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Per Brandtzaeg - One of the best experts on this subject based on the ideXlab platform.
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novel monoclonal antibodies for studies of human and rhesus macaque Secretory Component and human j chain
Monoclonal antibodies in immunodiagnosis and immunotherapy, 2016Co-Authors: Ruijun Zhang, Per Brandtzaeg, Munir S Alam, Richard M Scearce, Bradley Lockwood, Kwanki Hwang, Robert Parks, Sallie R Permar, Barton F HaynesAbstract:Immunoglobulin A (IgA) antibodies exist in monomeric, dimeric, and Secretory forms. Dimerization of IgA depends on a 15-kD polypeptide termed “joining (J) chain,” which is also part of the binding site for an epithelial glycoprotein called “Secretory Component (SC),” whether this after apical cleavage on Secretory epithelia is ligand bound in Secretory IgA (SIgA) or in a free form. Uncleaved membrane SC, also called the “polymeric Ig receptor,” is thus crucial for transcytotic export of SIgA to mucosal surfaces, where it interacts with and modulates commensal bacteria and mediates protective immune responses against exogenous pathogens. To evaluate different forms of IgA, we have produced mouse monoclonal antibodies (MAbs) against human J-chain and free SC. We found that J-chain MAb 9A8 and SC MAb 9H7 identified human dimeric IgA and SIgA in enzyme-linked immunoassay and western blot analysis, as well as functioning in immunohistochemistry to identify cytoplasmic IgA of intestinal lamina propria plasmabla...
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recombinant expression of polymeric iga incorporation of j chain and Secretory Component of human origin
European Journal of Immunology, 1999Co-Authors: Finneirik Johansen, Inger Natvig Norderhaug, Malfrid Roe, Inger Sandlie, Per BrandtzaegAbstract:Mucosal J (joining) chain-expressing IgA immunocytes produce dimeric IgA that is actively transported by the epithelial polymeric Ig receptor (pIgR) to exocrine secretions. Release of Secretory IgA (SIgA) occurs by cleavage of the covalently linked pIgR ectodomain, also known as bound Secretory Component. We have identified the human J-chain cDNA sequence through database screening, and isolated it from B cells for recombinant expression. Co-expression of this cDNA with an alpha heavy chain and a lambda light chain in Chinese hamster ovary (CHO) cells resulted in a mixture of recombinant monomeric and dimeric IgA in culture supernatants. This dimeric IgA was transported by the pIgR-mediated mechanism in vitro. Furthermore, expression of the human pIgR ectodomain together with the dimeric IgA, resulted in production of complete SIgA by the CHO cells. These results demonstrated that co-expression of the necessary polypeptide Components allows a single mammalian cell to produce SIgA. Development of production systems for human antigen-specific recombinant SIgA may be important for applications in passive mucosal vaccination.
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different regulatory pathways employed in cytokine enhanced expression of Secretory Component and epithelial hla class i genes
European Journal of Immunology, 1999Co-Authors: Ellen M Nilsen, Peter Krajci, Dag Kvale, Finneirik Johansen, Per BrandtzaegAbstract:The transmembrane Secretory Component (SC, or pIg receptor) plays a crucial role in mucosal immunity by translocating dimeric IgA and pentameric IgM through exocrine epithelia. This receptor is up-regulated by cytokines in parallel with increased epithelial HLA expression. By use of the human epithelial cell line HT-29m3, we show that IFN-gamma, TNF-alpha and IL-4 activate transcription of the SC gene. This activation was slow, suggesting mediation via newly synthesized protein factors. IFN-gamma and TNF-alpha, but not IL-4, also up-regulated expression of HLA class I genes. However, this gene induction was rapid and did not depend on new protein synthesis. Nuclear run-on experiments showed that the transcription rate of HLA class I genes nearly peaked after only 30 min of IFN-gamma or TNF-alpha stimulation, whereas the SC transcription rate did not peak until after 20-36 h of IFN-gamma, TNF-alpha or IL-4 stimulation. Gel electrophoresis mobility shift assays demonstrated binding of nuclear proteins from cytokine-stimulated HT-29 cells to consensus elements in the promoter of the SC gene, involving the binding site for the nuclear factor-kappaB p50 subunit after TNF-alpha stimulation, and IFN-stimulated response element after IFN-gamma stimulation (and weakly after TNF-alpha. Our observations in vitro likely parallel events in vivo by which activated mucosal T cells and macrophages enhance pIg receptor-mediated external transport of Secretory IgA and IgM and up-regulate epithelial HLA expression.
