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PubMed1982

Large-bowel carcinomas with different ploidy, related to secretory component, IgA, and CEA in epithelium and plasma.

Immunofluorescence staining for carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA was evaluated semiquantitatively in 85 large-bowel carcinomas in relation to degree of tumour differentiation, Dukes' stage, and plasma CEA level. The tumours were divided into a near-diploid (ND, 28) and an aneuploid group (AN, 57) by means of flow-cytometric DNA measurements. Expression of SC and IgA in neoplastic epithelium was positively related to differentiation in both groups. The AN tumours scored significantly higher for CEA than the ND ones, but the staining was apparently unrelated to differentiation or Dukes' stage. CEA expression in the transitional mucosa adjacent to ND tumours was negatively correlated with tumour differentiation, whereas epithelial IgA and SC in this zone showed a substantially higher positive correlation with tumour differentiation, and a somewhat stronger negative correlation with Dukes' stage in the ND than in the AN group. Plasma CEA levels were significantly related to Dukes' stage, only in patients with AN tumours, and only in this group were positively correlated with estimates of total tumour CEA for Dukes' stages A and B. For Dukes' stages C and D (disseminated tumours), moreover, the plasma CEA levels were found to be significantly higher in the AN group. These findings indicate that the DNA profile of large-bowel carcinomas is related both to the way neoplastic cells influence the activity of the transitional mucosa and their capacity for expression and release of epithelial products. AN tumours thus seem to be more active as "secretors" of CEA than ND ones.

Adenocarcinoma↗
PubMed1991

Cytokine regulation of the mucosal immune system: in vivo stimulation by interferon-gamma of secretory component and immunoglobulin A in uterine secretions and proliferation of lymphocytes from spleen.

The secretory immune system in the female reproductive tract is known to be regulated by sex hormones and antigen. The purpose of the present study was to examine the control by interferon-gamma (IFN gamma) of the secretory component (SC), the polymeric immunoglobulin A (IgA) receptor, and IgA in uterine secretions and to determine whether IFN gamma influences the proliferation of spleen cells in response to mitogens. When measured by RIA, SC levels in uterine secretions were elevated when increasing doses of IFN gamma (1000-5000 U/uterus) were placed in the uterine lumen of ovariectomized rats. In contrast, IFN alpha-beta (5000 U/uterus) placed in the uterine lumen had no effect on uterine SC levels. To determine whether IgA movement increases in response to IFN gamma, animals were treated with estradiol to increase uterine tissue IgA levels without stimulating the accumulation of IgA or SC in uterine secretions. Under these conditions, intrauterine IFN gamma increased SC and IgA levels in uterine secretions, suggesting that in vivo IFN gamma stimulation of uterine SC increases the transport of IgA from tissue to lumen. Analysis of uterine tissues indicated that intrauterine IFN gamma had no apparent effect on epithelial cell morphology. In contrast, intraepithelial lymphocytes and polymorphonuclear leucocytes, which were sparse in control tissues, increased markedly with IFN gamma treatment. This increase was antagonized when estradiol was administered along with IFN gamma. In other studies, IFN gamma placed in the uterine lumen significantly increased spleen cell proliferation in response to Concanavalin-A, phytohaemagglutinin, and lipopolysaccharide mitogens relative to those in spleen cells from control animals. These studies demonstrate that in vivo treatment with IFN gamma stimulates the mucosal immune system in the female reproductive tract by increasing SC and IgA levels in the uterine lumen and promoting the infiltration of intraepithelial lymphocytes and polymorphonuclear leucocytes into uterine tissue. Further, it suggests that antigen, in stimulating a local uterine response, may act through cytokines, particularly IFN gamma, to regulate the transport of IgA into uterine secretions as well as modulate lymphocyte proliferation at sites distal to the uterus.

Animals↗
PubMed1991

Comparative evaluation of carcinoembryonic antigen, secretory component, and mucins in index and metachronous adenomas of the colorectum.

