Cloning, chromosomal localization, and linkage analysis of the gene encoding human transmembrane secretory component (the poly-Ig receptor).
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Amino Acid Sequence↗
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Binding of secretory component to dimers of immunoglobulin A in vitro. A model for the interactions of the two moieties in secretory immunoglobulin A.
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Binding Sites↗
Neural, endocrine and immune regulation of secretory component production by lacrimal gland acinar cells.
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Acetylcholine↗
Subclass distribution and the secretory component of serum IgA anti-ganglioside antibodies in Guillain-Barré syndrome after Campylobacter jejuni enteritis.
Previously, we reported that IgA anti-GM1 antibody is more closely associated with preceding Campylobacter jejuni enteritis in Guillain-Barré syndrome (GBS) than are IgG and IgM antibodies. However, the mechanism of the induction of IgA anti-ganglioside antibodies is not clear. In this study, serum IgA antibodies against GM1, GM1b, and GD1a, and GalNAc-GD1a were examined in 152 GBS patients. In GBS, antecedent C. jejuni infection is closely associated with IgA antibodies, other than GM1, against GM1b. The IgA subclass distribution is completely restricted to IgA1, no secretory IgA anti-ganglioside antibody being detected. This result does not support the hypothesis that the serum IgA antibodies present in GBS after C. jejuni enteritis originate at mucosal sites, such as the gut mucosal immune system. Seventeen (85%) of 20 patients with IgA anti-ganglioside antibodies had serological evidence of C. jejuni infection and/or a history of antecedent diarrhea. Moreover, a motor nerve conduction study showed that patients with IgA antibodies frequently had axonal neuropathy, whereas none had demyelinating neuropathy. This may support the previous report that IgA isotype anti-GM1 antibodies are more closely associated with poor outcome than are the IgG or IgM isotypes. The induction mechanism of IgA anti-ganglioside antibodies must be clarified by determining whether concentrations of cytokines, which increase the IgA class switch, are elevated in patients with GBS after C. jejuni enteritis.
Antibodies↗
Secretory component is cleaved by neutrophil serine proteinases but its epithelial production is increased by neutrophils through NF-kappa B- and p38 mitogen-activated protein kinase-dependent mechanisms.
We previously showed that expression of polymeric immunoglobulin receptor (pIgR)/secretory component (SC), the epithelial receptor assuming transport of polymeric IgA in mucosal secretions, is strongly decreased in severe chronic obstructive pulmonary disease. Here, we evaluated in vitro the effects of polymorphonuclear neutrophil (PMN) mediators on pIgR/SC. On polyacrylamide gel electrophoresis analysis, soluble SC was rapidly cleaved by supernatants from phorbol-myristate-acetate-activated PMN, through a serine proteinase activity. Moreover, purified PMN serine proteinases also cleaved SC. Similarly, polymeric IgA was rapidly cleaved in monomers by neutrophil elastase, whereas secretory immunoglobulin A was relatively resistant to neutrophil elastase. Surface pIgR on human bronchial epithelial cells was also cleaved by serine proteinases, as shown by immunofluorescence. In contrast, pIgR/SC production by cultured epithelial cells (quantified by enzyme-linked immunosorbent assay) was significantly increased by supernatants from interleukin-8/formylmethionylleucylphenylalanine-activated PMN (122.6 +/- 17.3 versus 70.9 +/- 9 ng/mg protein, P < 0.01). Upregulation of pIgR/SC production by bronchial epithelial cells was abolished by nuclear factor kappa B- and p38 mitogen-activated protein kinase (MAPK) inhibitors. Moreover, supernatants from interleukin-8/formylmethionylleucylphenylalanine-activated PMN induced the phosphorylation of I kappa B-alpha and p38 MAPK in epithelial cells, independently of serine proteinases. Thus, PMN serine proteinases cleave pIgR/SC, whereas activated PMN induce an increased pIgR/SC expression through epithelial activation of nuclear factor kappa B and p38 MAPK pathways.
Bronchial Neoplasms↗
In vitro synthesis of immunoglobulins, secretory component, complement and lysozyme by human gastrointestinal tissues. II. Pathological tissues.