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spsa a novel pneumococcal surface protein with specific binding to Secretory immunoglobulin a and Secretory Component
Molecular Microbiology, 1997Co-Authors: Sven Hammerschmidt, Susanne R Talay, Per Brandtzaeg, Gursharan S ChhatwalAbstract:: The interaction of pathogenic bacteria with host serum and matrix proteins is a common strategy to enhance their virulence. Streptococcus pneumoniae colonizes the human upper respiratory tract in healthy individuals and is also able to cause invasive diseases. Here, we describe a novel pneumococcal surface protein, SpsA, capable of binding specifically to human Secretory immunoglobulin A (SIgA). The dissociation constant of SIgA binding to SpsA was 9.3 x 10(-9) M. Free Secretory Component (SC) also binds to S. pneumoniae, whereas serum IgA does not, suggesting that pneumococcal binding to SIgA is mediated by the SC. To our knowledge, this is the first defined interaction of SC with a prokaryotic protein. The spsA gene encodes a polypeptide of 523 amino acids with a predicted molecular mass of 59 151 Da. The SIgA- or SC-binding domain is located in the N-terminal part of SpsA and exhibits no significant homology to any other proteins. The purified SIgA-binding domain of SpsA could completely inhibit the binding of SIgA to pneumococci. SpsA was expressed by 73% of the tested S. pneumoniae isolates and was substantially conserved between different serotypes. The interaction between S. pneumoniae and SC via SpsA represents a novel biological interaction that might increase virulence by the impairment of bacterial clearance.
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glandular distribution of immunoglobulins j chain Secretory Component and hla dr in the human endometrium throughout the menstrual cycle
Human Reproduction, 1993Co-Authors: Sverre Bjercke, Per BrandtzaegAbstract:Two-colour immunofluorescence was used to study Components of the Secretory immune system in the endometrium. Tissue sampling was performed in the follicular, ovulatory and luteal menstrual phase from women admitted for laparoscopic sterilization. The specimens were prepared for immunohistochemistry by a method that removes most extracellular immunoglobulin (Ig). The stroma contained only a few Ig-producing immunocytes, but was rich in HLA-DR positive cells. Most of the IgA- and IgM-producing immunocytes also expressed J chain, which is necessary for the generation of polymeric Ig (poly-Ig) with affinity for epithelial Secretory Component (SC or poly-Ig receptor). Throughout the menstrual cycle there was increasing accumulation of Ig within the endometrial glands, with preferential apical and intraluminal occurrence of IgA and IgM, usually along with J chain and SC. It is likely that some monomeric IgA (without J chain) and IgG enter the endometrial glands by passive diffusion from the stroma, but there is clearly an additional active external poly-Ig transport. Some of the glands stained for HLA-DR irrespective of the menstrual phase or degree of SC expression. Our findings suggest that active SC-mediated external transport of serum-derived (and to some extent locally produced) poly-Ig is enhanced in the luteal phase, and that SC and HLA class II molecules are differently regulated in the endometrial glands.
David A Sullivan - One of the best experts on this subject based on the ideXlab platform.
