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Immunoglobulin A (IgA)-mediated mucosal immunity is important for the host because it contributes to reducing infection risk and to establishing host–microbe symbiosis. BTB and CNC homology 1 (Bach1) is a transcriptional repressor with physiological and pathophysiological functions that are of particular interest for their relation to gastrointestinal diseases. However, Bach1 effects on IgA-mediated mucosal immunity remain unknown. For this study using Bach1-deficient (Bach1−/−) mice, we investigated the function of Bach1 in IgA-mediated mucosal immunity. Intestinal mucosa, feces, and plasma IgA were examined using immunosorbent assay. After cell suspensions were prepared from Peyer's patches and colonic lamina propria, they were examined using flow cytometry. The expression level of polymeric immunoglobulin receptor (pIgR), which plays an important role in the transepithelial transport of IgA, was evaluated using Western blotting, quantitative real-time PCR, and immunohistochemistry. Although no changes in the proportions of IgA-producing cells were observed, the amounts of IgA in the intestinal mucosa were increased in Bach1−/− mice. Furthermore, plasma IgA was increased in Bach1−/− mice, but fecal IgA was decreased, indicating that Bach1−/− mice have abnormal secretion of IgA into the intestinal lumen. In fact, Bach1 deficiency reduced pIgR expression in colonic mucosa at both the protein and mRNA levels. In the human intestinal epithelial cell line LS174T, suppression of Bach1 reduced pIgR mRNA stability. In contrast, the overexpression of Bach1 increased pIgR mRNA stability. These results demonstrate that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen via suppression of pIgR expression. NEW & NOTEWORTHY: The transcriptional repressor Bach1 has been implicated in diverse intestinal functions, but the effects of Bach1 on IgA-mediated mucosal immunity remain unclear. We demonstrate here that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen, although the proportions of IgA-producing cells were not altered. Furthermore, Bach1 regulates the expression of pIgR, which plays an important role in the transepithelial transport of IgA, at the posttranscriptional level. [ABSTRACT FROM AUTHOR]

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Summary: Background: Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging. Methods: Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis. Findings: Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial–mesenchymal transition, and reduced the apoptosis of BECs. Interpretation: PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA. Funding: This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022).

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. [ABSTRACT FROM AUTHOR]

Secretory antibodies are the only component of our adaptive immune system capable of attacking mucosal pathogens topologically outside of our bodies. All secretory antibody classes are (a) relatively resistant to harsh proteolytic environments and (b) polymeric. Recent elucidation of the structure of secretory IgA (SIgA) has begun to shed light on SIgA functions at the nanoscale. We can now begin to unravel the structure–function relationships of these molecules, for example, by understanding how the bent conformation of SIgA enables robust cross-linking between adjacent growing bacteria. Many mysteries remain, such as the structural basis of protease resistance and the role of noncanonical bacteria–IgA interactions. In this review, we explore the structure–function relationships of IgA from the nano- to the metascale, with a strong focus on how the seemingly banal "license to clump" can have potent effects on bacterial physiology and colonization. [ABSTRACT FROM AUTHOR]

Interestingly, we detected significantly elevated IgG2 levels in the combined bronchial asthma group, which was attributable to an IgG2 increase in exogenous and endogenous bronchial asthma but not the mixed-type bronchial asthma group (Figure 1F). A total of 112 male and female subjects (controls I n i = 30, exogenous bronchial asthma I n i = 33, endogenous bronchial asthma I n i = 24, mixed-type bronchial asthma I n i = 25) between the age of 18-82 years were included in this cross-sectional study (Table 1). Keywords: bronchial asthma; microbiome; polymeric immunoglobulin receptor; secretory immunity; upper respiratory tract EN bronchial asthma microbiome polymeric immunoglobulin receptor secretory immunity upper respiratory tract 1213 1218 6 10/13/22 20221001 NES 221001 Key messages pIgR-mediated secretory immunity in the nasopharynx is not altered in mild bronchial asthma. Importantly, as the role of allergy (i.e. reactivity to aeroallergens) for bronchial asthma-related changes in the nasal microenvironment had so far not been addressed, we comparatively assessed mucosal Ig responses and the composition of the microbiota in 3 asthmatic patient cohorts (exogenous, endogenous and mixed-type bronchial asthma). [Extracted from the article]

Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with reduced overall survival in patients (HRmethylation 1.61, 95% CI [1.11-2.33]). These findings were validated by external TCGA and GEO data. Moreover, PIGR overexpression inhibits CRC cell malignant phenotypes in vitro and impedes CRC cells growth in male BALB/c nude mice. Mechanistically, PIGR physically associates with RE1 silencing transcription factor (REST) and blocks the transcription of laminin subunit beta 3 (LAMB3). Subsequently, the AKT-FOXO3/4 axis was suppressed by downregulated LAMB3. In the drug sensitive assay, PIGR-overexpressing cells were more sensitive to cisplatin and gemcitabine. Together, PIGR may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the AKT-FOXO3/4 axis by downregulating LAMB3 in CRC. Our study may offer a novel therapeutic strategy for treating CRC patients who highly express PIGR with cisplatin and gemcitabine. [ABSTRACT FROM AUTHOR]

Background: Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging., Methods: Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis., Findings: Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial-mesenchymal transition, and reduced the apoptosis of BECs., Interpretation: PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA., Funding: This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022)., Competing Interests: Declaration of interests The authors do not have any disclosures to report., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Transport of secretory immunoglobulin A (SIgA) through the airway epithelial cell barrier into the mucosal lumen by the polymeric immunoglobulin receptor (pIgR) is an important mechanism of respiratory mucosal host defense. Identification of immunomodulating substances that regulate secretory immunity might have therapeutic implications with regard to an improved immune exclusion. Thus, we sought to analyze secretory immunity under homeostatic and immunomodulating conditions in different compartments of the murine upper and lower respiratory tract (URT&LRT). Methods: Pigr gene expression in lung, trachea, and nasal-associated lymphoid tissue (NALT) of germ-free mice, specific pathogen-free mice, mice with an undefined microbiome, as well as LPS- and IFN-γ-treated mice was determined by quantitative real-time PCR. IgA levels in bronchoalveolar lavage (BAL), nasal lavage (NAL), and serum were determined by ELISA. LPS- and IFN-γ-treated mice were colonized with Streptococcus pneumoniae and bacterial CFUs were determined in URT and LRT. Results: Respiratory Pigr expression and IgA levels were dependent on the degree of exposure to environmental microbial stimuli. While immunostimulation with LPS and IFN-γ differentially impacts respiratory Pigr expression and IgA in URT vs. LRT, only prophylactic IFN-γ treatment reduces nasal colonization with S. pneumoniae. Conclusion: Airway-associated secretory immunity can be partly modulated by exposure to microbial ligands and proinflammatory stimuli. Prophylactic IFN-γ-treatment modestly improves antibacterial immunity in the URT, but this does not appear to be mediated by SIgA or pIgR. [ABSTRACT FROM AUTHOR]

Autosomal-dominant polycystic kidney disease (ADPKD) is a common life-threatening genetic disease that leads to renal failure. No treatment is available yet to effectively slow disease progression. Renal cyst growth is, at least in part, driven by the presence of growth factors in the lumens of renal cysts, which are enclosed spaces lacking connections to the tubular system. We have shown previously shown that IL13 in cyst fluid leads to aberrant activation of STAT6 via the IL4/13 receptor. Although antagonistic antibodies against many of the growth factors implicated in ADPKD are already available, they are IgG isotype antibodies that are not expected to gain access to renal cyst lumens. Here we demonstrate that targeting antibodies to renal cyst lumens is possible with the use of dimeric IgA (dIgA) antibodies. Using human ADPKD tissues and polycystic kidney disease mouse models, we show that the polymeric immunoglobulin receptor (pIgR) is highly expressed by renal cyst-lining cells. pIgR expression is, in part, driven by aberrant STAT6 pathway activation. pIgR actively transports dIgA from the circulation across the cyst epithelium and releases it into the cyst lumen as secretory IgA. dIgA administered by intraperitoneal injection is preferentially targeted to polycystic kidneys whereas injected IgG is not. Our results suggest that pIgR-mediated transcytosis of antagonistic antibodies in dIgA format can be exploited for targeted therapy in ADPKD.