An in vitro culture technique has been used to study synthesis of proteins by biopsies of human gastrointestinal mucosa which were obtained at endoscopy or surgery from patients with biliary gastritis, atrophic gastritis, peptic ulcer, gastric cancer, coeliac disease, Crohn's disease and ulcerative colitis. As in normal mucosa, immunoglobulin synthesis was found in all sites, but marked increases, especially in IgG, were seen in biliary gastritis and ulcerative colitis. In untreated coeliac disease, synthesis of IgG and IgM was increased. Synthesis of complement components did not differ from that found in normal mucosa. Increased lysozyme synthesis was seen in Crohn's disease. This study shows that useful information may be acquired from short-term culture studies of the small biopsies obtained with fibre optic endoscopes.
Complement C3↗
Immunohistochemical characterization of intracellular J-chain and binding site for secretory component (SC) in human immunoglobulin (Ig)-producing cells.
J-chain staining of IgA- and IgM-producing immunocytes was significantly enhanced when tissue sections were pretreated with acid urea, apparently because molecular unfolding exposed concealed J-chains. This indicated substantial completion of the Ig polymers at the cytoplasmic level, which was verified by diffuse binding of SC in vitro to the cytoplasm of most J-chain-positive IgA and IgM cells. This process involved specific non-covalent forces which showed the same interrelation as that noted for isolated dimeric IgA and 19S IgM--the latter as well as IgM cells exhibiting stronger binding of SC than the IgA counterparts. Conversely, J-chain staining of IgD and IgG immunocytes was not enhanced by acid urea and these cells did not generally express affinity for SC; rare exceptions could apparently be ascribed to artifacts or dual isotype production including IgA or IgM polymers. Parallel demonstration of J-chain and SC binding seems to be the best available method for studies of polymer-producing immunocyte populations and offers the advantage of in situ evaluation of cell distribution in relation to morphology. The reliability of this approach was attested to by the fact that IgA immunocytes in all secretory tissues investigated (salivary, mammary and lacrimal glands; nasal and intestinal mucosae) expressed J-chain (87-97%) and SC affinity (84-87%) in comparable proportions, indicating that almost 90% of the cells were engaged mainly in dimer production. The observation that most IgD and 50-70% of the IgG immunocytes in secretory tissues expressed J-chain, has implications for the differentiation of B-cell clones homing to such sites. Conversely, IgG cells in extra-glandular tissues showed strikingly reduced J-chain production and such sites contained IgA immunocytes with heterogeneous expression of J-chain and SC affinity. Thus, in the extra-follicular area of palatine tonsils 70-80% of the IgA cells seemed to be pure monomer producers and the remainders apparently generated a mixed product. Most immunocytes in extra-glandular tissues may therefore belong to mature clones with completely or partially repressed J-chain synthesis.
Antibody Affinity↗
A comparison of secretory component - immunoglobulin interactions amongst different species.
1) SC from many species may be isolated by affinity chromatography to human IgA-Sepharose. 2) In some species SC may exist in two molecular forms. 3) The SC-binding sites on polymeric IgA and IgM are not identical. 4) In some species SC binds to IgM with higher affinity than to polymeric IgA while in other species SC binds best to polymeric IgA. This difference may influence the relative concentrations of these two immunoglobulin classes in the secretions of different species. 5) The SC-binding site is present on high molecular weight immunoglobulin in species as primitive as the nurse shark.
Animals↗
[Comparison between the use of anti-secretory-component (sc) antibodies and anti-mucin-like-cancer-antigen (MCA) antibodies in the identification of cancer cells in serous effusions].
Evaluation between Antibodies SC and MCA in identification of carcinomatous cells in serous effusions. Authors have tested with MAbs MCA and SC twenty-seven cell-blocks from malignant effusions (epithelial neoplasms) in order to investigate the capacity of each antibody to discriminate neoplastic cells from mesothelial cells; moreover the two antibodies have been tested in relation to PAS-diastase test to verify their sensitivity to mucin detection. The "Chi square" statistical test demonstrates that MCA is much better than SC for sensitivity towards neoplastic cells, but that the SC is the best between two antibodies as markers of mucous producing features, and preferable to PAS-diastase test for better standardisation and interpretation.
Antibodies, Monoclonal↗
Studies on J chain and binding site for secretory component in circulating human B cells. II. The cytoplasm.
About 0-3-1-1% of the lymphoid cells from peripheral blood of healthy adults contained cytoplasmic immunoglobulin (Ig). The class distribution of these B cells varied greatly among individuals, with a preponderance of the IgA (26-65%) or the IgG (15-66%) class. A remarkably high percentage of the Ig-containing cells were positive for cytoplasmic J chain regardless of the class (100% for IgM, 87-97% for IgA, 50-100% FOR IgD, and 43-88% for IgG cells). This feature probably reflects that the cells represent circulating blasts derived from the early expansion phase of B-cell clones. The antigenic determinants of the J chain were in most IgA-containing cells considerably masked, indicating that this subunit was "correctly" arranged in the IgA dimers at the cytoplasmic level in the manner demonstrated for intestinal IgA plasma cells.