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androgen control of Secretory Component mrna levels in the rat lacrimal gland
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: Jianping Gao, R W Lambert, L A Wickham, G Banting, David A SullivanAbstract:The functional expression of the Secretory immune system of the eye is critically dependent upon Secretory Component (SC),1 the polymeric IgA receptor.2 This glycoprotein, which is produced by lacrimal gland epithelial cells, controls the transfer of Secretory IgA (slgA) antibodies to the ocular surface, whereupon sIgA defends against microbial agents and toxic compounds.1 Given this pivotal role of SC in ocular mucosal immunity, our research has sought to elucidate the processes involved in the synthesis and secretion of this lacrimal protein. Such studies have demonstrated that: [a] SC production by rat lacrimal tissue displays distinct, gender-related differences (i.e. glands of males produce significantly more SC than those of females);3,4 and [b] SC synthesis by rat lacrimal acinar cells is uniquely regulated by the endocrine, nervous and immune systems.5.6 Thus, SC production is stimulated by androgens, vasoactive intestinal peptide (VIP), β-adrenergic agonists (e.g. isoproterenol), interleukm-lα (EL-lα), interleukin-1β (IL-Iβ), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), and suppressed by cholinergic agonists (e.g. carbachol choline). Moreover, these gender-associated and neuroendocrinimmune effects on lacrimal SC synthesis appear to be unique to the eye, given that SC production by other mucosal sites: [a] may show no sexual dimorphism (e.g. salivary, respiratory, intestinal, D.A. Sullivan, unpublished data); and [b] may be enhanced or inhibited, depending upon the tissue, by estrogens, progestins, glucocorticoids, prolactin, thyroxine, substance P and γ-interferon (γ-IFN),7–13 which agents have no demonstrable impact on the constitutive SC Output by lacrimal acinar cells.6
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neural endocrine and immune regulation of Secretory Component production by lacrimal gland acinar cells
Advances in Experimental Medicine and Biology, 1995Co-Authors: R W Lambert, R S Kelleher, Jianping Gao, Alexandra L Wickham, David A SullivanAbstract:Our previous research has shown that the endocrine, nervous and immune systems regulate the production of Secretory Component (SC), the polymeric immunoglobulin receptor, by acinar (epithelial) cells from the rat lacrimal gland.1 Thus, acinar cell exposure in vitro to androgens (e. g., dihydrotestosterone [DHT]), vasoactive intestinal peptide (VIP), the adrenergic agonist, isoproterenol, cyclic AMP analogues (e. g., 8-bromoadenosine 3’:5’- cyclic monophosphate [bcAMP]), cyclic AMP inducers (e. g., cholera toxin, PGE2), phosphodiesterase inhibitors (e. g., 3-isobutyl-l-methylxanthine), IL-lα, IL-lβ, or TNF-α results in a significant increase in SC output.2-4 Conversely, cellular treatment with the cholinergic agent, carbachol, causes a significant suppression of both androgen-induced and basal SC release by acinar cells.3,4
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neuroendocrinimmune modulation of Secretory Component production by rat lacrimal salivary and intestinal epithelial cells
Investigative Ophthalmology & Visual Science, 1994Co-Authors: R W Lambert, Jp Vaerman, R S Kelleher, L A Wickham, David A SullivanAbstract:Purpose. To evaluate the kinetics, receptor specificity, molecular basis, and site selectivity of the endocrine and neural regulation of Secretory Component (SC) synthesis by rat lacrimal gland acinar cells. Methods. Acinar cells from male rat lacrimal and submandibular glands, as well as epithelial cells (IEC-6) from the rat small intestine, were cultured in supplemented, serum-free media and treated with dihydrotesterone, cholera toxin, carbachol, vehicle, or other agents for varying time periods. Media SC levels were measured by radioimmunoassay. Results. The authors' findings with lacrimal gland acinar cells demonstrate that: a significant, temporal delay exists between the initiation of stimulatory or inhibitory signals and the eventual cellular SC response to regulatory compounds; the parasympathetic analogue, carbachol, exerts a dual effect on SC output, i.e., an early stimulation (hours) followed by an extended suppression (days); the androgen and cholinergic control of SC is receptor-mediated; and the androgen modulation of SC may involve the induction of gene expression. In addition, the authors' results show that distinct, tissue-specific variations occur in the nature of SC regulation: Compounds that control SC output by lacrimal acinar cells do not necessarily alter SC production by epithelial cells from the rat submandibular gland or small intestine. Conclusions. These findings advance the authors' understanding of the neuroendocrine regulation of SC synthesis in acinar cells from the lacrimal gland. Moreover, the authors' results indicate that the nature of the neural, endocrine, and immune control of lacrimal SC may be unique.
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neural endocrine control of Secretory Component synthesis by lacrimal gland acinar cells specificity temporal characteristics and molecular basis
Advances in Experimental Medicine and Biology, 1994Co-Authors: R W Lambert, R S Kelleher, Jianping Gao, Alexandra L Wickham, David A SullivanAbstract:The ocular surface appears to be protected from bacterial and viral pathogens by polymeric IgA antibodies.1 These antibodies, which are produced by plasma cells in the lacrimal gland, bind to Secretory Component (SC) in the basolateral membrane of acinar epithelial cells, and are then transported to the apical membrane and secreted into tears.2 Of interest, the lacrimal secretion of sIgA, as well as free SC, appears to be significantly influenced by gender and hormones from the hypothalamic-pituitary-gonadal axis.2 Thus, almost 10 years ago, it was found that the concentrations of free SC and IgA in the tears of male rats were 2 to 5-fold higher than those in tears of female rats. These gender-associated differences in tear SC and IgA were shown to be caused by androgens.2 For example, castration led to a significant reduction in SC levels in tears of males, while having no impact on SC content in tears of females. In addition, administration of testosterone for 4 days to castrated male or female rats significantly increased tear SC levels. These studies showed that exposure of castrated rats to androgens resulted in alterations of lacrimal SC production.2 Moreover, later experiments demonstrated that this androgen control of SC, as well as IgA, is modulated by factors from the hypothalamus and pituitary.2 However, this research did not address whether androgens act directly on lacrimal tissue to change SC or IgA, or indirectly via an androgen-sensitive site, which in tum acts to modulate lacrimal SC and IgA.
