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PubMed1999

Carbohydrate moieties in human secretory component.

Human secretory component has seven putative sites for N-linked glycosylation. From tryptic and Glu-C digests we have isolated peptides encompassing asparagines 65, 72, 117, 168, 403, 451 and 481. Analysis by on line HPLC-electrospray mass spectrometry indicated that these residues were fully glycosylated and that the major carbohydrate moieties were far less diversified in composition than expected. Fast atom bombardment mass spectrometry performed on oligosaccharides released by peptide-N-glycosidase F treatment of fractionated and unfractionated SC digests showed the following glycan compositions: Fuc(2)Hex(5)HexNAc(4), Fuc(3)Hex(5)HexNAc(4), NeuAcFucHex(5)HexNAc(4), NeuAcFuc(2)Hex(5)HexNAc(4), NeuAc(2)Hex(5)HexNAc4 and NeuAc(2)FucHex(5)HexNAc(4). Three of these oligosaccharides are the major carbohydrate moieties in human lactoferrin. A possible biological role of the secretory component glycans in the protection of mucosal surfaces is discussed.

Amino Acid Sequence↗
PubMed1982

Serum IgM-bound secretory component (sIgM) in liver diseases: comparative molecular state of the secretory component in serum and bile.

The sera of 15 patients with liver disease and high serum concentrations of secretory component (SC) were analyzed by density gradient ultracentrifugation and radioimmunoassays for SC, IgA, and IgM to determine the molecular state of SC and IgA. Results in serum were compared to those obtained by simultaneous analysis of bile in five of the patients, and to those in serum and bile of a case of total IgA deficiency. Free SC was virtually not found in sera, although it was well represented in all bile, up to 88 and 97% of total bile SC in a case of complete biliary obstruction and in IgA deficiency, respectively. IgM-bound SC was found in all sera, amounting to 91% and 100% of total serum SC, respectively, in a case of acute hepatitis with a very high serum IgM concentration and in IgA deficiency. The proportions of SC bound to IgM and to polymeric IgA (p-IgA) in the sera correlated with their IgM/p-IgA molar ratio. This suggests that during liver disease, the hepatobiliary tissues could release free SC into the circulation, where it binds to p-IgA and IgM according to their respective concentrations and affinities for SC. The proportion of p-IgA in serum was not increased in four cases of biliary obstruction, in contrast to our cases of cirrhosis and acute hepatitis, indirectly supporting a minor transfer of p-IgA from blood to bile in humans, in contrast to rats and rabbits.

Acute Disease↗
PubMed1987

The structure of bovine secretory component.

Bovine secretory component (SC) has been cleaved with trypsin into a series of fragments and their N-terminal amino acid sequences have been determined. The close homology with the known sequence of human SC has enabled the sequential order of the fragments to be deduced. The results indicate that bovine SC consists of a single glycosylated polypeptide chain (Mr 74,000) folded into five globular immunoglobulin-like domains. A protein (Mr 94,000) has been isolated from detergent solubilised bovine epithelial membranes from liver, intestine and mammary gland. This membrane protein is specific for the binding of J-chain linked IgM and IgA dimers. It can be proteolytically cleaved into a water soluble SC-like portion and a detergent soluble hydrophobic portion. Bovine SC is therefore most likely to be the extracellular part of an epithelial receptor which mediates the transport of IgA dimers to mucosal surfaces. The various tryptic fragments from bovine SC have been shown to differ in their relative binding affinities for IgM and IgA dimers. The results imply that the first three domains of bovine SC are most involved in binding and domains 4 and 5 play subsidiary roles. Computerized prediction and modelling methods have been used to deduce possible tertiary and quaternary structures for SC. There are good indications that the molecule has an elonaged "zig-zag" structure stabilized by longitudinal inter-domain contacts. A model of SC bound to IgA dimer is presented.

Amino Acid Sequence↗
PubMed1979

Human secretory component. II. Easy detection of abnormal amounts of combined secretory component in human sera.

A simple method, allowing easy detection of abnormally increased sIgA levels is described. It consists in quantitation of combined SC by gel double diffusion, using appropriate anti-SC immune sera. The technical conditions, locating the threshold of sensitivity of precipitation at about 25 microgram/ml, a value higher than that found in normal sera, were established. Comparison with other classical methods (SRID, ELISA and IHA) emphasizes the validity and simplicity of the technique which has shown convenient whenever a large number of sera have to be tested.

Antibody Specificity↗
PubMed1981

Enumeration of the antigenic determinants of human secretory component (SC) and secretory IgA (sIgA).