Of 124 patients who underwent endoscopic polypectomy, 70 were colonoscopically reevaluated during a mean period of 10 years. On the basis of the clinical outcome, the patients were divided into three groups: group 1, 31 patients who had a colon still with no adenomas or cancer; group 2, 35 patients in whom one or more metachronous adenomatous polyps developed; and group 3, 4 patients in whom a carcinoma of the colon subsequently developed. In addition to the clinical and pathological features, the pattern of the immunohistologic staining for carcinoembryonic antigen and secretory component was studied. Moreover, the mucin histochemical staining intensity of neutral mucins, sulfomucins, and sialomucins was evaluated. The features of the 40 index adenomas obtained from patients in group 1 were compared with the features of the 51 index adenomas from patients in group 2. Furthermore, these characteristics of the index adenomas were compared with those in the 69 metachronous adenomas of the group 2 patients. It was found that male sex (P less than 0.005) and a history of colorectal neoplasia (P less than 0.02) are main factors for the development of new adenomas. The neutral mucins were less abundant in the group 2 index adenomas (r = -0.21; P less than 0.05). The expression of the other evaluated markers was not significantly different between both groups, although the group 2 index adenomas were significantly smaller (r = -0.22; P less than 0.05) and showed a trend toward a more pronounced cytoplasmic expression of carcinoembryonic antigen than the index adenomas from group 1 (22% vs. 12.5%). Moreover, it was found that in comparison with the index adenomas, metachronous adenomas were significantly smaller (r = -0.24; P less than 0.01) and more sessile (r = 0.20; P less than 0.002). Significant negative correlations, i.e., decrease, were also found in the expression of carcinoembryonic antigen (surface P less than 0.001; cytoplasmic P less than 0.05) and neutral mucins (P less than 0.005) between the index adenomas and the metachronous adenomas, whereas positive correlations were found for secretory component (P = 0.0001) and sulfomucins (P less than 0.05). These findings suggest that a limited production of neutral mucins in the goblet cells of a small index adenoma from a male patient with a history of colorectal neoplasia is indicative of an increased risk for the development of new colorectal adenomas. Furthermore, the clinical, mucin histochemical, and immunohistochemical findings of the metachronous adenomas show less malignancy-associated features than those of the index adenomas.

Adenocarcinoma↗
PubMed2001

Lactoferrin and free secretory component of human milk inhibit the adhesion of enteropathogenic Escherichia coli to HeLa cells.

BACKGROUND: Diarrhoea caused by Escherichia coli is an important cause of infant morbidity and mortality in developing countries. Enteropathogenic Escherichia coli (EPEC) is considered one of the major causes of diarrhoea in children living in developing countries. The ability of diarrhoeagenic strains of E. coli to adhere to and colonize the intestine is the first step towards developing the disease. EPEC strains adhere to enterocytes and HeLa cells in a characteristic pattern known as localized adherence. Many epidemiological studies of diarrhoea have shown that breast-feeding protects infants from intestinal infections. Both immunoglobulin and non-immunoglobulin elements of human milk are thought to contribute to the protection from diarrhoeal agents. RESULTS: The effects of human milk and its protein components on the localized adherence of EPEC were investigated. Non-immunoglobulin components of human milk responsible for the inhibition of EPEC adhesion to HeLa cells were isolated by chromatographic fractionation of human whey proteins. Besides secretory immunoglobulin A, which has been previously reported to affect the adhesion of EPEC, free secretory component (fSC) and lactoferrin (Lf) were isolated. Even in concentrations lower than those usually found in whole milk, fSC and Lf were able to inhibit the adhesion of EPEC. alpha-lactalbumin was also isolated, but showed no activity on EPEC adhesion. CONCLUSIONS: This study demonstrated that the immunoglobulin fraction, the free secretory component and lactoferrin of human milk inhibit EPEC adhesion to HeLa cells. These results indicate that fSC and Lf may be important non-specific defence factors against EPEC infections.