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influence of culture conditions on the androgen control of Secretory Component production by acinar cells from the rat lacrimal gland
Investigative Ophthalmology & Visual Science, 1991Co-Authors: L E Hann, R S Kelleher, David A SullivanAbstract:Research has shown that androgens regulate the production of Secretory Component (SC), the IgA antibody receptor, by lacrimal gland acinar cells in vivo. This study was designed to establish an optimal culture system to permit analysis of this endocrine-acinar cell interrelationship in vitro. Acinar cells were isolated from male rat lacrimal glands and cultured on Matrigel (Collaborative Research, Bedford, MA) in serum-free Dulbecco's modified Eagle's medium (DMEM)/Ham's F12 media that contained a variety of supplements. Under these conditions, acinar cells responded to dihydrotestosterone (DHT) exposure with a significant increase in SC output. Replacement of the DMEM/Ham's F12 media base with either Modified Eagle's Medium (MEM) or low-calcium MEM inhibited this hormone response and dramatically reduced cell recovery after 4 days of culture. Similarly, decreased concentrations or deletions of selected media supplements, including insulin, which binds to acinar cells, and dexamethasone, led to a significant diminution in the extent of androgen action, as well as to a decline in cell maintenance. In contrast, removal of high-density lipoprotein from culture media or the addition of fetal bovine serum (FBS) or cholera toxin significantly enhanced basal and DHT-associated SC production by acinar cells. With regard to extracellular matrices, Matrigel proved to be superior to collagen type I, laminin, fibronectin, or the Primaria (Falcon, Oxnard, CA) plastic surface in providing support for acinar cell association or hormone-related function. In summary, our results show that the media formulation, supplement profile, and extracellular matrix composition are important for maximal expression of androgen-induced effects by lacrimal gland acinar cells in vitro.
Blaise Corthesy - One of the best experts on this subject based on the ideXlab platform.
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human plasma derived polymeric iga and igm antibodies associate with Secretory Component to yield biologically active Secretory like antibodies
Journal of Biological Chemistry, 2013Co-Authors: Stephanie Longet, Blaise Corthesy, Sarah Miled, Marius Lotscher, Sylvia Miescher, Adrian ZuercherAbstract:Immunotherapy with monoclonal and polyclonal immunoglobulin is successfully applied to improve many clinical conditions, including infection, autoimmune diseases, or immunodeficiency. Most immunoglobulin products, recombinant or plasma-derived, are based on IgG antibodies, whereas to date, the use of IgA for therapeutic application has remained anecdotal. In particular, purification or production of large quantities of Secretory IgA (SIgA) for potential mucosal application has not been achieved. In this work, we sought to investigate whether polymeric IgA (pIgA) recovered from human plasma is able to associate with Secretory Component (SC) to generate SIgA-like molecules. We found that ∼15% of plasma pIgA carried J chain and displayed selective SC binding capacity either in a mixture with monomeric IgA (mIgA) or after purification. The recombinant SC associated covalently in a 1:1 stoichiometry with pIgA and with similar efficacy as colostrum-derived SC. In comparison with pIgA, the association with SC delayed degradation of SIgA by intestinal proteases. Similar results were obtained with plasma-derived IgM. In vitro, plasma-derived IgA and SIgA neutralized Shigella flexneri used as a model pathogen, resulting in a delay of bacteria-induced damage targeted to polarized Caco-2 cell monolayers. The sum of these novel data demonstrates that association of plasma-derived IgA or IgM with recombinant/colostrum-derived SC is feasible and yields SIgA- and SIgM-like molecules with similar biochemical and functional characteristics as mucosa-derived immunoglobulins.