The number of antigenic determinants of human SC and sIgA was determined with specific anti-SC antibodies isolated from a pool of two hyperimmunized sheep. The Fab' antibody fragments were prepared and [125I] labelled, while pure SC and pure sIgA, isolated from colostrum, were labelled with 131I. The [125I] Fab' antibodies were added, in very large molar excess, to the [131I] antigens at various ratios. The Fab'-Ag complexes were separated from the antibody excess by gel-filtration. The highest Fab'/Ag molar ratios of the complexes, which correspond to the maximal number of accessible antigenic determinants, were calculated. We found at least 16 sites (16.6 +/- 1.36) on free SC while only 12 (12.27 +/- 0.51) were located on sIgA. These results confirm the existence of a significant number of hidden determinants of the SC subunit of sIgA and establish that about 1/4 of the SC molecule is implied in this binding.

Binding Sites, Antibody↗
PubMed1975

Increased risistance of immunoglobulin A dimers to proteolytic degradation after binding of secretory component.

The contribution of secretory component to the stability of secretory IgA against proteolysis has been studied by a new approach, i.e., by comparing the proteolytic degradation of the complexes formed in vitro between these proteins and secretory component. The results show that attachment of secretory components to the dimeric backbone of the secretory IgA molecule is accompanied by a significantly increased resistance of this backbone against digestion by both trypsin and pepsin. This protective effect may be a physiologic function of secretory component or may be due merely to unspecific blocking by secretory component of one or more sensitive peptide bonds in the IgA backbone.

Absorption↗
PubMed1979

Structure of the carbohydrate chain of free secretory component from human milk.

Secretory component from human milk was found to contain 23.4% carbohydrate, which includes galactose, mannose, fucose, glucosamine, and sialic acid. Secretory component could be degraded by pronase or base-borohydride to yield the same, single type of carbohydrate chain. In the glycopeptide produced by pronase digestion, aspartic acid was the only amino acid present in molar quantities after amino acid analysis, which suggests that the carbohydrate moiety is linked to the polypeptide chain at asparagine residues. The positions of links between the various sugar units were studied by methylation analyses of: secretory component, periodate-oxidized and reduced secretory component, the fragment produced by base-borohydride treatment, and the pronase glycopeptide after treatment with specific glycosidases. Sugars released from the glycopeptide by various glycosidases were also quantitated. From the results of these studies a branched chain structure was assigned to the carbohydrate chain of secretory component.

Amino Acids↗
PubMed2002

Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo.

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.

Animals↗
PubMed1998

Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab')2: a possible implication for mucosal defense.

Secretory component (SC) represents the soluble ectodomain of the polymeric Ig receptor, a membrane protein that transports mucosal Abs across epithelial cells. In the protease-rich environment of the intestine, SC is thought to stabilize the associated IgA by unestablished molecular mechanisms. To address this question, we reconstituted SC-IgA complexes in vitro by incubating dimeric IgA (IgAd) with either recombinant human SC (rSC) or SC isolated from human colostral milk (SCm). Both complexes exhibited an identical degree of covalency when exposed to redox agents, peptidyl disulfide isomerase, and temperature changes. In cross-competition experiments, 50% inhibition of binding to IgAd was achieved at approximately 10 nM SC competitor. Western blot analysis of IgAd digested with intestinal washes indicated that the alpha-chain in IgAd was primarily split into a 40-kDa species, a phenomenon delayed in rSC- or SCm-IgAd complexes. In the same assay, either of the SCs was resistant to degradation only if complexed with IgAd. In contrast, the kappa light chain was not digested at all, suggesting that the F(ab')2 region was left intact. Accordingly, IgAd and SC-IgAd digestion products retained functionality as indicated by Ag reactivity in ELISA. Size exclusion chromatography under native conditions of digested IgAd and rSC-IgAd demonstrates that SC exerts its protective role in secretory IgA by delaying cleavage in the hinge/Fc region of the alpha-chain, not by holding together degraded fragments. The function of integral secretory IgA and F(ab')2 is discussed in terms of mucosal immune defenses.

Animals↗
PubMed1984

Charge heterogeneity of human secretory component: immunoglobulin and lectin binding studies.