Bacterial Adhesion↗
PubMed1975

Peculiar secretory IgA system identified in chickens. II. Identification and distribution of free secretory component and immunoglobulins of IgA, IgM, and IgG in chicken external secretions.

A homologue of a free secretory component (SC) was identified in chicken intestinal secretion by criteria based on its antigenic relationship with intestinal secretory IgA (SIgA), molecular size, sugar content, and electrophoretic mobility, as well as its elution characteristic from ion-exchange chromatography. SC was obtained in a form free from IgA from the intestinal secretion by salting out and DEAE chromatography, followed by density ultracentrifuguation or Sephadex G-200 gel-filtration. However, the free SC revealed some antigenic deficiency when compared to bound SC of intestinal SIgA and showed a failure of binding to serum-type-polymeric IgA of biliary IgA in vitro. Several kinds of chicken external secretions were examined for detection of SC and immunoglobulin classes of IgG, IgA, and IgM. In spite of the wide distribution of immunoglobulins in the external secretions, SC antigen could be detected only in intestinal secretion. Most IgA in the secretions had a molecular structure of a tetramer of serum-type IgA, lacking in SC and having 17S to 18.5S and 600,000 to 700,000 daltons. On the other hand, IgA in the intestinal secretion showed close similarity to the mammalian SIgA, associated with SC and having 11.2S and 350,000 daltons. Presence of antibody activity in the intestinal IgA to avian reovirus was confirmed by plaque reduction tests.

Animals↗
PubMed1995

Secretory component (polymeric immunoglobulin receptor) as an intrinsic inhibitor of biological functions of interferon gamma in keratinocytes.

Secretory component (SC) acts as a transmembrane polymeric immunoglobulin receptor of epithelial cells and is known to bind to polymeric IgA and to contribute to the secretion of secretory IgA (sIgA). We describe a new biological function for free SC (FSC) by which the expression of intercellular adhesion molecule-1 (ICAM-1) and HLA-DR induced by interferon gamma (IFN gamma) is inhibited in human keratinocytes. This activity coincided with suppression of adenosine cyclic 3,5-monophosphate (cyclic AMP) production in keratinocytes. Keratinocytes produced SC after stimulation with IFN gamma and this production was suppressed by the addition of H-7 or propranolol. The addition of propranolol resulted in prolongation of ICAM-1 expression on keratinocytes induced by IFN gamma. These results suggest that endogenously produced SC, as well as exogenously added FSC, acts as an inhibitor of IFN gamma. Therefore, our results suggest that SC plays an antiinflammatory role in the pathogenesis of inflammatory skin diseases via inhibition in keratinocytes of IFN gamma induced expression of ICAM-1 and HLA-DR.

Cells, Cultured↗
PubMed1980

Receptor-mediated transcellular transport of immunoglobulin: synthesis of secretory component as multiple and larger transmembrane forms.

We have characterized the early biosynthetic forms of secretory component (SC). SC is synthesized in various glandular epithelial cells and functions in transepithelial transport of certain polymeric immunoglobulins. In rabbit, mature SC is known to be heterogeneous, consisting of two or three immunologically related glycoproteins. Using translation of mRNA from rabbit mammary gland or liver in a wheat germ cell-free system supplemented with dog pancreas microsomal vesicles, we discovered that the translation products of SC mRNA include at least four distinct polypeptides. Moreover, we found that all four polypeptides are synthesized not as soluble secretory forms but as considerably larger transmembrane forms that are core-glycosylated and asymmetrically integrated into the dog pancreas microsomal vesicles in a translation-coupled manner. We therefore conclude that the mature secreted forms of SC are endoproteolytic fragments derived from and comprising the ectoplasmic portion of the transmembrane precursor forms. The detection of transmembrane precursor forms for mature SC provides a protein structural basis for their function as receptors mediating transepithelial transport of immuno-globulin molecules.

Cell-Free System↗
PubMed1984

Variations in the levels of secretory component in human uterine fluid during the menstrual cycle.