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n glycans on Secretory Component mediators of the interaction between Secretory iga and gram positive commensals sustaining intestinal homeostasis
Gut microbes, 2011Co-Authors: Amandine Mathias, Blaise CorthesyAbstract:Human beings live in symbiosis with billions of microorganisms colonizing mucosal surfaces. The understanding of the mechanisms underlying this fine-tuned intestinal balance has made significant processes during the last decades. We have recently demonstrated that the interaction of SIgA with Gram-positive bacteria is essentially based on Fab-independent, glycan-mediated recognition. Results obtained using mouse hybridoma- and colostrum-derived Secretory IgA (SIgA) consistently show that N-glycans present on Secretory Component (SC) play a crucial role in the process. Natural coating may involve specific Gram-positive cell wall Components, which may explain selective recognition at the molecular level. More widely, the existence of these complexes is involved in the modulation of intestinal epithelial cell (IEC) responses in vitro and the formation of intestinal biofilms. Thus, SIgA may act as one of the pillars in homeostatic maintenance of the microbiota in the gut, adding yet another facet to its multi...
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glycans on Secretory Component participate in innate protection against mucosal pathogens
Journal of Biological Chemistry, 2006Co-Authors: Norbert Sprenger, Clementine Perrier, Blaise CorthesyAbstract:In mucosal secretions, Secretory Component (SC) is found either free or bound to polymeric IgA within the Secretory IgA complex. SC displays numerous and various glycans, which are potential ligands for bacterial compounds. We first established that human SC (hSC) purified from colostrum (hSCcol) or produced in Chinese hamster ovary cells (hSCrec) exhibits the same lectin reactivity. Both forms bind to Clostridium difficile toxin A and functionally protect polarized Caco-2 cell monolayers from the cytopathic effect of the toxin. The interaction is mediated by glycans present on hSC and involves galactose and sialic acid residues. hSCcol and hSCrec were also shown to bind enteropathogenic Escherichia coli adhesin intimin and to inhibit its infectivity on HEp-2 cells in a glycan-dependent manner as well. SC remained operative in the context of the whole Secretory IgA molecule and can therefore enhance its Fab-mediated neutralizing properties. On the contrary, hSC did not interact with three different strains of rotavirus (RF, RRV, and SA11). Accordingly, infection of target MA104 cells with these rotavirus strains was not reduced in the presence of either form of hSC tested. Although not a universal mechanism, these findings identify hSC as a microbial scavenger contributing to the antipathogenic arsenal that protects the body epithelial surfaces.
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Secretory Component a new role in Secretory iga mediated immune exclusion in vivo
Immunity, 2002Co-Authors: Armelle Phalipon, Jeanpierre Kraehenbuhl, Ana Cardona, Lena Edelman, Philippe J Sansonetti, Blaise CorthesyAbstract:Secretory immunoglobulin (Ig) A (SIgA) is essential in protecting mucosal surfaces. It is composed of at least two monomeric IgA molecules, covalently linked through the J chain, and Secretory Component (SC). We show here that a dimeric/polymeric IgA (IgA(d/p)) is more efficient when bound to SC in protecting mice against bacterial infection of the respiratory tract. We demonstrate that SC ensures, through its carbohydrate residues, the appropriate tissue localization of SIgA by anchoring the antibody to mucus lining the epithelial surface. This in turn impacts the localization and the subsequent clearance of bacteria. Thus, SC is directly involved in the SIgA function in vivo. Therefore, binding of IgA(d/p) to SC during the course of SIgA-mediated mucosal response constitutes a crucial step in achieving efficient protection of the epithelial barrier by immune exclusion.
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expression purification and biochemical characterization of recombinant murine Secretory Component a novel tool in mucosal immunology
Biochemical Journal, 1999Co-Authors: Pascal Crottet, Sandra Cottet, Blaise CorthesyAbstract:Reconstitution of Secretory IgA (S-IgA) by the association in vitro of Secretory Component (SC) and polymeric IgA (pIgA) obtained from hybridomas is a valuable tool in the study of the structure-function relationship in this particular class of antibody. Although dimeric IgA (dIgA) can be obtained and purified from hybridoma clones, SC remains tedious to isolate in sufficient amounts from colostral milk. Several murine models for the study of mucosal immunity are available, which could potentially benefit from the use of cognate IgA antibodies in various molecular forms, including dIgA and S-IgA. We report here on the establishment of two expression systems allowing the production of milligram amounts of pure recombinant murine SC (rmSC) with preserved murine pIgA-binding capability. The first system relies on the use of recombinant vaccinia virus to prompt infected HeLa cells to express the murine SC protein, whereas the second system is based on a stably transfected cell clone exhibiting murine glycosylation. The second source of rmSC will permit the study of the role of its sugar moieties in pathogen-host interactions, and the evaluation of its function in passive protection without risking adverse immune responses. The extensive biochemical characterization conducted in this study demonstrates that rmSC is a dependable and convenient alternative to the natural product, and indicates that the J chain is dispensable in the recognition of pIgA and SC in vitro, whereas it is required for proper pIgA-polymeric Ig receptor interaction in vivo.