Adult↗
Complex formation between secretory component and human immunoglobulins related to their content of J chain.
The J-chain content of 3 IgM and 24 IgA preparations was quantitated by an immunochemical technique after reduction with 20mM dithiothreitol. The amounts released ranged from undetectable (less than 0.1 mg) to 7.3 mg per 100 mg of Ig. Most of the J-chain-deficient proteins were monomeric, but four polymeric IgA preparations were found to contain only 0.2-0.8 mg of J chain per 100 mg. The SC-binding capacity of these polymers, expressed as percentage of the amount added (2.5 mu g SC/100 mug Ig), was 6%-12% compared with 69%-82% for IgA and IgM polymers that contained more than 4.0 mg of J chain per 100 mg. Some monomeric IgA preparations showed a slight SC-binding capacity, which was explained by the presence of contaminating J-chain-positive polymers. Bound J chain therefore seems to be a structural prerequisite for a specific noncovalent complexing of Ig polymers with SC.
Centrifugation, Density Gradient↗
Butyrate differentially affects constitutive and cytokine-induced expression of HLA molecules, secretory component (SC), and ICAM-1 in a colonic epithelial cell line (HT-29, clone m3).
In conclusion, we have found that physiological concentrations of butyrate increase the constitutive levels of HLA class I and SC molecules in HT-29m3 cells. Moreover, butyrate at high concentrations induces de novo synthesis of HLA-DR but not ICAM-1 molecules. Our data further showed that butyrate generally facilitates the cytokine-induced expression of immunological molecules in these cells but, interestingly, it specifically reduces the stimulatory effects of TNF and IL-4 on HLA class I and SC, respectively. We are currently studying how butyrate affects transcriptional regulation of the genes encoding these molecules. Further knowledge about the effects of butyrate in relation to gene regulation is required. It is possible that butyrate might interfere with specific, cytokine-dependent regulatory elements in certain genes which, in turn, could have implications for immune regulation of colonic epithelial cells in vivo.
Adenocarcinoma↗
Differences between the in vitro combinations of secretory component (SC) and immunoglobulin polymers (Ig) by enumeration of SC epitopes.
The enumeration of the SC epitopes has been established on 125I-labelled free and combined SC, by binding to anti-SC coated beads, then by addition of 3H-labelled anti-SC Fab' fragments of various specificities. The number of moles of Fab' fragments found on the beads increases in relation to the introduced amount. The extrapolation to an infinite concentration of added Fab' fragments gives the maximal theoretical accessible number of SC epitopes. The number of hidden epitopes (cryptotopes) is established by subtracting the total number found on sIgA, IgA-SC and IgM-SC from those found for free SC. These values are confirmed with Fab' fragments specific for the inaccessible determinant of SC. There are 4 cryptotopes in the case of sIgA, 3 for IgA1-SC, 2 for dimer IgA-SC and only 1 for IgM-SC (polyclonal or monoclonal). Thus the in vitro combinations of SC with polyclonal IgA dimers are different from the in vitro combinations with polyclonal or monoclonal IgM. The structural implications of these differences are discussed.
Epitopes↗
Behçet's disease: possible role of secretory component deficiency, synovial inclusions, and fibrinolytic abnormality in the various manifestations of the disease.
Detailed study of four patients with BD, four controls with recurrent aphthous stomatitis, and 12 healthy controls has demonstrated markedly decreased levels of salivary SC in both its free and bound forms, and normal total protein concentration in BD salivas. In two BD patients, SC deficiency was also found in jejunal fluids. Depressed in vitro response of blood T cells to mitogens was also noted in BD. Levels of IgA in serum were normal, as well as total numbers of T cells and IgA-carrying B cells in blood. A fluid phase abnormality of the fibrinolytic system as tested by the clot lysis assay was demonstrated in the blood from BD patients. Studies of BD SF and synovial membrane by light and electron microscopy showed inclusions composed of degenerated neutrophils inside monocytes. Abnormalities of host defense mechanisms at the mucous membrane level due to SC deficiency, together with a systemic T cell functional defect and fibrinolytic abnormality, could be important mechanisms in the pathogenesis of recurrent mucosal ulcers and thrombosis in BD.
