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PubMed2004

Oligosaccharide side chains on human secretory IgA serve as receptors for ricin.

Secretory IgA (sIgA) Abs are polymeric Igs comprised of two or more IgA monomers joined together at their C termini and covalently associated with a 70-kDa glycoprotein called secretory component. As the predominant Ig type in gastrointestinal sections, sIgA Abs are centrally important in adaptive immunity to enteropathogenic bacteria, viruses, and toxins. In this study, we demonstrate that sIgA Abs may also function in innate defense against ricin, a naturally occurring, galactose-specific plant lectin with extremely potent shiga toxin-like enzymatic activity. In lectin blot overlay assays, we found that ricin bound to secretory component and the H chain of human IgA, and this binding was inhibited by the addition of excess galactose. The toxin also recognized IgM (albeit with less affinity than to IgA), but not IgG. Ricin bound to both human IgA1 and IgA2, primarily via N-linked oligosaccharide side chains. At 100-fold molar excess concentration, sIgA (but not IgG) Abs inhibited ricin attachment to the apical surfaces of polarized intestinal epithelial cells grown in culture. sIgA Abs also visibly reduced toxin binding to the luminal surfaces of human duodenum in tissue section overlay assays. We conclude that sIgA Abs in mucosal secretions may serve as receptor analogues for ricin, thereby reducing the effective dose of toxin capable of gaining access to glycolipid and glycoprotein receptors on epithelial cell surfaces.

Cell Polarity↗
PubMed1997

The conserved tetracysteine motif in the general secretory pathway component PulE is required for efficient pullulanase secretion.

The PulE component of the pullulanase secretion pathway, a typical main terminal branch of the general secretory pathway, has a tetracysteine motif (4Cys) that is also present in almost all of the many PulE homologues, including those involved in type-IV piliation and conjugal DNA transfer. The 4Cys resembles a zinc-binding motif found in other proteins such as adenylate kinases, which may be pertinent in view of the fact that PulE has a consensus ATP-binding motif and since at least one PulE homologue has been reported to have kinase activity. In PulE, the Cys residues of this motif form scrambled intra- and intermolecular disulfide bonds when cells are disrupted. Replacement of one or more Cys of this motif by Ser reduces PulE function, but at least two adjacent Cys must be replaced to prevent intramolecular disulfide bond formation.

Adenosine Triphosphate↗
PubMed1985

Intermediate-sized filaments and specific markers in a human salivary gland adenocarcinoma cell line and its nude mouse tumors.

The adenocarcinoma cell line HSG from human salivary gland, which proliferates in vitro or in nude mice, was examined by the immunoperoxidase method for the expression of three different types of intermediate-sized filaments (IFs) and of specific antigens such as carcinoembryonic antigen, S-100 protein, secretory component, lactoferrin, myosin, tropomyosin, and actin. The cultured HSG cells were found to express three different types of IFs defined by antibodies to keratin, vimentin, and desmin. In HSG cells proliferating in vitro at 34 degrees C and 37 degrees C but not at 39 degrees C, the expression of tropomyosin and carcinoembryonic antigen was observed, although myosin and S-100 protein were not detected. The expressions of actin, lactoferrin, and secretory component were restricted to cultured HSG cells at 39 degrees C and 37 degrees C, respectively. Transplantation of HSG cells into nude mice resulted in the establishment of a nude mouse system with malignant characteristics such as invasion and metastasis. The expression of IFs in the primary tumors was restricted to keratin and desmin IFs, whereas coexpression of keratin, vimentin, and desmin IFs was observed in some neoplastic cells present in the metastatic tumors in regional lymph nodes and lung. In addition, expression of actin, myosin, tropomyosin, and S-100 protein was found in the metastatic tumors, whereas myosin and S-100 protein were not detected in the primary tumors. Moreover, the metastatic tumors were almost occupied by the neoplastic cells with oncocytic changes, although oncocytic change was not found in the cultured HSG cells and their primary tumors.

