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PubMed1976

Further characterization of IgA in chicken serum and secretions with evidence of a possible analogue of mammalian secretory component.

Immunochemical studies of the intestinal secretory immune system of the chicken have led to further characterization of IgA in bile, intestinal contents and serum. A component was detected in late Sephadex G-200 fractions of caecal and intestinal contents which showed partial identity with bile, intestinal and a high molecular weight fraction of serum IgA. This component showed similar sedimentation characteristics to bovine serum albumin in sucrose density gradients, a fast electrophoretic mobility on polyacrylamide gel and is a possible analogue of mammalian secretory component (SC). Fractionation of serum from birds affected with infectious synovitis revealed two moleculare classes of IgA. Comparative double diffusion studies produced a reaction of complete identity between bile IgA and high molecular weight serum IgA (15S) and partial identity with low molecular weight serum IgA (7S), suggesting a lack of an SC determinant on the latter. A spur of partial identity between 15S and 7S serum IgA was also observed. Although no direct structural homology with mammalian or human IgA could be demonstrated by immunological cross-reactivity, the similarities of molecular characteristics, particularly emphasized by the presence of a secretory component, favour a functional analogy between the secretory immune system of the fowl and mammalian species.

Animals↗
PubMed1975

A study of the association of human secretory component with IgA and IgM proteins.

Human secretory component (SC) was isolated from colostral whey, and the binding of 125I-SC to purified IgA and IgM monoclonal proteins was studied using two methods to separate free from immunoglobulin-bound 125I-SC: a) gel filtration on Sephadex G-200, and b) precipitation of 125I-SC-Ig complexes with anti-Ig antibody. Both IgA dimeric proteins and IgM pentamers bound 125I-SC with approximately one SC-binding site per mole of polymer and similar affinity. Assuming a reversible equilibrium, an apparent association constant congruent to 10-8 M-1 was calculated to govern the binding of 125I-SC to immunoglobulin polymers. The assignment of a single association constant may be an oversimplication, particularly for the case of IgA polymers, since evidence was obtained that disulfide bonds were formed in the 125I-SC-IgA complex. Despite the complexity of the reaction, binding of 125I-SC to both IgA and IgM polymers could be analyzed by standard methods of saturation analysis, and both were shown to have a similar affinity for 125I-SC. No differences were noted in the affinity of 125I-SC binding to the IgA1 and IgA2 subclasses. Binding of monomeric IgA and IgM proteins could not be measured and was at least 100-fold lower than that found for IgA and IgM polymers. Complexes of 125I-SC with IgA dimers were presumed to involve covalent bond formation, since these complexes did not dissociate in guanidine-HCl. One IgA2 trimer did not form a covalent bond since it was completely dissociated in guanidine. In contrast, 125I-SC-IgM complexes were dissociated in denaturing solvent, indicating that such complexes were held together primarily by non-covalent bonds. Experiments with (Fc)5 mu isolated by high temperature tryptic digestion of IgM showed that binding of 125I-SC was to the Fc region of IgM proteins. It was suggested that the binding of SC with similar affinity to both IgA and IgM polymers may be important in the biologic function of both these immunoglobulin classes.

Absorption↗
PubMed1981

Immunoperoxidase localization of secretory component in reactive mesothelium and mesotheliomas.

Immunoperoxidase localization of the secretory component (SC) of immunoglobulin (Ig) A was undertaken on paraffin-embedded tissue to investigate its usefulness in differentiating epithelial from mesothelial neoplasms. Epithelial cells, but not mesothelial cells, have been previously reported to contain SC, which may be involved in the intraepithelial transport of secretory IgA. In this study we report, for the first time, focal but unequivocal staining for SC in reactive mesothelium and mesotheliomas (10/16). Reactivity was not associated with any histologic subtype of malignant mesothelioma although staining was usually seen in the "epithelial" type. The significance in terms of possible mesothelial secretory IgA transport is discussed.

