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Keith E. Mostov - One of the best experts on this subject based on the ideXlab platform.

  • Chapter 12 – Immunoglobulin Transport and the Polymeric Immunoglobulin Receptor
    Mucosal Immunology, 2005
    Co-Authors: Charlotte S. Kaetzel, Keith E. Mostov
    Abstract:

    The polymeric Immunoglobulin Receptor plays a unique role in the mucosal immune system, acting both as an epithelial transporter and as an integral component of secretory Immunoglobulins. Major advances in the past several years with use of the approaches of immunology, protein chemistry, cell biology, and molecular biology have increased the understanding of the structure, function, and regulation of polymeric Immunoglobulin Receptor (pIgR). Production of mice genetically deficient in pIgR expression has allowed a more defined characterization of its biological functions. Molecular characterization of the gene encoding pIgR in humans and several animal species has provided important insights into the mechanisms by which its transcription is regulated by the immune and endocrine systems. Further characterization of molecular mechanisms of pIgR regulation, at the level of both synthesis and transcytosis, would increase the understanding of the integration of this important molecule with other effectors of the mucosal immune system.

  • The mammalian retromer regulates transcytosis of the polymeric Immunoglobulin Receptor
    Nature cell biology, 2004
    Co-Authors: Marcel Verges, Frédéric Luton, Carmen Gruber, Frank Tiemann, Lorri G. Reinders, Lan Huang, Alma L. Burlingame, Carol Renfrew Haft, Keith E. Mostov
    Abstract:

    Epithelial cells have separate apical and basolateral plasma membrane domains with distinct compositions. After delivery to one surface, proteins can be endocytosed and then recycled, degraded or transcytosed to the opposite surface. Proper sorting into the transcytotic pathway is essential for maintaining polarity, as most proteins are endocytosed many times during their lifespan. The polymeric Immunoglobulin Receptor (pIgR) transcytoses polymeric IgA (pIgA) from the basolateral to the apical surface of epithelial cells and hepatocytes. However, the molecular machinery that controls polarized sorting of pIgR-pIgA and other Receptors is only partially understood. The retromer is a multimeric protein complex, originally described in yeast, which mediates intracellular sorting of Vps10p, a Receptor that transports vacuolar enzymes. The yeast retromer contains two sub-complexes. One includes the Vps5p and Vps17p subunits, which provide mechanical force for vesicle budding. The other is the Vps35p-Vps29p-Vps26p subcomplex, which provides cargo specificity. The mammalian retromer binds to the mannose 6-phosphate Receptor, which sorts lysosomal enzymes from the trans-Golgi network to the lysosomal pathway. Here, we show a function for the mammalian Vps35-Vps29-Vps26 retromer subcomplex in promoting pIgR-pIgA transcytosis.

  • Direct Interaction between Rab3b and the Polymeric Immunoglobulin Receptor Controls Ligand-Stimulated Transcytosis in Epithelial Cells
    Developmental cell, 2002
    Co-Authors: Sven C.d. Van Ijzendoorn, Michael J. Tuvim, Thomas Weimbs, Burton F. Dickey, Keith E. Mostov
    Abstract:

    We have examined the role of rab3b in epithelial cells. In MDCK cells, rab3b localizes to vesicular structures containing the polymeric Immunoglobulin Receptor (pIgR) and located subjacent to the apical surface. We found that GTP-bound rab3b directly interacts with the cytoplasmic domain of pIgR. Binding of dIgA to pIgR causes a dissociation of the interaction with rab3b, a process that requires dIgA-mediated signaling, Arg657 in the cytoplasmic domain of pIgR, and possibly GTP hydrolysis by rab3b. Binding of dIgA to pIgR at the basolateral surface stimulates subsequent transcytosis to the apical surface. Overexpression of GTP-locked rab3b inhibits dIgA-stimulated transcytosis. Together, our data demonstrate that a rab protein can bind directly to a specific cargo protein and thereby control its trafficking.