R W Lambert - One of the best experts on this subject based on the ideXlab platform.
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androgen control of Secretory Component mrna levels in the rat lacrimal gland
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: Jianping Gao, R W Lambert, L A Wickham, G Banting, David A SullivanAbstract:The functional expression of the Secretory immune system of the eye is critically dependent upon Secretory Component (SC),1 the polymeric IgA receptor.2 This glycoprotein, which is produced by lacrimal gland epithelial cells, controls the transfer of Secretory IgA (slgA) antibodies to the ocular surface, whereupon sIgA defends against microbial agents and toxic compounds.1 Given this pivotal role of SC in ocular mucosal immunity, our research has sought to elucidate the processes involved in the synthesis and secretion of this lacrimal protein. Such studies have demonstrated that: [a] SC production by rat lacrimal tissue displays distinct, gender-related differences (i.e. glands of males produce significantly more SC than those of females);3,4 and [b] SC synthesis by rat lacrimal acinar cells is uniquely regulated by the endocrine, nervous and immune systems.5.6 Thus, SC production is stimulated by androgens, vasoactive intestinal peptide (VIP), β-adrenergic agonists (e.g. isoproterenol), interleukm-lα (EL-lα), interleukin-1β (IL-Iβ), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2), and suppressed by cholinergic agonists (e.g. carbachol choline). Moreover, these gender-associated and neuroendocrinimmune effects on lacrimal SC synthesis appear to be unique to the eye, given that SC production by other mucosal sites: [a] may show no sexual dimorphism (e.g. salivary, respiratory, intestinal, D.A. Sullivan, unpublished data); and [b] may be enhanced or inhibited, depending upon the tissue, by estrogens, progestins, glucocorticoids, prolactin, thyroxine, substance P and γ-interferon (γ-IFN),7–13 which agents have no demonstrable impact on the constitutive SC Output by lacrimal acinar cells.6
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neural endocrine and immune regulation of Secretory Component production by lacrimal gland acinar cells
Advances in Experimental Medicine and Biology, 1995Co-Authors: R W Lambert, R S Kelleher, Jianping Gao, Alexandra L Wickham, David A SullivanAbstract:Our previous research has shown that the endocrine, nervous and immune systems regulate the production of Secretory Component (SC), the polymeric immunoglobulin receptor, by acinar (epithelial) cells from the rat lacrimal gland.1 Thus, acinar cell exposure in vitro to androgens (e. g., dihydrotestosterone [DHT]), vasoactive intestinal peptide (VIP), the adrenergic agonist, isoproterenol, cyclic AMP analogues (e. g., 8-bromoadenosine 3’:5’- cyclic monophosphate [bcAMP]), cyclic AMP inducers (e. g., cholera toxin, PGE2), phosphodiesterase inhibitors (e. g., 3-isobutyl-l-methylxanthine), IL-lα, IL-lβ, or TNF-α results in a significant increase in SC output.2-4 Conversely, cellular treatment with the cholinergic agent, carbachol, causes a significant suppression of both androgen-induced and basal SC release by acinar cells.3,4
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neuroendocrinimmune modulation of Secretory Component production by rat lacrimal salivary and intestinal epithelial cells
Investigative Ophthalmology & Visual Science, 1994Co-Authors: R W Lambert, Jp Vaerman, R S Kelleher, L A Wickham, David A SullivanAbstract:Purpose. To evaluate the kinetics, receptor specificity, molecular basis, and site selectivity of the endocrine and neural regulation of Secretory Component (SC) synthesis by rat lacrimal gland acinar cells. Methods. Acinar cells from male rat lacrimal and submandibular glands, as well as epithelial cells (IEC-6) from the rat small intestine, were cultured in supplemented, serum-free media and treated with dihydrotesterone, cholera toxin, carbachol, vehicle, or other agents for varying time periods. Media SC levels were measured by radioimmunoassay. Results. The authors' findings with lacrimal gland acinar cells demonstrate that: a significant, temporal delay exists between the initiation of stimulatory or inhibitory signals and the eventual cellular SC response to regulatory compounds; the parasympathetic analogue, carbachol, exerts a dual effect on SC output, i.e., an early stimulation (hours) followed by an extended suppression (days); the androgen and cholinergic control of SC is receptor-mediated; and the androgen modulation of SC may involve the induction of gene expression. In addition, the authors' results show that distinct, tissue-specific variations occur in the nature of SC regulation: Compounds that control SC output by lacrimal acinar cells do not necessarily alter SC production by epithelial cells from the rat submandibular gland or small intestine. Conclusions. These findings advance the authors' understanding of the neuroendocrine regulation of SC synthesis in acinar cells from the lacrimal gland. Moreover, the authors' results indicate that the nature of the neural, endocrine, and immune control of lacrimal SC may be unique.