Adenocarcinoma↗
PubMed1986

Production of secretory immunoglobulin A in rat self-filling blind loops. Local secretory immunoglobulin A immune response to luminal bacterial flora.

The immunoglobulin A (IgA) response to small intestinal bacteria was studied in rats with self-filling blind loops (SFBLs), surgically constructed in continuity with the intestine or at the end of a Roux-en-Y loop (RY-SFBL) so as to avoid filling with chyme. Total bile salt in the RY-SFBL lumen was much lower (4.35 +/- 0.8 mumol) than in the SFBL lumen (116 +/- 15 mumol), but other parameters, such as the number of anaerobic bacteria and disaccharidase activities were similar. Within 1 wk of establishing the blind loops, they had accumulated at least 14 times as much IgA as found in the normal jejunum. Luminal IgA per milligram mucosal protein was almost as high in the RY-SFBL as in the SFBL, indicating that a significant proportion of the IgA must be nonbiliary and probably mucosal in origin. Oral treatment with lincomycin significantly reduced luminal IgA accumulation in the RY-SFBL. Column chromatography and enzyme-linked immunosorbent assay (ELISA), which employed antirat secretory component antibody, established that the majority of the luminal IgA was nonmonomeric and complexed with secretory component. Centrifugation of luminal contents to separate soluble and particulate bound IgA showed that the RY-SFBL contained a higher proportion of precipitable IgA than either the SFBL or lincomycin-treated RY-SFBL. Immunoglobulin A eluted from the precipitates by KSCN was bound to a greater extent by bacterial sonicates than IgA in the supernatant. For either precipitate or supernatant IgA, the greatest binding was observed when the IgA was obtained from the RY-SFBL. These observations indicate that rat intestinal mucosa rapidly responds to bacterial overgrowth by secreting secretory immunoglobulin A (sIgA) with specificity for luminal bacterial antigens. As the sIgA present within the SFBL is to a certain extent derived from bile, the lower proportion of SFBL sIgA bound by bacterial antigens than of RY-SFBL sIgA suggests that biliary sIgA is less specific for local antigens than the sIgA that is secreted by the local mucosa.

Animals↗
PubMed1984

Breast-milk antimicrobial factors of rural Gambian mothers. I. Influence of stage of lactation and maternal plane of nutrition.

The concentrations of IgA, IgG, IgM, C3, C4, lactoferrin, lysozyme and secretory component in the mature breast milk of 152 rural Gambian mothers were measured up to 26 months lactation. The concentrations and daily secretion of all the immunoproteins, except lysozyme, decreased during the first year of lactation, but were well maintained thereafter. The production of lysozyme increased progressively throughout lactation. Compared with 10 mothers in Cambridge, U.K., the daily secretion of IgG, IgM, C3 and C4 was higher in The Gambia, that of IgA and lactoferrin was similar in the two communities, and that of lysozyme and secretory component was lower in The Gambia. A dietary supplement given to 90 Gambian mothers, raised the mean daily energy intake from a maximum of 1650 kcal/day and a hungry-season minimum of 1 200 kcal/day to 2 300 kcal/day throughout the study. The supplement did not enhance the production of breast milk immunoproteins.

Complement C3↗
PubMed1986

Salivary antibody responses to oral and parenteral vaccines in children.

Salivary IgA antibody to poliovirus and tetanus toxoid was measured in whole salivas of 151 children between 2 and 48 months of age from North America and from Scandinavia. Children from urban and suburban populations in the greater Boston, MA, area receive both oral poliovaccine and a parenteral injection with tetanus toxoid (TT), initially at approximately 2 months of age. Children from Göteborg, Sweden, initially receive parenteral injections of TT at 2 months of age and parenteral injections of killed polio vaccine initially at 9 to 10 months of age. Twenty-six percent of the Boston subjects who were less than 12 months old had detectable salivary IgA antibody to poliovirus after oral immunization. In contrast, within the first year after parenteral immunization with killed poliovirus, the Swedish group had detectable salivary antibody in 9% (1 of 13) of the subjects. Forty to 65% of the children in the older Boston-area age groups had positive salivary IgA antibody levels to this antigen. No differences were seen in salivary IgA antibody to TT among the three populations. By 36 months of age at least 50% of all populations had detectable salivary antibody to TT. The ratio of enzyme-linked immunosorbent assay (ELISA) activity using rabbit anti-human secretory component versus rabbit anti-human alpha chain was significantly higher in subjects less than 12 months of age compared with older groups. This suggested either that free secretory component was binding to tetanus toxoid or that secretory antibody of isotypes other than IgA was present in these youngest subjects.