To determine whether variations in the level of secretory component (SC) occur during the menstrual cycle, we compared the amounts of SC in human uterine secretions during the proliferative, secretory, and menstrual phases. Uterine washes were obtained from women (ages: 18-49) with histologically normal endometria by lavage with Gravlee jet wash device using isotonic glycine. SC was measured by a radioimmunoassay which recognizes primarily free SC. Levels of uterine luminal SC, when expressed as the percentage of total wash protein, were highest during the secretory phase, significantly reduced during the proliferative phase and lowest during menstruation. The mean protein concentration in uterine fluids did not vary significantly during the menstrual cycle. Total amounts of SC were also greatest during the secretory phase, averaging two times higher than SC levels in proliferative samples. These results demonstrate that fluctuations do occur in the SC content of human uterine secretions during the menstrual cycle and suggest that hormones play an important role in the secretory immune system of the human uterus.

Adenocarcinoma↗
PubMed1980

Secretory component in immmunoglobulin deficiency: and immunoelectron microscopic study of intestinal epithelium.

The ultrastructural sites of secretory component (SC) in the intestinal epithelium of severely immunoglobulin-deficient and immunologically intact persons were compared. SC was found in the same sites in the immunoglobulin-deficient and normal epithelium: perinuclear spaces, rough endoplasmic reticulum, Golgi complexes, external surfaces and endocytic invaginations of the basolateral plasmalemma, and in membranous vesicles throughout the cytoplasm. These observations suggest that the synthesis, external expression and transcellular migration of SC occur independent of the presence of immunoglobulins. The migration of SC from the basolateral cell surfaces to apical surfaces may be an inherent property of epithelial cells and the primary event in the translocation of polymeric immunoglobulins across the cells to external body fluids.

Cell Membrane↗
PubMed1985

Secretory component in breast cancer. Analysis of the levels in primary and metastatic disease.

Levels of secretory component (SC) were measured in breast tumors from 95 patients with primary or metastatic cancer. Tumor cytosols were prepared by polytron disruption and high speed centrifugation (105,000 g X 30 min) and SC was measured using a sensitive radioimmunoassay which detects primarily free SC. In frozen samples stored for up to 5 months SC resisted degradation and could be measured quantitatively without interference. In primary tumors from patients between ages 28 and 97, SC positive samples ranged from 4 ng/mg protein to 600 ng/mg protein. In metastatic lesions, SC positive samples ranged no higher than 46 ng/mg protein. The studies indicate that SC can be measured quantitatively in both primary and metastatic tumors and that prolonged storage does not interfere with measurements of SC. The wide variation in SC levels in primary tumor samples may be related to a susceptibility to metastasis. Further, the low levels of SC in metastatic lesions could indicate a potential for SC involvement in immune regulation of tumor growth.

Adult↗
PubMed1997

The polymeric immunoglobulin receptor (secretory component) in a human intestinal epithelial cell line is up-regulated by interleukin-1.

Secretory component (SC or polymeric immunoglobulin receptor) on mucosal epithelial cells mediates transcytosis of polymeric immunoglobulin into external fluids and functions as a receptor for polymeric immunoglobulin. SC expression in a human colonic adenocarcinoma cell line, HT-29 has been reported to be up-regulated by various cytokines, such as interferon-gamma, tumour necrosis factor-alpha and interleukin-4 (IL-4). However, up-regulation of SC by IL-1 is controversial. In this study, we investigated the effect of human recombinant IL-1 alone on SC expression in HT-29 cells in detail. Immunocytochemistry and Northern blot analysis revealed that IL-1 beta increased both the number of SC-positive cells and SC mRNA expression. Enzyme-linked immunosorbent assay revealed that IL-1 beta enhanced secretion by HT-29 cells in both time- and dose-dependent manners. IL-1 alpha had the same effects on HT-29 cells. Northern blot analysis demonstrated that cycloheximide and actinomycin D abolished the effect of IL-1. Moreover, we detected IL-1 receptor (IL-1R) type I mRNA in HT-29 cells by polymerase chain reaction (PCR) and sequenced the PCR-amplified product. We think that it reflects the possibility of the presence of IL-1R in HT-29 cells. From these data, we concluded that IL-1 beta and IL-1 alpha play regulatory roles in SC expression, and their effects depend on de novo protein synthesis and transcription.

