[Humoral reactivity against the secretory component of secretory IgA in rheumatoid arthritis, Sjögren's syndrome and systemic lupus erythematosus].
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Adolescent↗
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[Secretory component. II. Isolation and purification of free secretory component].
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Colostrum↗
Human secretory component--IV. Aggregation and fragmentation of free secretory component.
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Centrifugation, Density Gradient↗
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↗
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↗
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↗
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↗
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↗
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↗
The presence and measurement of secretory component in human bile and blood.
Five monoclonal antibodies which recognized three separate epitopes on the free secretory component molecule were produced using free secretory component obtained from human colostrum. Two-site immunoradiometric assays were developed to measure free secretory component and secretory IgA. Monoclonal antibody M9 was used on coated plates as the capture antibody. Monoclonal antibody M7 was used as the labelled signal antibody for the assay of free secretory component and a commercially available monoclonal anti-IgA antibody was used as the labelled signal antibody for the assay of secretory IgA. Free secretory component was found in human serum and bile. In serum, its concentration was raised in patients with high serum alkaline phosphatase due to liver disorders but not in patients with high serum alkaline phosphatase due to non-liver disorders. In bile from bile duct drains collected during the first week after liver transplantation, free secretory component was found in concentrations of up to 33 mg/l, in vast excess of that found in bile from gallstone patients (up to 0.3 mg/l). Bile from gallstone patients but not from liver transplant patients produced proteolytic degradation of free secretory component when incubated in vitro. The finding of large amounts of free secretory component, the free cleaved fragment of the polymeric IgA receptor in human bile, further supports the existence of the blood to bile transhepatocytic pathway in humans.
Alkaline Phosphatase↗
Binding of secretory component to human immunoglobulin M.
The binding of human free secretory component to immoglobulin M (IgM) has been studied in vitro as a model for the formation of complexes between the two proteins in vivo. Three IgM myelomas and normal serum IgM were found to bind secretory component in amounts from 0.8 to 2.0 mol per mol of IgM. This variation in binding was not related to a corresponding variation of the J-chain content of the immunoglobulins, but more likely it was due to varying amounts of unspecifically bound serum proteins blocking the attachment of secretory component. In contrast to complexes with immunoglobulin A (IgA), the binding of secretory component to IgM appeared to be solely of a noncovalent nature, as all secretory component was released from complexes with IgM during gel chromatography in 6 M guanidine hydrochloride. Studies with tryptic fragments of one of the IgM myelomas indicated that the binding site for secretory component is located on the (Fc)5mu part of the IgM pentamer. Finally, only minimal conformational changes were found to accompany complex formation between secretory component and IgM, analogous to what has earlier been reported for the attachment of the secretory component to IgA.
Binding Sites↗
Probing the topography of free and polymeric Ig-bound human secretory component with monoclonal antibodies.
Secretory component (SC), an integral membrane protein expressed on basolateral surfaces of secretory epithelial cells, mediates the transport of polymeric Ig (PIg) into external secretions. The ectoplasmic segment of SC is released into secretions either in a free form (FSC) or bound to PIg as secretory IgA or IgM. The topography of human SC in its free and PIgA-bound form was studied by using mAb directed against each form of SC. Competition experiments identified a minimum of nine SC epitopes, one of which was dependent on an N-glycosidic moiety. Three of the polypeptide-derived epitopes were displayed on denatured, reduced, and alkylated SC, whereas the others were fully or partially dependent on the native conformation of SC. Epitopes recognized by the latter class of antibodies were mapped to discrete domains of SC, based on amino acid sequence and antibody-binding analysis of limited proteolytic fragments. One of the mAb (6G11), which was directed against an epitope on domain I of SC, inhibited the binding of FSC to PIgA. Overall, our results provide evidence that a region within domain I, as well as protease-sensitive interdomain regions of FSC, become masked or altered when SC binds to PIgA. Furthermore, the binding of SC to PIgA results in conformational changes, or formation of combinatorial epitopes, involving regions within domains II and III of SC but not domain V.
Alkylation↗
Structural composition of canine secretory component and immunoglobulin A.
Dog serum and colostral immunoglobulin A (IgA) and free secretory component from colostrum were isolated using affinity chromatography. Both serum and colostral IgA showed similar susceptibility to reduction with dithiothreitol, but only colostral IgA released the additional subunit, bound secretory component. This released secretory component was identical with free secretory component with respect to electrophoretic migration, isoelectric focusing point, and molecular weight, but lacked some antigenic determinants. The amino acid composition and the N-terminal sequence of canine free secretory component was similar to that reported for the cow.
Amino Acids↗
Circulating secretory component in relation to early diagnosis and treatment of liver metastasis from colorectal carcinomas.