Objectives: Autism spectrum disorders (ASD) are neurodevelopmental disorders with changes in the gut and oral microbiota. Based on the intimate relationship between the oral microbiota and oral mucosal immunity, this study aimed to investigate changes in salivary immunoglobulin A (IgA) level in ASD and the underlying mechanism for any such changes.Methods: We recruited 36 children diagnosed with ASD and 35 normally developing children and measured their salivary IgA content using enzyme-linked immunosorbent assay (ELISA). The valproate (VPA) -treated ASD mouse model was established by prenatal exposure to valproate and mouse salivary IgA content was also quantified by ELISA. The submandibular glands of VPA and control mice were isolated and analyzed using qRT-PCR, immunofluorescence staining, and flow cytometry. ASD-related Streptococci were co-incubated with the human salivary gland (HSG) cell line, and western blotting was used to detect the levels of relevant proteins.Results: We found that salivary IgA content was significantly decreased in patients with ASD and had a significant ASD diagnostic value. The salivary IgA content also decreased in VPA mice and was significantly correlated with autistic-like behaviors among them. The mRNA and protein levels of the polymeric immunoglobulin receptor (Pigr) were downregulated in the submandibular glands of VPA mice and the Pigr mRNA level was positively correlated with mouse salivary IgA content. HSG cells treated with ASD-related Streptococci had reduced PIGR protein level.Conclusion: Therefore, protective IgA levels were reduced in the saliva of individuals with ASD, which correlated with the bacteria-induced downregulation of Pigr in salivary glands. This study suggests a new direction for ASD diagnosis and prevention of oral diseases in ASD cohorts and provides evidence for the ASD mucosal immunophenotype in the oral cavity.

Objectives: Autism spectrum disorders (ASD) are neurodevelopmental disorders with changes in the gut and oral microbiota. Based on the intimate relationship between the oral microbiota and oral mucosal immunity, this study aimed to investigate changes in salivary immunoglobulin A (IgA) level in ASD and the underlying mechanism for any such changes. Methods: We recruited 36 children diagnosed with ASD and 35 normally developing children and measured their salivary IgA content using enzyme-linked immunosorbent assay (ELISA). The valproate (VPA) -treated ASD mouse model was established by prenatal exposure to valproate and mouse salivary IgA content was also quantified by ELISA. The submandibular glands of VPA and control mice were isolated and analyzed using qRT-PCR, immunofluorescence staining, and flow cytometry. ASD-related Streptococci were co-incubated with the human salivary gland (HSG) cell line, and western blotting was used to detect the levels of relevant proteins. Results: We found that salivary IgA content was significantly decreased in patients with ASD and had a significant ASD diagnostic value. The salivary IgA content also decreased in VPA mice and was significantly correlated with autistic-like behaviors among them. The mRNA and protein levels of the polymeric immunoglobulin receptor (Pigr) were downregulated in the submandibular glands of VPA mice and the Pigr mRNA level was positively correlated with mouse salivary IgA content. HSG cells treated with ASD-related Streptococci had reduced PIGR protein level. Conclusion: Therefore, protective IgA levels were reduced in the saliva of individuals with ASD, which correlated with the bacteria-induced downregulation of Pigr in salivary glands. This study suggests a new direction for ASD diagnosis and prevention of oral diseases in ASD cohorts and provides evidence for the ASD mucosal immunophenotype in the oral cavity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Largemouth bass pIgR could combine with IgM. • Largemouth bass pIgR could bind to Aeromonas hydrophila and Micrococcus luteus. • Largemouth bass pIgR had binding capability to LPS, PGN and various saccharides. • Saccharide binding was an important interaction mechanism between largemouth bass pIgR and bacteria. The polymeric immunoglobulin receptor (pIgR) is an important molecule in the mucosal immunity of teleosts. Previous studies have shown that pIgR can bind and transport polymeric immunoglobulins (pIgs), but few studies have focused on the binding of teleost pIgR to bacteria. In this study, we identified a gene encoding pIgR in largemouth bass (Micropterus salmoides). The pIgR gene contained two Ig-like domains (ILDs), which were homologous to ILD1 and ILD5 of mammalian pIgR. Our results showed that largemouth bass pIgR-ILD could combine with IgM. Moreover, we also found that largemouth bass pIgR-ILD could bind to Aeromonas hydrophila and Micrococcus luteus. Further analysis showed that largemouth bass pIgR-ILD could also combine with lipopolysaccharide (LPS), peptidoglycan (PGN) and various saccharides, and reduced binding to bacteria was observed with LPS and PGN treatment, indicating that largemouth bass pIgR could bind to bacteria to prevent infection and that saccharide binding is an important interaction mechanism between pIgR and bacteria. These results collectively demonstrated that largemouth bass pIgR not only combines with IgM but also binds to bacteria by various saccharides. [ABSTRACT FROM AUTHOR]