Age Factors↗
PubMed1990

Detection of secretory IgM in tears of IgA deficient individuals.

Tears from normal (n = 5) and serum IgA deficient (n = 3) individuals were investigated for the presence of secretory Immunoglobulin A (sIgA), sIgM and free secretory component (SC) by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) using 10-15% gradient minigels (PhastSystem), followed by immunoblotting using various immunological probes. Tear samples were treated in denaturing (SDS) sample buffer under non-reducing as well as reducing conditions, prior to analysis. All normal tear samples contained sIgA as well as free SC (estimated MW: 82kD) but only traces of IgM. Tears from the three serum IgA deficient subjects lacked sIgA but did contain free SC. In two of them sIgM was clearly detected and after treatment of tears with reducing agent, IgM (mu) heavy chain fragments (estimated MW: 78kD) were identified and could be distinguished from other tear proteins after SDS-PAGE. These findings indicate lacrimal secretion of free secretory component, even in the absence of its ligand. On the ocular surface, sIgM may play a compensatory role in IgA deficiency.

Adult↗
PubMed1992

Sudden infant death syndrome victims show local immunoglobulin M response in tracheal wall and immunoglobulin A response in duodenal mucosa.

Twenty-two sudden infant death syndrome (SIDS) cases and 22 controls were examined immunohistochemically with regard to IgA, IgM, and IgG plasma cells in tracheal wall and duodenal mucosa. Furthermore, the presence of secretory component in tracheal surface and gland epithelium as well as in duodenal crypt and villus epithelium were evaluated. The examined specimens were obtained at autopsies. The control groups consisted of 11 infants who died of noninfectious causes and 11 who died of infections. In the tracheal wall, the SIDS group had higher IgM cell numbers than the control group that died of noninfectious causes (p less than 0.01), whereas the SIDS victims had lower IgA and IgM cell numbers than the infectious control group (p less than 0.01). In the duodenal mucosa, the SIDS group had significantly higher IgA cell numbers than the noninfectious control group (p less than 0.02) but lower IgA cell numbers than the infection group (p less than 0.01). Secretory component was present in the epithelium from all SIDS cases and controls, both in the tracheal wall glands and in the duodenal crypt mucosa. These findings indicate that the mucosal immune system is stimulated in SIDS.

Antibody-Producing Cells↗
PubMed1986

Isolation and characterization of different clones including myoepithelial-like variants from a clonal neoplastic epithelial duct cell line of human salivary gland origin.

A clonal neoplastic epithelial duct cell (HSGc) of human salivary gland origin has a fine structure similar to the intercalated duct cell and the capacity to express secretory component and lactoferrin. HSGc cells tend to form an occasional glandular arrangement in vitro and in vivo, and transplantation of cells into nude mice resulted in production of adenocarcinoma. By repeated single cell cloning, different types of clones could be isolated from HSGc. Cuboidal clones resemble the parent cell, but fail to form the glandular arrangement or express lactoferrin, suggesting a less differentiated type. Elongated clones have a fine structure similar to myoepithelial cells and carry myoepithelial markers such as S100 protein, actin, and myosin which are not detected in the HSGc and its cuboidal clones. These myoepithelial-like clones are able to express secretory component, lactoferrin, and lysozyme and to produce glycosaminoglycans, suggesting that they are a functionally active form of the neoplastic cell but different from the normal myoepithelial cell. Judging from their growth properties in vitro and in vivo, the myoepithelial-like clones are less malignant than HSGc or its cuboidal clones. Of four elongated clones, two did not produce tumors in athymic mice, while all of the cuboidal clones were tumorigenic. These findings suggest a possible conversion of the neoplastic duct cell to myoepithelial-like variants with low malignancy.