  • The Polymeric Immunoglobulin Receptor Translocates Pneumococci across Human Nasopharyngeal Epithelial Cells
    Cell, 2000
    Co-Authors: Jing-ren Zhang, Michael E. Lamm, Keith E. Mostov, Masanobu Nanno, Shin-ichiro Shimida, Makoto Ohwaki, Elaine I. Tuomanen
    Abstract:

    The polymeric Immunoglobulin Receptor (pIgR) plays a crucial role in mucosal immunity against microbial infection by transporting polymeric Immunoglobulins (pIg) across the mucosal epithelium. We report here that the human pIgR (hpIgR) can bind to a major pneumococcal adhesin, CbpA. Expression of hpIgR in human nasopharyngeal cells and MDCK cells greatly enhanced pneumococcal adherence and invasion. The hpIgR-mediated bacterial adherence and invasion were abolished by either insertional knockout of cbpA or antibodies against either hpIgR or CbpA. In contrast, rabbit pIgR (rpIgR) did not bind to CbpA and its expression in MDCK cells did not enhance pneumococcal adherence and invasion. These results suggest that pneumococci are a novel example of a pathogen co-opting the pIg transcytosis machinery to promote translocation across a mucosal barrier.

  • Signal transduction by the polymeric Immunoglobulin Receptor suggests a role in regulation of Receptor transcytosis.
    The Journal of cell biology, 1996
    Co-Authors: Michael H. Cardone, Bradley L. Smith, Patricia A. Mennitt, Daria Mochly-rosen, Randi B. Silver, Keith E. Mostov
    Abstract:

    Many membrane traffic events that were previously thought to be constitutive recently have been found to be regulated by a variety of intracellular signaling pathways. The polymeric Immunoglobulin Receptor (pIgR) transcytoses dimeric IgA (dIgA) from the basolateral to the apical surface of polarized epithelial cells. Transcytosis is stimulated by binding of dIgA to the pIgR, indicating that the pIgR can transduce a signal to the cytoplasmic machinery responsible for membrane traffic. We report that dIgA binding to the pIgR causes activation of protein kinase C (PKC) and release of inositol 1,4,5-trisphosphate (IP3). The IP3 causes an elevation of intracellular Ca. Artificially activating PKC with phorbol myristate acetate or poisoning the calcium pump with thapsigargin stimulates transcytosis of pIgR, while the intracellular Ca chelator BAPTA-AM inhibits transcytosis. Our data suggest that ligand-induced signaling by the pIgR may regulate membrane traffic via well-known second messenger pathways involving PKC, IP3, and Ca. This may be a model of a general means by which membrane traffic is regulated by Receptor-ligand interaction and signaling pathways.

Charlotte S. Kaetzel - One of the best experts on this subject based on the ideXlab platform.

  • cooperativity among secretory iga the polymeric Immunoglobulin Receptor and the gut microbiota promotes host microbial mutualism
    Immunology Letters, 2014
    Co-Authors: Charlotte S. Kaetzel
    Abstract:

    Abstract Secretory IgA (SIgA) antibodies in the intestinal tract form the first line of antigen-specific immune defense, preventing access of pathogens as well as commensal microbes to the body proper. SIgA is transported into external secretions by the polymeric Immunoglobulin Receptor (pIgR). Evidence is reported here that the gut microbiota regulates production of SIgA and pIgR, which act together to regulate the composition and activity of the microbiota. SIgA in the intestinal mucus layer helps to maintain spatial segregation between the microbiota and the epithelial surface without compromising the metabolic activity of the microbes. Products shed by members of the microbial community promote production of SIgA and pIgR by activating pattern recognition Receptors on host epithelial and immune cells. Maternal SIgA in breast milk provides protection to newborn mammals until the developing intestinal immune system begins to produce its own SIgA. Disruption of the SIgA-pIgR-microbial triad can increase the risk of infectious, allergic and inflammatory diseases of the intestine.