Mucosal immunity is dominated by secretory IgA and IgM, although these are less favorable compared to IgG molecules for therapeutic development. Polymeric IgA and IgM are actively transported across the epithelial barrier via engagement of the polymeric Ig receptor (pIgR), but IgG molecules lack a lumen-targeted active transport mechanism, resulting in poor biodistribution of IgG therapeutics in mucosal tissues. In this work, we describe the discovery and characterization of single-domain antibodies (VHH) that engage pIgR and undergo transepithelial transport across the mucosal epithelium. The anti-pIgR VHH panel displayed a broad range of biophysical characteristics, epitope diversity, IgA competition profiles and transcytosis activity in cell and human primary lung tissue models. Making use of this diverse VHH panel, we studied the relationship between biophysical and functional properties of anti-pIgR binders targeting different domains and epitopes of pIgR. These VHH molecules will serve as excellent tools for studying pIgR-mediated transport of biologics and for delivering multispecific IgG antibodies into mucosal lumen, where they can target and neutralize mucosal antigens.

Abstract Objective To conduct a proof-of-concept study on preferential binding of polymeric IgA (pIgA) using a novel recombinant rabbit/human chimeric secretory component (cSC) and preliminary assessment of the diagnostic potential of virus-specific pIgA in discriminating acute hepatitis A, E, and C (HAV, HEV, HCV) patients and uninfected controls using an indirect enzyme-linked immunoassay. Results cSC binds > 0.06 μg/ml of purified human and mouse pIgA with negligible cross-reactivity against IgM and IgA. Virus-specific pIgA was significantly higher in serum of acute HAV (n = 6) and HEV (n = 12) patients than uninfected samples (HEV: p

Abstract The Polymeric Immunoglobulin Receptor (pIgR) gene has been proved to play an important role in transporting polymeric immunoglobulin (Ig) in the mucosal tissues of mammals. pIgR gene also exists in teleost, but the genetic diversity and functions of this gene still need to be further explored. We obtained seven grass carp pIgR splicing transcripts, a full-length pIgR (CipIgR-1) and six truncated variants (CipIgR-2 to CipIgR-7). The full-length pIgR contained two immunoglobulin-like domains (ILD), a transmembrane domain (TMD) and a cytoplasmic domain (CyD). The CipIgR-2 lacked a small part in CyD, and CipIgR-3 lost TMD and CyD. Partial cDNA sequences of the other four grass carp pIgR variants (CipIgR-4 to CipIgR-7) were also cloned. The total expression levels of CipIgR and its variants in different tissues were detected by real-time quantitative PCR. The highest expression was found in the intestine, followed by the spleen and the skin. The function of the two extracellular ILDs of CipIgR was investigated based on its combining capacity with grass carp immunoglobulin M (IgM) and aquatic pathogenic bacteria. The cDNA sequences of two ILDs were cloned and expressed in Escherichia coli BL21 (DE3). Recombinant ILDs protein was purified and incubated with different bacteria respectively. Results of Western blot showed the recombinant protein could combine Bacillus subtilis , Vibrio parahaemolyticus , and Escherichia coli. In addition, binding activity of rILDs with grass carp IgM was detected. Collectively, these results indicated that multiple variants of pIgR gene in grass carp might be involved in the antibacterial immunity. Highlights • Seven alternative splicing transcripts of Grass carp pIgR gene were cloned. • Recombinant immunoglobulin-like domains of grass carp pIgR can bind with serum IgM. • Recombinant immunoglobulin-like domains could combine B. subtilis , V. parahaemolyticus , and E. coli. [ABSTRACT FROM AUTHOR]