Actins↗
PubMedDate not supplied

Intracellular processing of human vs. rat immunoglobulin A in the rat liver.

It is well established that in the rat, rat dimeric IgA is transported from blood to bile across rat liver parenchymal cells via a series of minute smooth membrane-limited vesicles. This pathway is unique from that taken by a number of other ligands, which are internalized for degradation, in that there appears to be little involvement of coated vesicles, multivesicular bodies and lysosomes. The transmembrane receptor for IgA, secretory component, is not recycled but is secreted in part with the ligand into bile and must be produced continuously within the liver cell. Several recent studies have suggested that the receptor for asialoglycoproteins, as well as the structures involved in its processing, may play an important role in IgA processing. It was noted, however, that in all of these studies human polymeric IgA1 was used in the rat model. Using purified rat and human IgA preparations, we have demonstrated by light and quantitative electron microscopic autoradiography, as well as by certain biochemical procedures, that the two ligands are processed quite differently from one another in the rat. Human IgA disappears from the plasma at a slower rate and is much less efficiently transported into the bile. In addition, up to as much as 30% of the human IgA is diverted to the lysosomal pathway. This diversion of human polymeric IgA may be related to either the association of a serine-linked oligosaccharide at the hinge region of the human polymeric IgA1 or that large polymers, often found in human IgA preparations may initiate secretory component receptor aggregation, which in turn, interferes with the normal physiological processing of the IgA molecule.

Animals↗
PubMedDate not supplied

Recent studies of the interaction of rabbit dimeric IgA with its polymeric immunoglobulin receptor.

Rabbit secretory components (SC) constitute a highly heterogeneous population of glycoprotein molecules that are present in secretions as free or bound forms to polymeric immunoglobulins (Ig). Two SC families are known, one of high molecular weight (approximately equal to 80 Kd) composed of five (perhaps six) domains related to Ig variable domains, and one of low molecular weight (approximately equal to 55 Kd). An account of our most recent experimental data is reviewed in this article. We have shown: 1) that both the high and low Mr SC families possess the same relative avidity for binding to dimeric IgA of the g-subclass; 2) that the first NH2-terminal domain of SC derived from the high and low Mr polypeptides is necessary and sufficient for efficient non-covalent binding to dimeric IgA of the g-subclass; 3) that the low Mr SC polypeptide derives from the high Mr SC by the internal deletion of the entire second and third domains, suggesting that these domains are not involved in the binding reaction with polymeric Ig; 4) that the heterogeneity of rabbit secretory components is, in large part, due to the expression of several polymorphic forms (allotypes) susceptible to be recognized by specific alloantisera; the biochemical characterization of the three known SC allotypes (t61, t62 and t63) reveals that t62 and t63 are structurally very similar to each other and markedly divergent from the t61 homologue; 5) that by using non-cross-reactive alloantisera, the major immunodominant allotopes are confined within the COOH-terminal domains 3, 4 and 5 of SC; 6) that the location of the residues involved in the attachment of the carbohydrate unit within domain 1 varies according to the allotype: t61 is N-linked glycosylated at position 70, whereas about 75% of t62 molecules are devoid of sugars; the remaining 25% of t62 molecules are glycosylated at residue position 90; these oligosaccharide chain units are linked to asparagine residues in the acceptor site consensus sequence, Asn-X-Thr/Ser; 7) that the presence of the carbohydrate unit in domain 1 is not required for efficient binding of this domain to polymeric Ig: indeed, after enzymatic deglycosylation, domain 1 exhibits a relative binding avidity which is indistinguishable from that of the native glycosylated domain 1.

Amino Acid Sequence↗
PubMed1981

J chain is covalently bound to both monomer subunits in human secretory IgA.