  • The Polymeric Immunoglobulin Receptor
    eLS, 2013
    Co-Authors: Charlotte S. Kaetzel
    Abstract:

    Secretory Immunoglobulin A (SIgA) antibodies represent the first line of antigen-specific immune defence protecting the mucosal surfaces against environmental pathogens and antigens and maintaining homoeostasis with the commensal microbiota. The polymeric Ig Receptor (pIgR) plays the dual role of transporting locally produced dimeric IgA across mucosal epithelia and serving as the precursor of the secretory component moiety of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimise the role of SIgA in mucosal immunity. Recent discoveries highlight the dynamic cross-talk between pIgR, SIgA and the commensal microbiota that populate our mucosal surfaces. Dysregulation of pIgR expression and/or function can result in profound consequences for the pathogenesis of infectious, inflammatory and neoplastic diseases. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of diseases that originate at mucosal surfaces. Key Concepts: Secretory IgA (SIgA) antibodies represent the first line of antigen-specific immune defence at mucosal surfaces. The polymeric Immunoglobulin Receptor (pIgR) transports dimeric IgA across mucosal epithelial cells and serves as the precursor for the secretory component of SIgA. Transcription of the PIGR gene in mucosal epithelial cells is regulated by signalling pathways initiated by host cytokines and microbial factors, involving the cytoplasmic adapter protein, myeloid differentiation primary response protein 88 (MyD88). SIgA mediates immune protection by immune exclusion, intracellular neutralisation of antigens and pathogens and excretion of IgA-containing immune complexes by pIgR-mediated epithelial transcytosis. Cross-talk between pIgR, SIgA and commensal bacteria regulates the composition of the gut microbiota and promotes intestinal homoeostasis. Dysregulated expression or function of pIgR can contribute to the pathology of infectious, inflammatory and neoplastic diseases. Keywords: polymeric Immunoglobulin Receptor; secretory IgA; mucosal immunity; epithelial transcytosis; microbiota; cytokines; Toll-like Receptors; NF-κB; infectious diseases; inflammatory bowel disease; cancer

  • Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric Immunoglobulin Receptor, mucin-2, and antibacterial peptides
    Mucosal Immunology, 2012
    Co-Authors: Aubrey L. Frantz, Eric Rogier, Christopher R. Weber, L Shen, Donald A. Cohen, L A Fenton, Maria E. C. Bruno, Charlotte S. Kaetzel
    Abstract:

    Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like Receptor signaling is a key mediator of microbial–host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88ΔIEC). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric Immunoglobulin Receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIγ and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88ΔIEC mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88ΔIEC mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis.

  • regulation of the polymeric Immunoglobulin Receptor and iga transport new advances in environmental factors that stimulate pigr expression and its role in mucosal immunity
    Mucosal Immunology, 2011
    Co-Authors: Finneirik Johansen, Charlotte S. Kaetzel
    Abstract:

    Secretory IgA (SIgA) antibodies represent the first line of antigen-specific immune defense protecting the mucosal surfaces against environmental pathogens and antigens, and maintaining homeostasis with the commensal microbiota. The polymeric Immunoglobulin Receptor (pIgR) has the dual role of transporting locally produced dimeric IgA across mucosal epithelia, and serving as the precursor of secretory component, a glycoprotein that enhances the immune functions of SIgA. The complex regulation of pIgR expression and transcytosis by host and microbial factors is finely tuned to optimize the role of SIgA in mucosal immunity. Disruption of this regulatory network in disease states similar to inflammatory bowel disease can result in profound consequences for mucosal homeostasis and systemic sequelae. Future research into the function and regulation of pIgR and SIgA may offer new insights into the prevention and treatment of infectious and inflammatory diseases that originate at mucosal surfaces.