Aim: To investigate the expression of polymeric immunoglobulin receptor (pIgR) in endometrial adenocarcinoma and the relationship between pIgR and the clinicopathological features of endometrial adenocarcinoma. To investigate the role of pIgR in the biological behavior of endometrial adenocarcinoma cell lines.Methods: First, the paraffin-embedded endometrial adenocarcinoma samples and clinicopathological data from the Chao-Yang Hospital were collected. Next, immunohistochemistry was conducted to test the expression of pIgR in endometrial adenocarcinoma; the correlations between pIgR and clinicopathological features were detected. Then, the expression of pIgR in the Ishikawa cells was interfered with short-interfering RNA (siRNA). Finally, the migration and proliferation abilities of Ishikawa cells were detected by transwell and CCK8 assays before and after interference.Results: pIgR had a high expression level and higher H-score in endometrial adenocarcinoma (P = 0.013) than in noncancerous tissues. There was no correlation between pIgR and the histopathological features of endometrial adenocarcinoma (P ≥ 0.418). The migration ability of Ishikawa cells was increased after interference with pIgR (P = 0.023). The proliferation of Ishikawa cells was not different between the untreated and siRNA215-treated groups (P = 0.967).Conclusion: PIgR may be a predictive biomarker of endometrial adenocarcinoma and a potential target protein for immunotherapy of endometrial adenocarcinoma. [ABSTRACT FROM AUTHOR]

Salivary immunoglobulin A (IgA) plays a vital role in preventing upper respiratory tract infections (URTI). In our previous study, we showed that the intake of carbohydrates increases the intestinal levels of short-chain fatty acids (SCFAs), which in turn increase salivary IgA levels. However, the mechanism underlying this phenomenon has not been fully elucidated. In this study, we investigated in rats the effect of polydextrose (PDX) ingestion on salivary IgA level and SCFA concentration in cecal digesta and the portal vein. Five-week-old rats were fed with a fiber-free diet (control) or with 40 g/kg of PDX for 28 days. Compared to the control, ingestion of PDX led to a higher salivary IgA flow rate (p = 0.0013) and a higher concentration of SCFAs in the portal vein (p = 0.004). These two data were positively correlated (rs = 0.88, p = 0.0002, n = 12). In contrast, the concentration of SCFAs in cecal digesta and cecal digesta viscosity were significantly lower following PDX ingestion, compared to the control (p = 0.008 and 0.05, respectively). These findings suggest that the ingestion of PDX increases the absorption rate of SCFAs in the intestine through PDX-induced fermentation, which is accompanied by an increase in SCFA levels in the blood, and ultimately leads to increased salivary IgA levels.

Porcine deltacoronavirus (PDCoV) is a porcine enteropathogenic coronavirus that causes watery diarrhea, vomiting, and frequently death in piglets, causing serious economic losses to the pig industry. The strain CHN-JS-2017 was isolated and identified by cytopathology, immunofluorescence assays, transmission electron microscopy, and sequence analysis. A nucleotide sequence alignment showed that the whole genome of CHN-JS-2017 is 97.4%−99.6% identical to other PDCoV strains. The pathogenicity of the CHN-JS-2017 strain was investigated in orally inoculated five-day-old piglets; the piglets developed acute, watery diarrhea, but all recovered and survived. CHN-JS-2017 infection-induced microscopic lesions were observed, and viral antigens were detected mainly by immunohistochemical staining in the small intestine. The neonatal Fc receptor (FcRn) and polymeric immunoglobulin receptor (pIgR) are crucial immunoglobulin (Ig) receptors for the transcytosis ofimmunoglobulin G (IgG), IgA, or IgM. Importantly, CHN-JS-2017 infected five-day-old piglets could significantly down-regulate the expression of FcRn, pIgR, and nuclear factor-kappa B (NF-κB)in the intestinal mucosa. Note that the level of FcRn mRNA in the intestinal mucosa of normal piglets is positively correlated with pIgR and NF-κB. At the same time, the expressions of FcRn, pIgR, and NF-κB mRNA are also positively correlated in infected piglets. These results may help explain the immunological and pathological changes associated with porcine deltacorononirus infection.

Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously, we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week after immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in lamina propria (LP) submucosa and epithelial cells of the hindgut at 30 min, increased proceeding toward the distal portion of intestinal folds, reached a peak at 2–3 h, and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into LP submucosa and excreted across intestinal epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in LP submucosa but not in intestinal epithelium due to the lack of OVA-specific antibody. Accordingly, in intestinal epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM, and pIgR was illuminated by multiple-label immunofluorescence confocal microscopy and analyzed using Image J software. Furthermore, in gut mucus but not in serum, an ~800-kDa protein band showed IgM-positive, OVA-positive, and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC–polymeric IgM–OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM–OVA complexes from LP across intestinal epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM–antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish.