Previous work has established that the secretory component (SC) in human secretory IgA is covalently linked to only one of the two IgA monomer subunits, but it has not been clear whether the J chain is covalently linked to one or to both of these subunits. In view of the asymmetry in the disulfide bonding between SC and the IgA subunits, an arrangement which follows disulfide interchange, several models for the disulfide linkage of J chain and the bonds between IgA subunits were envisaged and investigated. When sIgA was gel filtered through Sephadex G-200 in acetic acid, a single major symmetrical peak eluted at the front. This material contained SC, alpha and L chains, and all of the J chain. The greater resolution afforded by polyacrylamide gel electrophoresis in detergent confirmed that human sIgA contains no major noncovalently linked components in the 150,000-200,000 molecular weight range. In another series of experiments the Fc monomer, which is not covalently attached to SC, isolated after treatment of sIgA with IgA protease and cyanogen bromide, was investigated to learn whether alpha chain COOH-terminal octapeptides could be released by reduction. The results were negative. The available data thus favor a model in which J chain is disulfide-bonded to both IgA monomer subunits in sIgA.

Colostrum↗
PubMed1983

Specific quantitation of secretory immunoglobulin A with enzyme immunoassay using activated thiol--Sepharose for separation method.

A specific and sensitive enzyme immunoassay system for human secretory IgA was developed using anti-alpha-chain antibodies coupled to activated thiol-Sepharose, and anti-secretory component antibodies labeled with beta-D-galactosidase from Escherichia coli. The dose response of the enzyme activity in eluate was observed between 3 and 1000 ng of secretory IgA with little cross-reactions with IgA, IgG, IgM and secretory component. The assay method could be employed for the measurement of secretory IgA in saliva, urine, feces, intestine and serum without interferences by the abundant IgA in the same samples.

Animals↗
PubMed1998

An exocytotic mutant of Paramecium caudatum: membrane fusion without secretory contents release.

This is a detailed characterization of a secretory mutant incapable of releasing secretory contents despite normal exocytotic membrane fusion performance. Trichocyst non-discharge strain tnd1 of Paramecium caudatum and its wildtype (wt) both show a transient cortical [Ca2+]i increase and exocytotic membrane fusion in response to the polyamine secretagogue, aminoethyldextran (AED), or to caffeine. tnd1 cells frequently display spontaneous Ca2+ signals parallelled by spontaneous exocytotic membrane fusion. This remains undetected, unless the trichocyst matrix is shown to be freely accessible to the inert, non-membrane permeable fluorochrome, F2FITC, from the outside. In these tnd1 cells, spontaneous and AED- or caffeine-induced membrane fusion, always without contents expulsion by decondensation (i.e. several-fold stretching), is ascertained by electron microscopy. Exocytotic openings, with condensed trichocysts retained, may persist for hours without impairing cells. Trichocyst decondensation normally requires micromolar [Ca2+]e, but an increase to 10 mM has no effect on tnd1 trichocyst expansion in vivo or in vitro (when isolated and exposed to ionophore A23187 + Ca2+). Paracrystalline packing of the major secretory components (trichynins) does occur, despite incomplete proteolytic precursor processing (according to SDS-PAGE). However, 45Ca(2+)-binding by secretory components is considerably reduced--the likely cause of the non-discharge phenotype. Our findings imply significant untriggered membrane fusion in a system normally following the triggered pathway and clear separation of exocytotic membrane fusion from any later Ca(2+)-dependent steps of the secretory cycle.

Animals↗
PubMed2000

An ELISA method to measure total and specific human secretory IgA subclasses based on selective degradation by IgA1-protease.