AIMS: To evaluate serum secretory component in relation to early detection and clinical management of liver metastasis in patients with colorectal cancer. METHODS: Secretory component and carcinoembryonic antigen (CEA) were analysed in serial serum samples from 23 patients who had liver metastases as the only apparent recurrence, and in sera from 54 matched controls. Results of surgical treatment of recurrences were classified peroperatively as radical when no residual tumour was apparent and resection margins were free of disease. RESULTS: In total, 18 (78%) patients had increased secretory component during the whole follow up period (median 16 months); 12 (52%) had raised secretory component concentrations before clinical recurrence (median lead time 5.2 months). There was no difference before recurrence between circulating secretory component and CEA in sensitivity and lead times. Seventeen patients underwent surgery for hepatic metastasis; seven had radical hepatic resection of which only two (29%) showed increased secretory component concentrations before clinical recurrence; both had concurrent raised CEA values. By contrast, secretory component was raised in 83% of those cases considered inoperable. CONCLUSIONS: Although serum secretory component clearly increases in most patients with liver metastases, its clinical value seems questionable because secretory component apparently indicates mainly inoperable hepatic metastases.
Adult↗
Disulfide bonding of secretory component to a single monomer subunit in human secretory IgA.
The arrangement of disulfide bonds joining secretory component (SC) to the alpha chains in secretory IgA was studied by determining the molecular size of the principal fragments resulting from CNBr digestion of secretory dimeric Fc fragments from IgA (Fc)2alpha fragments). In vitro complexes formed by incubating 125I-free SC and myeloma 131I-(Fc)2alpha fragments were isolated by gel filtration and subsequently digested with cyanogen bromide. The CNBr digests of SC-(Fc)2alpha fragments were analyzed by gel filtration in 5 M guanidine. Two principal fragments were obtained, one containing a monomeric Fc fragment from IgA (Fcalpha) associated with SC (m.w. congruent to 110,000) and a second containing the second Fcalpha monomer (m.w. congruent to 50,000) from the dimeric SC-(Fc)2alpha. Similar results were obtained when secretory (Fc)2alpha fragments isolated from native secretory IgA dimer were subjected to CNBr digestion. The data indicate that SC is disulfide bonded to a single monomer subunit in secretory IgA dimer.
Chemical Phenomena↗
Study of secretory component in patients with metastatic breast cancer.
A radioimmunoassay was developed for secretory component, a glandular epithelial cell product secreted as an accessory protein with dimeric immunoglobulins A and M. Forty-four normal women between the ages of 40 and 70 had plasma concentrations of secretory component of 7.195 microgram/ml +/- 3.590 (+/-2 SD). Of the patients with metastic breast cancer of epithelial origin, 34 (91.9%) had plasma concentrations greater than 8.990 microgram/ml; 29 (78.1%) had plasma concentrations greater than 10.785 microgram/ml; 10 (27%) had concentrations greater than 15.000 microgram/ml; and 3 (8.1%) had concentrations greater than 22.710 microgram/ml. Serial plasma concentrations (averaging 3.48 per patient) of 35 (94.6%) of these patients reflected the clinical course of the disease. All patients had some combination of surgery, radiation therapy, and chemotherapy. No direct correlation was noted between the type of therapy and concentration of secretory component. However, plasma secretory component served as a marker in the systemic circulation of a change in the status of the metastatic breast cancer. The impact of this research may lie in its incorporation into clinical management.
Adenocarcinoma↗
Reactive half-cystine peptides of the secretory component of human exocrine immunoglobulin A.
On the basis of previous work the two forms of human secretory component, namely that which is covalently bound as a part of the exocrine immunoglobulin A molecule and the free form, are probably different states of the same protein. From autoradiographs of trypic peptide maps of bound and free secretory components which were radioactively alkylated after partial reduction, it was concluded that the same half-cystines in each are sensitive to reduction. in the present work the easily reduced half-cystines of the bound and free secretory components have been studies in more detail. In each form there are two such half-cystines. In the case of bound secretory component they provide the linkage to the remainder of the exocrine immunoglobulin A molecule. Peptides from the sensitive half-cystines were isolated from tryptic-peptic digests of free secretory component and sequenced. By diagonal electrophoresis these two peptides were shown to be joined in an intrachain disulfide bridge. Therefore, it is proposed that the exocrine immunoglobulin A molecule becomes fully assembled when a single, reactive intrachain disulfide bridge in free secretory component rearranges to yeild two interchain bridges with dimeric serum-type immunoglobulin A. This process is thought to occur within the epithelial lining cells of mucous membranes.
Amino Acids↗
The finding that secretory component is not associated with gamma-glutamyltranspeptidase activity.
The gamma-glutamyltranspeptidase activity of human milk was concentrated by ammonium sulphate precipitation. On gel chromatography of the dissolved precipitate, the activity was eluted in the high-molecular-weight fraction containing secretory IgA, while no activity appeared in the eluate at the position of free secretory component. Various antisera were added to portions of the pool of active fractions. No change of gamma-glutamyltranspeptidase activity appearedse activity was obtained with antisera against either IgA, secretory IgA or secretory component, while a large reduction of activity was seen with anti-human colostrum. Finally, purified free secretory component, secretory IgA and in vitro complexes between secretory component and IgA dimers were shown to be inactive in the gamma-glutamltranspeptidase assay, both in the absence and presence of zinc ions. Thus secretory component, either when free or bound to IgA, does not exhibit gamma-glutamyltranspeptidase activity, and therefore cannot function as such an enzyme in the transport of IgA across mucous membranes, as has been suggested previously.
Animals↗