Chronic inflammation of the liver is a risk factor that promotes the progression of hepatocellular carcinoma, and in the presence of viral infection, enhanced Fc receptor signal will further aggravate inflammatory response and participate in the process of canceration. Polymeric immunoglobulin receptor (pIgR) not only plays a critical role in first-line anti-infection immunity, but also promotes the metastasis and growth of early-stage hepatocellular carcinoma. Identifying pIgR as a predictive index for metastatic potential in patients with early-stage liver cancer can help to promote the stratification and treatment decisions for such patients, which has a positive significance in improving patient prognosis. Targeted inhibition of the pIgR/Yes signal cascade as a potential treatment option may provide more treatment options for controlling tumor size to allow resection or transplantation. [ABSTRACT FROM AUTHOR]

Objective This study aimed to evaluate functions of APOBEC3F gene in biological process of hepatocellular carcinoma (HCC) and anti-tumor mechanisms of bufalin. Methods Effect of APOBEC3F and bufalin on cell proliferation and migration abilities were evaluated by CCK-8, wounding healing tests and transwell assays in SK-Hep1 and Bel-7404 cells. Bioinformatic analysis were also used to compare APOBEC3F expression levels, detect coexpressed genes and enrichment of pathways. Results APOBEC3F was overexpressed in tumor tissues compared to adjacent tissues in HCC patients. And, APOBEC3F promotes cell proliferation and migration in SK-Hep1 and Bel-7404 cells. Bufalin inhibits cell proliferation and migration and reduces APOBEC3F expression. GO and KEGG enrichment of APOBEC3F-coexpressed genes revealed that APOBEC3F might active intestinal immune network for IgA production signaling pathway, leading to malignant biological behaviors of HCC cells. Additionally, siAPOBEC3F could decrease pIgR, CCR9, CCR10 and CXCR4 protein levels. And, bufalin inhibits the pIgR, CCR9, CCR10 and CXCR4 protein expressions. Conclusions Bufalin inhibits cell proliferation and migration of HCC cells via APOBEC3F induced intestinal immune network for IgA production signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Human milk immunoglobulins (Ig) are an important support for the naïve infant immune system; yet the extent to which these proteins survive within the infant digestive tract, particularly for preterm infants, is poorly studied. Objectives: Our objective was to evaluate the survival of human milk Igs in the preterm stomach across postprandial time. Methods: Human milk and infant gastric samples were collected from 11 preterm (23–32 weeks gestational age) mother-infant pairs within 7–98 days postnatal age. Preterm gastric samples were collected 1, 2, and 3 h after the beginning of the feeding. Samples were analyzed for concentration of total IgA (secretory IgA [SIgA]/IgA), total secretory component (SC/SIgA/SIgM), total IgM (SIgM/IgM), and IgG via enzyme-linked immunosorbent assay. Ig-chain fragment peptides were determined using peptidomic analysis. One-way analysis of variance with repeated measures followed by Tukey's multiple comparison tests was applied. Results: Concentrations of total IgA were lower in the gastric contents at 3 h postprandial compared with human milk and gastric contents at 1 and 2 h. Human milk SC/SIgA/SIgM, IgG, and total IgM concentrations remained stable in the preterm stomach across postprandial time. Peptide counts from the Ig alpha-chain and the Ig gamma-chain increased in gastric contents from 1 to 2 h postprandial. Peptide counts from the human milk Ig-chain, Ig-chain, and SC were stable across postprandial time. These peptides from Ig-chains were not present in human milk but were released in the stomach due to their partial degradation. Conclusions: Human milk total SC (SIgA/SC/SIgM), total IgM, and IgG survived mostly intact through the preterm infant stomach, while total IgA was -partially digested. [ABSTRACT FROM AUTHOR]

Polymeric immunoglobulin receptor (pIgR) functions in transporting polymeric immunoglobulin across epithelial cells into external secretion in animals. During animal evolution, fish was situated at a transition point on the phylogenetic spectrum between species possessing only innate immunity (i.e., invertebrates) and species depending heavily on adaptive immunity (i.e., mammals). Previous studies reported that fish and mammals significantly differ in pIgR. This review summarized the differences in pIgR structure, function, and transcriptional regulation between fish and mammals. A model of the transcriptional regulation of the pIgR gene was suggested. In this model, microbes could activate Toll-like receptor, trigger the cascade reactions in the signaling pathway, and then activate transcription factors that regulate pIgR expression through combining with the pIgR promoter. This review provides some suggestions for further studies on the function and regulatory mechanism of pIgR in fish and other animals. [ABSTRACT FROM AUTHOR]