Free secretory component purified from human milk showed considerable charge heterogeneity in the pH range 4.7-6.5 when analysed by isoelectric focusing in thin layer agarose gels. Unlike rabbit secretory component, allotypic variation could not be identified by comparing samples from different individuals. Treatment with neuraminidase resulted in a basic shift of secretory component charge isomers. The charge heterogeneity appeared to be unrelated to the immunoglobulin binding property of secretory component since all charge isomers bound 125I-labelled IgM. 125I-labelled secretory component bound more strongly to purified IgM compared with polymeric IgA, and predominantly to the IgM-containing region of focused normal human serum. Lectin-secretory component interaction was demonstrated by concanavalin A and wheat germ agglutinin binding in a dot-blot nitrocellulose assay and precipitation with concanavalin A by Ouchterlony immunodiffusion. Despite the relatively high carbohydrate composition of both secretory component and the polymeric immunoglobulins, no evidence for lectin-like binding was obtained by sugar inhibition and sugar desorption studies. Similarly, desialation of secretory component did not prevent secretory component-IgM binding. These observations suggest that the charge heterogeneity and sugar composition of secretory component are unrelated to immunoglobulin binding in vitro.

Autoradiography↗
PubMed1976

Synthesis of secretory component by colonic neoplasms.

The secretory component (SC) polypeptide chain of secretory immunoglobulin A can be considered as a differentiation marker in that it is normally synthesized in the non-mucus-containing columnar epithelial cells, but not goblet cells, of the large intestine. With this in mind, we have studied the expression of SC in 36 colonic adenocarcinomas and 15 polyps (adenomatous and villous) by the fluorescent antibody technique. As in the normal mucosa, the synthesis of SC in tumors found in non-mucus-containing columnar cells and was absent from goblet cells. However, in several well-differentiated carcinomas it appeared that columnar cells contained both SC and mucin; these cells could be analogous to the normal mucosal precursor of both cell types. SC was synthesized throughout all adenomatous polyps and villous adenomas with the exception of some atypical nonmucinous areas of adenomatous polyps. Secretory component synthesis by carcinomas was associated with mucus production, although goblet cells did not contain SC. The presence of SC also correlated with the degree of differentiation. Secretory component was absent from half of the carcinomas as well as from atypical nonmucinous areas of polyps, and this could represent one of the earliest changes associated with the development of malignancy.

Adenocarcinoma↗
PubMed1997

Characterization of the human secretory component gene promoter.

Secretory Component (SC) is a receptor molecule implicated in the transepithelial transport of polymeric immunoglobulins. We have cloned and characterized the first exon, part of the first intron and 3500 bp of the upstream region of the gene and determined the transcription initiation region. A GC rich region immediately upstream of the transcription start region is interrupted by a potential TATA-box (TTTAA) at position -28. Promoter activity was demonstrated in transient transfection experiments in HepG2 and HeLa cells. The smallest fragment still showing transcriptional activity contains 48 bp of SC promoter. A number of putative recognition sites for transcription factors possibly involved in the regulation of SC transcription by steroids, peptide hormones and cytokines were found in the upstream region.

Base Sequence↗
PubMed1975

Secretory component in human mammary carcinoma.

Since secretory component is thought to be a normal glandular epithelial cell product, surgical specimens from patients with mammary carcinoma, an epithelial cancer, were studied with antisera to human free secretory component by indirect immunofluorescence microscopy. Normal breast tissue (10 cases) showed fluorescent epithelial cells confined to normal ducts. This was in marked contrast to ubvasive mammary carcinoma (20 cases), which showed intense staining of tumor cells and stromal cells in addition to the normal ductular epithelium. Metastases in axillary lymph nodes (2 cases) showed intense fluorescence for secretory component, whereas axillary nodes without metastases from 2 patients with breast cancer showed no fluorescence. In both normal and tumor tissue, antiimmunoglobulin A stained only ducts and subepithelial plasma cells, thus establishing that the secretory component in tumor cells was not part of an intact secretory immunoglobulin A molecule. This finding was not restricted to mammary carcinoma, since preliminary studies of colon, lung, and bladder carcinoma also demonstrated tumor cells with cytoplasmic fluorescence for secretory component. In contrast, the tumor cells in 2 cases of sarcoma, a nonepithelial cancer, did not exhibit fluorescence for secretory component.

Animals↗
PubMed1975

Distribution of covalently bound and non-covalently bound secretory component on sbuclasses of rabbit secretory IgA.

The distribution of non-covalently bound secretory component (SC) on the two subclasses, IgA-f and IgA-g of rabbit secretory IgA (sIgA) was determined; the two subclasses were separated from each other by the use of antibody-immunosorbent columns and were subjected to SDS polyacrylamide gel electrophoresis. No SC appeared to be dissociated from the IgA-f molecules from each of 11 different rabbits; the IgA-g molecules, however, did have SC which was dissociated by SDS. Thus, all of the noncovalently bound SC on rabbit sIgA resides on the IgA-g subclass molecules.

Animals↗