

Background Immune homeostasis of the tracheobronchial epithelium is essential to the defense against pathogens for the lung. EpCAM is localized in the tracheobronchial epithelium, but the function and mechanisms of it on regulating the immunity in the respiratory tract remain unclear. Methods The lung tissues from the EpCAM-deficient and wild type (WT) mice at E18.5, P0 and P3 stages were analyzed. The H&E staining was performed to check the morphological and histological changes of the mutant lungs. The qRT-PCR, western blot and immunofluorescence technologies were used to compare the expression and activities of genes related to inflammatory factors, immune cells and inflammation-associated signal pathways in the lungs from WT and EpCAM −/− embryos and pups. Results The morphological changes and injuries of the lungs from the P3 EpCAM-deficient pups were detected. Several genes related to inflammatory factors and immune cells were upregulated in the mutant lungs. Furthermore, the lung abundant matrix metalloproteinases, such as MMP3 and MM8, were increased and the MAPK signal pathways were hyperactivated in the lungs from EpCAM −/− mice. The pIgR and IgA were significantly downregulated in the lungs from EpCAM-deficient mice. Additionally, signaling pathways regulating pIgR transcription were substantially suppressed in the lung tissues from the EpCAM −/− mice. Conclusions These results demonstrated the association between the EpCAM deficiency, the hyperactivation of immune signal pathways and the downregulation of pIgR in the lungs of mice, and the regulation of the pIgR expression might be the important mechanism of EpCAM on maintaining the immune homeostasis of the tracheobronchial epithelium.

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR −/− ) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR −/− mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR −/− mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema. The mechanisms driving lung inflammation and remodelling in chronic obstructive pulmonary disease (COPD) are incompletely understood. Here the authors show that lack of secretory IgA promotes bacterial invasion in small airways, resulting in leukocyte recruitment and a COPD-like phenotype.

There is significant interest in the use of primary intestinal epithelial cells in monolayer culture to model intestinal biology. However, it has proven to be challenging to create functional, differentiated monolayers using current culture methods, likely due to the difficulty in expanding these cells. Here, we adapted our recently developed method for the culture of intestinal epithelial spheroids to establish primary epithelial cell monolayers from the colon of multiple genetic mouse strains. These monolayers contained differentiated epithelial cells that displayed robust transepithelial electrical resistance. We then functionally tested them by examining immunoglobulin A (IgA) transcytosis across Transwells. IgA transcytosis required induction of polymeric Ig receptor (pIgR) expression, which could be stimulated by a combination of lipopolysaccharide and inhibition of γ-secretase. In agreement with previous studies using immortalized cell lines, we found that tumor necrosis factor-α, interleukin (IL)-1β, IL-17, and heat-killed microbes also stimulated pIgR expression and IgA transcytosis. We used wild-type and knockout cells to establish that among these cytokines, IL-17 was the most potent inducer of pIgR expression/IgA transcytosis. Interferon-γ, however, did not induce pIgR expression, and instead led to cell death. This new method will allow the use of primary cells for studies of intestinal physiology.

The polymeric immunoglobulin receptor (pIgR) mediates trans cytosis of IgA, a pivotal anti-inflammatory player of the mucosal immune system. Transcytosis mediated by pIgR entails protein effectors of vesicle-mediated transport involved in signal pathway activation that lead to the sorting of pIgR-IgA complexes from the basolateral to apical membrane. Each step of pIgR transport encompasses multiple targets for regulation, but the role of cholinergic system components, acetylcholine (ACh), the ligand of nicotinic (nAChR) and muscarinic (mAChR) receptors, is unclear. This study evaluated the effect of the cholinergic system on pIgR at transcriptional and protein levels. Accordingly, lipopolysaccharide (LPS)-primed Caco-2 cells were treated with nicotine (nAChR agonist) and/or mecamylamine (nAChR antagonist) or with muscarine (mAChR agonist) and/ or atropine (mAChR antagonist), and then pIgR was analysed by immunofluorescence and by RT-qPCR. In general terms, cholinergic antagonists counteracted the upmodu latory outcome of both cholinergic agonists on both pIgR cellular location and mRNA levels. These findings suggest that the cholinergic system plays a key role in the regulation of epithelial immunity by modulating pIgR expression. The study provides insights into the interaction between the cholinergic system and intestinal immune mechanisms for future research in mucosal immunity and possible therapeutic strategies.

Abstract Loss of secretory IgA (SIgA) is common in chronic obstructive pulmonary disease (COPD) small airways and likely contributes to disease progression. We hypothesized that loss of SIgA results from reduced expression of pIgR (polymeric immunoglobulin receptor), a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice used immunostaining, primary murine tracheal epithelial cell culture, and transgenic mice with secretory or ciliated cell–specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from nontypeable Haemophilus influenzae was evaluated in vitro. We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and nontypeable H. influenzae–secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Loss of the SIgA immunobarrier in small airways of patients with severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.