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neural endocrine control of Secretory Component synthesis by lacrimal gland acinar cells specificity temporal characteristics and molecular basis
Advances in Experimental Medicine and Biology, 1994Co-Authors: R W Lambert, R S Kelleher, Jianping Gao, Alexandra L Wickham, David A SullivanAbstract:The ocular surface appears to be protected from bacterial and viral pathogens by polymeric IgA antibodies.1 These antibodies, which are produced by plasma cells in the lacrimal gland, bind to Secretory Component (SC) in the basolateral membrane of acinar epithelial cells, and are then transported to the apical membrane and secreted into tears.2 Of interest, the lacrimal secretion of sIgA, as well as free SC, appears to be significantly influenced by gender and hormones from the hypothalamic-pituitary-gonadal axis.2 Thus, almost 10 years ago, it was found that the concentrations of free SC and IgA in the tears of male rats were 2 to 5-fold higher than those in tears of female rats. These gender-associated differences in tear SC and IgA were shown to be caused by androgens.2 For example, castration led to a significant reduction in SC levels in tears of males, while having no impact on SC content in tears of females. In addition, administration of testosterone for 4 days to castrated male or female rats significantly increased tear SC levels. These studies showed that exposure of castrated rats to androgens resulted in alterations of lacrimal SC production.2 Moreover, later experiments demonstrated that this androgen control of SC, as well as IgA, is modulated by factors from the hypothalamus and pituitary.2 However, this research did not address whether androgens act directly on lacrimal tissue to change SC or IgA, or indirectly via an androgen-sensitive site, which in tum acts to modulate lacrimal SC and IgA.
Peter Krajci - One of the best experts on this subject based on the ideXlab platform.
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different regulatory pathways employed in cytokine enhanced expression of Secretory Component and epithelial hla class i genes
European Journal of Immunology, 1999Co-Authors: Ellen M Nilsen, Peter Krajci, Dag Kvale, Finneirik Johansen, Per BrandtzaegAbstract:The transmembrane Secretory Component (SC, or pIg receptor) plays a crucial role in mucosal immunity by translocating dimeric IgA and pentameric IgM through exocrine epithelia. This receptor is up-regulated by cytokines in parallel with increased epithelial HLA expression. By use of the human epithelial cell line HT-29m3, we show that IFN-gamma, TNF-alpha and IL-4 activate transcription of the SC gene. This activation was slow, suggesting mediation via newly synthesized protein factors. IFN-gamma and TNF-alpha, but not IL-4, also up-regulated expression of HLA class I genes. However, this gene induction was rapid and did not depend on new protein synthesis. Nuclear run-on experiments showed that the transcription rate of HLA class I genes nearly peaked after only 30 min of IFN-gamma or TNF-alpha stimulation, whereas the SC transcription rate did not peak until after 20-36 h of IFN-gamma, TNF-alpha or IL-4 stimulation. Gel electrophoresis mobility shift assays demonstrated binding of nuclear proteins from cytokine-stimulated HT-29 cells to consensus elements in the promoter of the SC gene, involving the binding site for the nuclear factor-kappaB p50 subunit after TNF-alpha stimulation, and IFN-stimulated response element after IFN-gamma stimulation (and weakly after TNF-alpha. Our observations in vitro likely parallel events in vivo by which activated mucosal T cells and macrophages enhance pIg receptor-mediated external transport of Secretory IgA and IgM and up-regulate epithelial HLA expression.