Rationale: Asthma is associated with increased lung IgE production, but whether the secretory IgA system is affected in this disease remains unknown.Objectives: We explored mucosal IgA transport in human asthma and its potential regulation by T-helper cell type 2 inflammation.Methods: Bronchial biopsies from asthma and control subjects were assayed for bronchial epithelial polymeric immunoglobulin receptor (pIgR) expression and correlated to T-helper cell type 2 biomarkers. Bronchial epithelium reconstituted in vitro from these subjects, on culture in air-liquid interface, was assayed for pIgR expression and regulation by IL-4/IL-13.Measurements and Main Results: Downregulation of pIgR protein was observed in the bronchial epithelium from patients with asthma (P = 0.0002 vs. control subjects). This epithelial defect was not observed ex vivo in the cultured epithelium from patients with asthma. Exogenous IL-13 and IL-4 could inhibit pIgR expression and IgA transcytosis. Mechanistic experiments showed that autocrine transforming growth factor-β mediates the IL-4/IL-13 effect on the pIgR, with a partial contribution of upregulated transforming growth factor-α/epidermal growth factor receptor.Conclusions: This study shows impaired bronchial epithelial pIgR expression in asthma, presumably affecting secretory IgA-mediated frontline defense as a result of type 2 immune activation of the transforming growth factor pathway. [ABSTRACT FROM AUTHOR]

The polymeric immunoglobulin receptor (pIgR) plays a pivotal role in mucosal immune response by transporting polymeric immunoglobulins onto the surface of mucosal epithelia to protect animals from invading pathogens. In this study, the full-length cDNA of pIgR was firstly cloned in Qihe crucian carp ( Carassius auratus ), hereafter designated as CapIgR , by using reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The molecular characterization and expression of CapIgR were investigated. The full-length cDNA sequence of CapIgR was composed of 1409 bp, which included a 112 bp 5ʹ-untranslated region (UTR), a 984 bp ORF, and a 313 bp 3ʹ-UTR, with a putative polyadenylation signal sequence AATAAA located upstream of the poly(A) tail. The deduced amino acid sequence indicated that CapIgR was a single-spanning transmembrane protein with 327 amino acids and possessed a signal peptide, an extracellular region containing two immunoglobulin-like domains, a transmembrane region, and an intracellular region. The mRNA expression levels of CapIgR were detected in different tissues of healthy C. auratus by quantitative real-time PCR, and the highest expression level was found in the liver. After Aeromonas hydrophila challenge, CapIgR expression was upregulated in different tissues at certain time points, and temporal expression changes of CapIgR fluctuated in a time-dependent manner. CapIgR exhibited rapid immune response to A. hydrophila challenge and played an important role in the immune defense of fish. These findings provided insights into the structure, function, and immune defense mechanism of CapIgR in C. auratus . This study can serve as a basis for developing disease control strategies in aquaculture. [ABSTRACT FROM AUTHOR]

Background: The mechanism underlying transient increases in immunoglobulin (Ig) A concentrations in the cecal contents of rats fed fructo-oligosaccharide (FOS) is unclear.Objective: This study was designed to test whether increased IgA concentrations represent one aspect of the inflammatory response to increased permeability induced by FOS in the cecum.Methods: Seven-week-old male Wistar rats were fed a fiber-free semipurified diet (FFP) with or without supplemental FOS (60 g/kg diet) for 9 or 58 d [experiment (expt.) 1], 7 d (expt. 2), or 7 or 56 d (expt. 3). In addition to measuring IgA concentrations in cecal content, we assessed gut permeability, inflammatory responses (expt. 1), the number of IgA plasma cells in the cecal lamina propria, polymeric Ig receptor (pIgR) expression in the cecal mucosa (expt. 2), and the condition of the cecal mucus layer (expt. 3).Results: The cecal IgA concentration in the FOS-fed rats was 15-fold higher than that of the rats fed FFP for 9 d (P < 0.05). Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation to mesenteric lymph nodes, myeloperoxidase activity, and expression of inflammatory cytokine genes in the cecal mucosa was greater in the FOS-fed rats than in the rats fed FFP for 9 d. These effects were not observed in the rats fed FOS for 58 d (expt. 1). Accompanying the higher cecal IgA concentration, pIgR protein and the number of IgA plasma cells in the cecal mucosa were higher in the FOS-fed rats than in the rats fed FFP for 7 d (expt. 2). Destruction of the mucus layer on the epithelial surface, as evidenced by Alcian blue staining in the cecal sections, was evident in the rats fed FOS for 7 d, but the mucus layer appeared normal in the rats fed FOS for 56 d (expt. 3).Conclusions: These findings suggest that transient increases in cecal IgA concentrations induced by FOS in rats are associated with mucosal inflammation in response to increased gut permeability; these are presumably evoked by disruption of the cecal mucus barrier. The observed responses could contribute to the maturation of the gut immune system. [ABSTRACT FROM AUTHOR]