Blotting, Northern↗
PubMed2006

Glycans on secretory component participate in innate protection against mucosal pathogens.

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.

Animals↗
PubMed1981

Serum and salivary immunoglobulin A and free secretory component in ulcerative colitis.

Patients with ulcerative colitis have been investigated for evidence of defects in secretory immunity. Total serum IgA concentration, serum IgA antibody titres to Candida albicans, salivary IgA and free secretory component concentrations have been measured in thirty-six patients with ulcerative colitis and thirty-six normal controls. None of the parameters was significantly different between patients with proctitis and patients with extensive colitis or between the colitis patients and normal controls.

Adolescent↗
PubMed1999

Free secretory component as a standardization protein for nasopharyngeal specimens from children with upper respiratory tract infection.

Free secretory component (FSC) has been recommended as a reliable protein for correction of the unknown dilution in tracheal aspirate samples from preterm infants. To investigate whether FSC would also provide a valid standardization protein for samples of nasopharyngeal secretions, this study determined the intersubject variation and the alteration over time in the concentrations of FSC in nasal secretions from 35 children (median age 14 months) who participated in an antibiotic efficacy trial. Nasopharyngeal aspirates were obtained at enrolment and after 2-3 d. FSC in the specimens was quantified by a direct enzyme immunoassay. The concentrations of FSC in the nasal secretions ranged from 0.08 to 189.6 microg ml(-1) (median 12.3 microg ml(-1); the ratio of the highest to the lowest concentrations was 2370, the difference between the 90th and 10th percentile concentrations was 189-fold and the difference between the 75th and 25th percentile values was 26. FSC concentrations were significantly lower in children aged < or =12 months (median 2.2 microg ml(-1) than in the older children (median 21.5 microg ml(-1); p = 0.035). Between the first and the follow-up specimens, 65% of the children had > or =2-fold difference in the levels of FSC in the secretions. Because an optimal standardization protein should show minimal variation between individuals and over time, FSC may not be a suitable protein for correction of the unknown dilution of nasopharyngeal specimens from children with upper respiratory tract infection.

Child, Preschool↗
PubMed1988

Up-regulation of the expression of secretory component and HLA molecules in a human colonic cell line by tumour necrosis factor-alpha and gamma interferon.

Secretory component (SC) acts as a receptor for polymeric IgA (pIgA) and pIgM on the basolateral face of secretory epithelia. This study showed that both the production and surface membrane expression of SC were additively up-regulated by tumour necrosis factor-alpha (TNF) and gamma interferon (IFN-gamma) in a human colonic cell line (HT-29m2). TNF likewise enhanced membrane expression of HLA class I determinants. Moreover, TNF augmented synergistically the IFN-induced de novo synthesis of HLA class II (DR) molecules. These data suggest that there are different regulatory mechanisms for the action of TNF and IFN and for the expression of HLA-DR and SC/HLA class I. Addition of actinomycin D abolished the cytokine-mediated increase of SC synthesis and expression. This observation suggested that transcriptional events are required for the cytokine-mediated up-regulation of SC.

Antigens, Surface↗
PubMed2001

IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component.