Behcet Syndrome↗
Heterogeneous epithelial expression of class II (HLA-DR) determinants and secretory component related to dysplasia in ulcerative colitis.
The intensity and degree of heterogeneous epithelial marker expression were evaluated immunohistochemically in 29 mucosal biopsy specimens from 7 ulcerative colitis (UC) patients with dysplasia. Biopsy specimens from UC patients with mild (n = 7) or severe (n = 6) inflammation and from histologically normal samples (n = 7) served as controls. HLA-DR showed heterogeneous epithelial expression in all lesions with high grade dysplasia and in 6 of 8 with low grade dysplasia. SC was heterogeneous stained in 17 of 21 lesions with high grade dysplasia and in all but two lesions with low grade dysplasia. In histologically normal mucosa, SC was homogeneously expressed and epithelial DR was virtually absent. In mildly inflamed UC lesions, SC exhibited patchy distribution in only one sample and DR in two, whereas both SC and DR showed a slight degree of heterogeneous expression in all lesions with severe inflammation. Moreover, the overall intensity of SC staining tended to decrease with increasing degree of inflammation, whereas the opposite was seen for DR. Decreased SC and increased DR expression thus seemed to be related to intensified inflammatory activity, whereas heterogeneous expression of these markers was significantly more related to dysplasia.
Adolescent↗
The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA.
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.
Animals↗
Secretory component: the polymeric immunoglobulin receptor. What's in it for the gastroenterologist and hepatologist?
The primary function of the SC-pIg system is to secrete pIgs into various external secretions. The cellular mechanism responsible for this transport is schematically depicted in Figure 5. Polymeric immunoglobulin A, which is synthesized by plasma cells that are part of the mucosa-associated lymphoid tissue, gains access to the SC on the abluminal surface of epithelial cells by diffusion from sites of synthesis in mucosae or enters the blood circulation and is cleared, largely by hepatic transport, into bile. The pIgA binds to SC on the abluminal surface of the epithelial cells (and probably hepatocytes) initially by noncovalent interactions that are saturable, reversible, and specific for pIgA and IgM. Subsequently, covalent interaction between SC and its ligand occurs to a variable degree in different species. The SC-IgA complex is endocytosed by the epithelial cell or hepatocyte and is transported across the cell into the external secretions by a microtubule-dependent vesicular transport mechanism. At some point during the transport, the complex is rendered soluble by proteolytic cleavage of the membrane-associated SC molecule to release the soluble sIgA into the gland lumen or the canaliculus. In the intestinal lumen, SC helps protect the sIgA molecule from proteolytic degradation. The sIgA may play a major role in the mucosal defense against pathogenic organisms or harmful antigens. The SC-pIg system differs from many of the other known receptor-ligand interactions in several important ways. First, the synthesis or expression of the receptor (SC), or both, are not regulated by the concentration of the ligand. Second, SC probably is not dissociated from its ligand or recycled to the cell surface as it is secreted in complex with its ligand (pIg) into the external secretions. Third, the interaction of pIgs with their receptor does not function to regulate an intracellular process, but results in transcellular transport of the ligand, which acts in the external environment. Fourth, after initial noncovalent, reversible binding between the receptor and its ligand, the interaction becomes covalent by the formation of disulfide linkages between SC and the pIg. Finally, SC is initially inserted into the abluminal domain of epithelial cells as an integral membrane protein and subsequently is proteolytically cleaved to a soluble molecule which is secreted by the cell. Thus, in contrast to many cell-surface receptor-ligand interactions in which the ligand is ultimately degraded and the receptor is conserved, the SC-pIgA interaction results in partial proteolytic degradation of the receptor and conservation of the ligand.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
The spinal origin of the sympathetic nerve fibres to the vascular and secretory components of the rat submaxillary salivary gland.
The spinal origin of the sympathetic vasoconstrictor and secretory fibres to the submaxillary gland of the rat was identified in the pithed rat preparation by means of selective stimulation of small segments of the spinal outflow. Secretory and vascular responses were similar following stimulation in pithed rats to those following stimulation of the isolated superior cervical nerve trunk in anaesthetized rats. The spinal origin of the secretory and vascular fibres was coincident and it is concluded that if a separate control of blood flow and secretion by sympathetic fibres does exist that it must occur at the level of C.N.S. but that the nerves share a common pathway to the gland.
Animals↗