  • Regulation of the polymeric Immunoglobulin Receptor in intestinal epithelial cells by Enterobacteriaceae: implications for mucosal homeostasis.
    Immunological investigations, 2010
    Co-Authors: Maria E. C. Bruno, Aubrey L. Frantz, Eric Rogier, Andrew T. Stefka, Stephanie N. Thompson, Charlotte S. Kaetzel
    Abstract:

    The commensal microbiota of the human colon profoundly impacts host gene expression and mucosal homeostasis. Secretory IgA antibodies, which influence the composition of the intestinal microbiota and provide immunity against pathogens, are transported across intestinal epithelial cells (IEC) by the polymeric Immunoglobulin Receptor (pIgR). To compare the effects of different colonic bacteria on pIgR expression, the human IEC line HT-29 was stimulated with various species representing the 4 major phyla of colonic bacteria. Only bacteria from the family Enterobacteriaceae (phylum Proteobacteria) induced expression of pIgR and other target genes of bacterial pattern recognition Receptors. HT-29 cells responded to purified ligands for Toll-like Receptor (TLR)4 but not TLR2. Expression of pIgR and transport of IgA were significantly reduced in colons of mice deficient in the TLR adaptor MyD88, consistent with a role for TLR signaling in the regulation of pIgR by colonic bacteria. Induction of pIgR expression i...

Vera Jankowski - One of the best experts on this subject based on the ideXlab platform.

  • Associations of urinary polymeric Immunoglobulin Receptor peptides in the context of cardio-renal syndrome
    Scientific Reports, 2020
    Co-Authors: Justyna Siwy, Jochen Metzger, William Mullen, Harald Mischak, Joost Schanstra, Petra Zürbig, Vera Jankowski
    Abstract:

    The polymeric Immunoglobulin Receptor (pIgR) transports Immunoglobulins from the basolateral to the apical surface of epithelial cells. PIgR was recently shown to be associated with kidney dysfunction. The immune defense is initiated at the apical surface of epithelial cells where the N-terminal domain of pIgR, termed secretory component (SC), is proteolytically cleaved and released either unbound (free SC) or bound to Immunoglobulins. The aim of our study was to evaluate the association of pIgR peptides with the cardio-renal syndrome in a large cohort and to obtain information on how the SC is released. We investigated urinary peptides of 2964 individuals available in the Human Urine Proteome Database generated using capillary electrophoresis coupled to mass spectrometry. The mean amplitude of 23 different pIgR peptides correlated negatively with the estimated glomerular filtration rate (eGFR, rho = -0.309, p 

Michael E. Lamm - One of the best experts on this subject based on the ideXlab platform.

  • The Polymeric Immunoglobulin Receptor Translocates Pneumococci across Human Nasopharyngeal Epithelial Cells
    Cell, 2000
    Co-Authors: Jing-ren Zhang, Michael E. Lamm, Keith E. Mostov, Masanobu Nanno, Shin-ichiro Shimida, Makoto Ohwaki, Elaine I. Tuomanen
    Abstract:

    The polymeric Immunoglobulin Receptor (pIgR) plays a crucial role in mucosal immunity against microbial infection by transporting polymeric Immunoglobulins (pIg) across the mucosal epithelium. We report here that the human pIgR (hpIgR) can bind to a major pneumococcal adhesin, CbpA. Expression of hpIgR in human nasopharyngeal cells and MDCK cells greatly enhanced pneumococcal adherence and invasion. The hpIgR-mediated bacterial adherence and invasion were abolished by either insertional knockout of cbpA or antibodies against either hpIgR or CbpA. In contrast, rabbit pIgR (rpIgR) did not bind to CbpA and its expression in MDCK cells did not enhance pneumococcal adherence and invasion. These results suggest that pneumococci are a novel example of a pathogen co-opting the pIg transcytosis machinery to promote translocation across a mucosal barrier.

  • Disulfide Bond Formation Between Dimeric Immunoglobulin-a and the Polymeric Immunoglobulin Receptor During Hepatic Transcytosis
    Hepatology (Baltimore Md.), 1994
    Co-Authors: Koteswara R. Chintalacharuvu, Anthony S. Tavill, Loizos N. Louis, Jean-pierre Vaerman, Michael E. Lamm, Charlotte S. Kaetzel
    Abstract:

    The polymeric Immunoglobulin Receptor on rat hepatocytes binds dimeric IgA on the sinusoidal surface and mediates its transport to the canaliculus, where the complex of dimeric IgA and secretory component, the cleaved extracellular domain of polymeric Immunoglobulin Receptor, is secreted into bile. This process is unique in that disulfide bonds are formed between dimeric IgA and polymeric Immunoglobulin Receptor during transcytosis, permanently preventing their dissociation. Here we present three lines of evidence that disulfide bonding between dimeric IgA and polymeric Immunoglobulin Receptor occurs predominantly in a late transcytotic compartment and that hepatic transcytosis can proceed in the absence of disulfide bond formation. First, throughout the course of transcytosis the percentage of intracellular dimeric IgA disulfide bonded to polymeric Immunoglobulin Receptor is less than half that in bile, suggesting that disulfide bond formation is a late event in transcytosis. Second, dimeric IgA that recycles from early endocytotic compartments into the circulation is mostly noncovalently bound to secretory component. Finally, the rate of transcytosis of dimeric IgA and its appearance in bile are not affected when disulfide bond formation with polymeric Immunoglobulin Receptor is inhibited by blocking of free thiol groups on dimeric IgA with iodoacetamide. These results are consistent with other findings in the literature and indicate that the main physiological role of disulfide bond formation between dimeric IgA and polymeric Immunoglobulin Receptor is not to facilitate transcytosis but, rather, to stabilize the dimeric IgA-secretory component complex after its release into external secretions such as bile and intestinal secretions.

  • intracellular neutralization of virus by Immunoglobulin a antibodies
    Proceedings of the National Academy of Sciences of the United States of America, 1992
    Co-Authors: Mary B Mazanec, Charlotte S. Kaetzel, Michael E. Lamm, David Fletcher, John G Nedrud
    Abstract:

    Abstract IgA is thought to neutralize viruses at the epithelial surface of mucous membranes by preventing their attachment. Since IgA, a polymeric Immunoglobulin, is transported through the lining of epithelial cells by the polymeric-Immunoglobulin Receptor and since viruses are obligate intracellular parasites, we hypothesized that IgA antibodies may also interfere with viral replication by binding to newly synthesized viral proteins within infected cells. Polarized monolayers of Madin-Darby canine kidney epithelial cells expressing the polymeric-Immunoglobulin Receptor were infected on the apical surface with Sendai virus. Anti-Sendai virus IgA monoclonal antibody delivered from the basolateral surface colocalized with viral protein within the cell, as documented by immunofluorescence. More importantly, anti-viral IgA reduced virus titers greater than 1000-fold (P less than 0.0001) in apical supernatants and greater than 10-fold (P less than 0.0001) in cell lysates from monolayers treated with anti-viral IgA compared with those treated with either anti-viral IgG or an irrelevant IgA monoclonal antibody. We believe that the differences in viral titers between cell layers treated with specific IgA, which enters the epithelial cell by binding to the polymeric-Immunoglobulin Receptor, and those treated with specific IgG, which does not enter the cells, or irrelevant IgA indicate that specific intracellular IgA antibodies can inhibit viral replication. Thus, in addition to the classical role of humoral antibodies in extracellular defense, IgA antibody may be able to neutralize microbial pathogens intracellularly, giving IgA a role in host defense that has traditionally been reserved for cell-mediated immunity.

  • the polymeric Immunoglobulin Receptor secretory component mediates transport of immune complexes across epithelial cells a local defense function for iga
    Proceedings of the National Academy of Sciences of the United States of America, 1991
    Co-Authors: Charlotte S. Kaetzel, Koteswara R. Chintalacharuvu, Jane Robinso, Jeanpierre Vaerma, Michael E. Lamm
    Abstract:

    The polymeric Immunoglobulin Receptor (pIgR) on mucosal epithelial cells binds dimeric IgA (dIgA) on the basolateral surface and mediates transport of dIgA to the apical surface. Using Madin-Darby canine kidney epithelial cells stably transfected with pIgR cDNA, we found that soluble immune complexes (ICs) of 125I-labeled rat monoclonal antidinitrophenyl (DNP) dIgA (125I-dIgA) and DNP/biotin-bovine serum albumin were transported from the basolateral to the apical surface and then released. Monomeric IgA ICs were not transported, consistent with the specificity of pIgR for polymeric Immunoglobulins. Essentially all the 125I-dIgA in apical culture supernatants was streptavidin precipitable, indicating that dIgA remained bound to antigen during transcytosis. While both dIgA and dIgA ICs bound pIgR with equal affinity (Kd approximately 8 nM), the number of high-affinity binding sites per cell was 2- to 3-fold greater for dIgA than for dIgA ICs. The extent of endocytosis of dIgA and dIgA ICs was correlated with the number of high-affinity binding sites. SDS/PAGE analysis of intracellular dIgA and dIgA ICs demonstrated that in both cases IgA remained undegraded during transport. The results suggest that the pathways of epithelial transcytosis of free dIgA and dIgA ICs are the same. Given the high population density of mucosal IgA plasma cells and the enormous surface area of pIgR-expressing mucosal epithelium, it is likely that significant local transcytosis of IgA ICs occurs in vivo. Such a process would allow direct elimination of IgA ICs at the mucosal sites where they are likely to form, thus providing an important defense function for IgA.

Apiwat Mutirangura - One of the best experts on this subject based on the ideXlab platform.

  • Polymeric Immunoglobulin Receptor polymorphisms and risk of nasopharyngeal cancer
    BMC Genetics, 2003
    Co-Authors: Rungnapa Hirunsatit, Narisorn Kongruttanachok, Kanjana Shotelersuk, Narin Voravud, Anavaj Sakuntabhai, Pakpoom Supiyaphun, Apiwat Mutirangura
    Abstract:

    Background Epstein-Barr virus (EBV) associated nasopharyngeal cancer (NPC) is an important squamous cell cancer endemic in Southeast Asia and the Far East and can be considered a multifactorial genetic disease. This research explores potential associations between nasopharyngeal epithelial EBV Receptor and NPC susceptibility. To prove the hypothesis, we evaluated two candidate genes, complement Receptor 2 (CR2) and polymeric Immunoglobulin Receptor (PIGR) by using 4 SNPs, CR2 IVS2-848C→T, PIGR IVS3-156G→T, PIGR 1093G→A and PIGR 1739C→T, to genotype 175 cases and 317 controls, divided into Thai, Chinese and Thai-Chinese based on their respective ethnic origins.

  • Polymeric Immunoglobulin Receptor polymorphisms and risk of nasopharyngeal cancer
    BMC Genetics, 2003
    Co-Authors: Rungnapa Hirunsatit, Narisorn Kongruttanachok, Kanjana Shotelersuk, Narin Voravud, Anavaj Sakuntabhai, Pakpoom Supiyaphun, Apiwat Mutirangura
    Abstract:

    Background Epstein-Barr virus (EBV) associated nasopharyngeal cancer (NPC) is an important squamous cell cancer endemic in Southeast Asia and the Far East and can be considered a multifactorial genetic disease. This research explores potential associations between nasopharyngeal epithelial EBV Receptor and NPC susceptibility. To prove the hypothesis, we evaluated two candidate genes, complement Receptor 2 ( CR2 ) and polymeric Immunoglobulin Receptor ( PIGR ) by using 4 SNPs, CR2 IVS2-848C→T, PIGR IVS3-156G→T, PIGR 1093G→A and PIGR 1739C→T, to genotype 175 cases and 317 controls, divided into Thai, Chinese and Thai-Chinese based on their respective ethnic origins. Results The results obtained indicated that PIGR is an NPC susceptibility gene. The risk association pertaining to each ethnic group was detected for homozygous PIGR 1739C with a significant ethnic group adjusted OR (95%CI) of 2.71(1.72–4.23) and p < 0.00001. Haplotype of the two missense PIGR SNPs, 1093G→A and 1739C→T, and sequence analyses have confirmed the role of the nucleotide PIGR 1739 and excluded possibility of an additional significant nonsynonymous NPC susceptibility SNP. 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. The PIGR 1739C→T is a missense mutation changing alanine to valine near endoproteolytic cleavage site. This variant could alter the efficiency of PIGR to release IgA-EBV complex and consequently increase the susceptibility of populations in endemic areas to develop NPC.