The bronchial epithelium is a source of both alpha and beta chemokines and, uniquely, of secretory component (SC), the extracellular ligand-binding domain of the polymeric IgA receptor. Ig superfamily relatives of SC, such as IgG and alpha(2)-macroglobulin, bind IL-8. Therefore, we tested the hypothesis that SC binds IL-8, modifying its activity as a neutrophil chemoattractant. Primary bronchial epithelial cells were cultured under conditions to optimize SC synthesis. The chemokines IL-8, epithelial neutrophil-activating peptide-78, growth-related oncogene alpha, and RANTES were released constitutively by epithelial cells from both normal and asthmatic donors and detected in high m.w. complexes with SC. There were no qualitative differences in the production of SC-chemokine complexes by epithelial cells from normal or asthmatic donors, and in all cases this was the only form of chemokine detected. SC contains 15% N-linked carbohydrate, and complete deglycosylation with peptide N-glycosidase F abolished IL-8 binding. In micro-Boyden chamber assays, no IL-8-dependent neutrophil chemotactic responses to epithelial culture supernatants could be demonstrated. SC dose-dependently (IC(50) approximately 0.3 nM) inhibited the neutrophil chemotactic response to rIL-8 (10 nM) in micro-Boyden chamber assays and also inhibited IL-8-mediated neutrophil transendothelial migration. SC inhibited the binding of IL-8 to nonspecific binding sites on polycarbonate filters and endothelial cell monolayers, and therefore the formation of haptotactic gradients, without effects on IL-8 binding to specific receptors on neutrophils. The data indicate that in the airways IL-8 may be solubilized and inactivated by binding to SC.

Asthma↗
PubMed1981

Secretory component of IgA: a marker for differentiation of ocular epithelium.

Secretory component (SC) was studied by indirect immunofluorescence of the ocular surface epithelium. We find that conjunctival epithelium produces this component, and that it is absent in the corneal epithelium. Conjunctival epithelium loses its SC staining within 1 to 2 days as it grows over a denuded corneal stroma. This implies a very rapid turn-off of the SC gene and rapid export of the gene product previously formed. However, conjunctival flap epithelium does not change its characteristic structure or functions. Vascularization of corneas resurfaced by conjunctival epithelium usually leads to a rapid reversal of both morphological and biochemical characteristics in the surface epithelium, as judged by the reappearance of goblet cells and positive staining for SC. Vascularization of normal corneas leaves the epithelium unchanged, so that neither goblet cells nor SC appear. Thus metaplasia of conjunctival to corneal epithelium is incomplete, permitting reversion to type under certain conditions.

Animals↗
PubMed2000

Circulating thyroglobulin transcytosed by thyroid cells in complexed with secretory components of its endocytic receptor megalin.

After its endocytosis from the colloid, some thyroglobulin (Tg) is transcytosed intact across thyrocytes, accounting in part for its presence in the circulation. We previously showed that megalin (gp330), an endocytic Tg receptor, mediates apical to basolateral Tg transcytosis. Here we investigated whether a portion of megalin remains combined with Tg after its transcytosis, using studies with cultured thyroid cells and in vivo observations. FRTL-5 cells, a rat thyroid cell line, cultured on filters in dual chambers form tight junctions and exhibit features of polarity, with expression of megalin exclusively on the upper (apical) surface. After the addition of unlabeled Tg to the upper chamber and incubation at 37 C, some Tg was transcytosed intact across FRTL-5 cells into the lower chamber. Two antimegalin ectodomain antibodies precipitated transcytosed Tg in fluids collected from the lower chamber. After the addition of Tg to surface-biotinylated FRTL-5 cells, an anti-Tg antibody and the two antimegalin ectodomain antibodies precipitated high molecular mass biotinylated material in fluids collected from the lower chamber, corresponding to much of the megalin ectodomain, as well as smaller amounts of lower molecular mass material. The results indicate that Tg transcytosed across FRTL-5 cells remains complexed with megalin ectodomain components, which we refer to as megalin secretory components. In aminotriazole-treated rats, which develop increased megalin-mediated Tg transcytosis, antimegalin antibodies precipitated some of the Tg in the serum. Tg was also precipitated by antimegalin antibodies in sera from patients with Graves' disease, in which we found increased megalin expression on the apical surface of thyrocytes. In contrast, in thyroidectomized patients with metastatic papillary thyroid carcinoma, in whom Tg is directly secreted by neoplastic thyroid cells into the circulation rather than transcytosed, serum Tg was not precipitated by antimegalin antibodies. The detection of Tg-megalin complexes may help identify the source of serum Tg in patients with thyroid diseases.

Adult↗