We have taken advantage of the property of IgA1-proteases to selectively cleave the human IgA1 subclass into Fabalpha and Fcalpha-J chain-secretory component (Fcalpha-J-SC) fragments in order to design a novel ELISA method for measuring the two secretory IgA (S-IgA) subclasses in secretions. The assay is based on the loss of detection of S-IgA1 by a combination of peroxidase-labelled antibodies to secretory component and Fab following IgA1-protease treatment. The specificity is that of the protease and the sensitivity of the detection is 5 ng/ml. Moreover, the use of purified S-IgA1 and S-IgA2 controls is not necessary. The assay has been successfully applied to the analysis of colostral S-IgA antibodies (Abs) to HIV-1-gp160 from HIV-1 positive women. The major subclass of colostral S-IgA antibodies to gp160 was found to be of the alpha1 isotype but the specific activity of anti-HIV-gp160 S-IgA2 was, however, higher than that of S-IgA1.

Adult↗
PubMed2003

Immunopathological study of mesonephric lesions of cervix uteri and vagina.

Seventeen cases of mesonephric cervical remnants, four cases of mesonephric cervical carcinoma and nine vaginal Gardner cysts were studied by histochemical and immunohistochemical methods for the presence of mucin, proteoglucans, glucogen, CEA, cytokeratins, secretory component and vimentin. Mesonephric lesions in contrast to endocervical glandular lesions are negative for mucin, glucogen, CEA, and secretory component and positive for vimentin, and broad spectrum cytokeratins. Mesonephric carcinomas present certain immunopathological characteristics that permit their identification and proper treatment.

Adenocarcinoma↗
PubMed1990

[Measurement of secretory IgA in salivary juice and the localization of secretory IgA in duodenal mucosa in patients with IgA nephropathy].

In order to clarify whether or not the local IgA immune system plays a role on the pathogenesis of IgA nephropathy, we measured serum levels of IgA, serum and salivary levels of secretory IgA in patients with IgA nephropathy and in healthy subjects, and compared them with the results of immunohistochemical study of the duodenal mucosa obtained from patients with IgA nephropathy and healthy subjects. The results were as follows. 1. The serum levels of IgA were significantly higher in patients with IgA nephropathy than in healthy subjects. 2. The salivary levels of secretory IgA were significantly higher in patients with IgA nephropathy and non IgA nephropathy than in healthy subjects. 3. There was no significant difference in the serum levels of secretory IgA between patients with IgA nephropathy and healthy subjects, but they were significantly higher in patients with hematuria than without hematuria. 4. The salivary levels of secretory IgA were lower in some patients with IgA nephropathy, in spite of the intense staining of the secretory component and J chain in the duodenal mucosa, than in healthy subjects. On the other hand, the salivary levels of secretory IgA were lower in other patients with IgA nephropathy, in addition to the weak staining of secretory component and J chain in the duodenal mucosa than in healthy subjects. These results suggested that the disorder of IgA mucosal immunity may contribute to the pathogenesis of IgA nephropathy.

Adult↗
PubMed1989

An increased pool of secretory hormones and peptides in adrenal medulla of stroke-prone spontaneously hypertensive rats.

Secretory components of the adrenal medulla were compared in normotensive Wistar-Kyoto (WKY) rats and in stroke-prone spontaneously hypertensive rats (SHRSP) at both 4 and 12 months of age. Noradrenaline, adrenaline, dopamine, neuropeptide Y, and chromogranins A and B were significantly higher in adrenal glands of SHRSP than those of WKY rats at 4 months. At 12 months, the levels of these components in SHRSP had increased even more (about 200% in WKY rats). There was no change in the relative composition of the adrenal "secretory cocktail." Neither the chromogranin A/chromogranin B ratio nor their apparent proteolytic processing in chromaffin granules differed between SHRSP or WKY rats. The lack of a significant change in membrane-bound cytochrome b561 and the small increase in dopamine beta-hydroxylase suggest that the higher levels of secretory components in SHRSP are not simply caused by an increase in the number of chromaffin granules, but possibly by a selective increase in the secretory content of these organelles providing a larger package for quantal release by exocytosis. This may be relevant for the elevation of blood pressure in this strain. The immunological methods described in this paper allow for the first time a determination of the secretory quantal levels in catecholamine storage. This should be useful for further studies in hypertensive models.

Adrenal Medulla↗