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interferon gamma stimulation of messenger rna for human Secretory Component poly ig receptor depends on continuous intermediate protein synthesis
Scandinavian Journal of Immunology, 1993Co-Authors: Peter Krajci, Dag Kvale, Kjetil Tasken, Per BrandtzaegAbstract:Secretory Component (SC or poly-Ig receptor) plays a key role in mucosal external body fluids. The aim of this study was to elucidate the molecular events underlying IFN-γ-dependent up-regulation of SC. Using a human SC cDNA clone isolated by our laboratory, we found that IFN-γ up-regulated SC mRNA levels in a time- and concentration-dependent manner. Moreover, in situ hybridization showed a striking increase of SC mRNA-positive HT-29 cells after IFN-γ treatment. Inhibition with 5,6-dichloro-l-β-ribofuranosyl-benzimidazole (DRB) indicated a half-life for IFN-γ-induced SC mRNA of approximately 1 h. Cycloheximide (CHX) abolished the IFN-γ-induced accumulation of SC mRNA in a reversible manner; the time-course suggested that de novo synthesis of protein factor(s) with a turnover time shorter than 6 h was required for accumulation of SC message. IFN-γ-stimulated up-regulation of SC expression therefore appears to depend on molecular events similar to those taking place for the activation of several other genes in the Ig supergene family.
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epithelial expression of hla Secretory Component poly ig receptor and adhesion molecules in the human alimentary tract
Annals of the New York Academy of Sciences, 1992Co-Authors: Per Brandtzaeg, Dag Kvale, Peter Krajci, T S Halstensen, Henrik S Huitfeldt, Helge Scott, P S ThraneAbstract:Epithelial HLA class II is differentially expressed (DR >> DP) only after birth in salivary glands and small intestinal mucosa, in contrast to class I determinants and Secretory Component (SC) which appear early in gestation. However, there is a brisk postnatal increase in SC expression along with the class II induction, suggesting stimulation by cytokines from activated immune cells. T lymphocytes remain quite scanty in postnatal salivary glands, and the striking SC and class II expression might reflect a synergistic effect of IFN-gamma and TFN-alpha on immature epithelial cells. Enhanced epithelial expression of both SC and class II in salivary glands from sudden infant death victims could be the effect of immunostimulation caused by an infectious agent. Strikingly upregulated SC and epithelial class II expression (DR > DP > DQ) is seen in various inflammatory lesions such as obstructive sialadenitis, Sjogren's syndrome, chronic gastritis, and celiac disease. IFN-gamma and TNF-alpha are most likely involved as the expression patterns can be reproduced with these cytokines in vitro on colonic epithelial cell lines. However, these molecules of the Ig supergene family do not show a selective response in epithelia of inflammatory lesions because increased expression is also seen for lysozyme, lactoferrin and some other proteins. ICAM-1 can be upregulated on epithelial cells by various cytokines in vitro although the situation remains uncertain in mucosal inflammation. The expression pattern in IBD is complicated by dysplastic epithelial changes leading to reduced SC levels which may thus, in turn, jeopardize the poly-Ig transport mechanism. Epithelial class II molecules appear to have antigen-presenting properties, but the immunopathologic role of their increased expression in inflammatory disease in terms of induction of autoimmunity and/or abrogation of oral tolerance is a matter of continuing dispute.
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molecular cloning and exon intron mapping of the gene encoding human transmembrane Secretory Component the poly ig receptor
European Journal of Immunology, 1992Co-Authors: Peter Krajci, Dag Kvale, Kjetil Tasken, Per BrandtzaegAbstract:Secretory Component (SC or the poly-Ig receptor) plays a crucial role in mucosal immunity by translocating polymeric IgA and IgM through Secretory epithelial cells into external body fluids. Labeled restriction fragments from human SC cDNA were used to screen a human genomic leukocyte library. Three overlapping clones, spanning a total of 19 kb of the human SC gene, including 3 kb of the 5' flanking region, were characterized. The putative TATA box candidate, preceded by a CAAT-like box, was found 329 nucleotides upstream of the first exon. Altogether 11 exons covering the entire coding region were identified. The exon size ranged from 59 to 657 nucleotides and exon-intron junctions followed known consensus sequences. Three of the five extracellular Ig-related domains (D1, D4 and D5) were confined to one exon each (E3, E5 and E6), whereas D2 and D3 were encoded by the same exon (E4). The latter exon corresponds to that involved in alternate splicing of rabbit SC. The membrane-spanning segment was confined to part of one exon (E8). The cytoplasmic tail was encoded by four exons (E8-E11), whose boundaries encompassed fairly well the structural determinants proposed to be responsible for intracellular sorting of SC in the rabbit. The polymorphic restriction site reported earlier for Pvu II was localized to the third intron.