Fish vitellogenin (Vg) has been shown to mediate the phagocytosis via interaction with a Fcγ-like phagocytic receptor on macrophages, but identification of such a receptor and its functional characterization remains lacking. In this study, we isolated a cDNA of polymeric immunoglobulin receptor (pIgR) from sea bass, which encoded a single-spanning transmembrane protein of 326 amino acids including a 21-amino acid signal peptide, an extracellular region, a transmembrane region and a 36-amino acid intracellular region included two Ig-like domains (ILDs), and was expressed in multiple lymphoid organs. We then showed that recombinant extracellular domain of sea bass pIgR was capable of binding to Vg as well as IgG and IgM. We also showed that Vg as well as IgG and IgM interacted with pIgR-expressing HEK 293T cells. Importantly, we demonstrated that Vg as well as IgG and IgM were all capable of enhancing phagocytosis by HEK 293T cells and inducing expression of tnf-α and il-1β , via interacting with pIgR. Collectively, these results suggest that fish Vg, analogous to IgG and IgM, can interact with pIgR and result in similar down-stream immune responses, providing an additional evidence that Vg plays an antibody-like role. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract houses millions of microbes, and thus has evolved several host defense mechanisms to keep them at bay, and prevent their entry into the host. One such mucosal surface defense is the secretion of secretory immunoglobulins (SIg). Secretion of SIg depends on the polymeric immunoglobulin receptor (pIgR), which transports polymeric Ig (IgA or IgM) from the basolateral surface of the epithelium to the apical side. Upon reaching the luminal side, a portion of pIgR, called secretory component (SC) is cleaved off to release Ig, forming SIg. Through antigen-specific and non-specific binding, SIg can modulate microbial communities and pathogenic microbes via several mechanisms: agglutination and exclusion from the epithelial surface, neutralization, or via host immunity and complement activation. Given the crucial role of SIg as a microbial scavenger, some pathogens also evolved ways to modulate and utilize pIgR and SIg to facilitate infection. This review will cover the regulation of the pIgR/SIg cycle, mechanisms of SIg-mediated mucosal protection as well as pathogen utilization of SIg.

Polymeric immunoglobulin receptor ( pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. The expression of pIgR was reported to be up-regulated and related to the prognosis of several human cancers. However, the clinical significance of pIgR in nasopharyngeal carcinoma (NPC) remains unclear. The purpose of this study was to detect the pIgR expression and its prognostic value in NPC. The expression of serum pIgR was measured in NPC patients and healthy controls by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting analyses. The relationship between its expression and clinical factors was analyzed by chi-square test. Then, the overall survival of patients was assessed by Kaplan-Meier analysis while the prognostic value of serum pIgR was estimated using univariate and multivariate analyses with cox regression analysis. Serum pIgR was down-regulated in NPC patients compared to that in healthy controls both at messenger RNA (mRNA) and protein levels. Especially, its expression was also significantly lower in patients at advantage stages (III-IV) than those at early stages (I-II). And, the low pIgR expression was strongly associated with advanced clinical stages, T stage, N stage, and distant metastasis. Kaplan-Meier analysis demonstrated that patients with low pIgR expression had a significantly shorter overall survival than those with high expression at any stages. Cox regression analysis suggested that pIgR was closely related to the prognosis of NPC. Serum pIgR expression was reduced in NPC, and it could be an independent prognostic predictor for patients with this cancer. [ABSTRACT FROM AUTHOR]