Epithelium↗
PubMed1977

Rat bile as a convenient source of secretory IgA and free secretory component.

Rat hepatic bile contains three proteins as major constituents: secretory IgA (SIgA), free secretory component (FSC) and albumin. Traces of alpha-macroglobulin, transferrin, IgG and IgM are also detectable. The bile duct daily pours between 5-12 mg each of SIgA and FSC into the rat duodenum. The origin and function of these proteins in bile may represent important clues in the understanding of the SIgA system.

Animals↗
PubMed1989

Ontogeny of secretory component in rat liver.

The ontogeny of the expression of secretory component (SC), the receptor for transepithelial transport of polymeric immunoglobulins, in the rat liver was assessed by measuring the SC concentration in liver homogenates of rats killed from birth to 60 days of age, and by quantifying the daily SC secretion of in vitro cultured hepatocytes isolated from rats similarly killed from 2 days before birth to 60 days of age. With both methodologies, only very small amounts of SC were produced by the rat liver up to 20 days of age, whereafter expression of SC markedly increased. The development of SC production in the rat liver was co-ordinate with that previously reported in the rat small intestine, preceding the appearance of large numbers of intestinal IgA plasmacytes. These data further emphasize the importance of the liver contribution, via the bile, to the intestinal secretory IgA system of the rat.

Aging↗
PubMed1988

Cyanogen bromide cleavage of bovine secretory component and its tryptic fragments.

1. Five-domain bovine secretory component and its two-domain and three-domain tryptic fragments have been treated with cyanogen bromide. 2. N-terminal sequence analysis of the purified products showed that cleavage occurred within the disulphide bridged polypeptide loop of domain 2. The site lies within the region that binds IgM and IgA dimers. 3. The relative binding of the CNBr fragments to IgM has been measured and indicates that domains 1 and 3 are directly involved. 4. A possible role for domain 2 is less clear and domains 4 and 5 do not participate in binding.

Amino Acid Sequence↗
PubMed1987

Uncoupling of the secretory pathways for IgA and secretory component by cholestasis.

Circulating polymeric immunoglobulin A (IgA) binds to secretory component (SC) on the surface of rat hepatocytes and is internalized and transported by vesicles to the canalicular membrane where the IgA-SC complex is secreted into bile. To further characterize this transport pathway, we examined the effects of bile flow reduction or transient bile duct obstruction on the secretion of IgA and SC into bile. In response to gradually increasing resistance to bile flow, the biliary concentration of IgA decreased as bile flow decreased, whereas total biliary protein concentration was little changed. After 2 h of bile duct clamping, the amount of IgA secreted into bile during the postclamp period was decreased to one-tenth of control values. Similarly, transport of biosynthetically labeled monoclonal IgA ([3H]MoIgA) during the postclamp period was reduced three-fold. In contrast to the impairment in IgA secretion, secretion of SC continued at nearly normal levels after resumption of bile flow. The reduced transport of IgA was not due to a failure of IgA to reach the hepatocyte, a functional alteration of the IgA, or a decrease in the number of hepatic IgA receptors. Our studies indicate that secretion of IgA is sensitive to bile flow and that the biliary secretory pathways for IgA and SC are dissociated after brief periods of cholestasis.

Animals↗
PubMed1988

Proteolytic processing of rat liver membrane secretory component. Cleavage activity is localized to bile canalicular membranes.

Membrane secretory component (mSC) mediates the transcellular movement of polymeric IgA from the sinusoidal to the bile canalicular surface of rat hepatocytes. Prior to or concomitant with arrival at the bile canalicular membrane, mSC is cleaved, producing a soluble proteolytic fragment (fSC) which is released into the bile. Conversion of mSC to fSC occurs at the cell surface of cultured rat hepatocytes (Musil, L. S., and Baenziger, J. U. (1987) J. Cell Biol. 104, 1725-1733), suggesting that vectorial release of fSC into bile in vivo may reflect localization of a mSC-specific protease to bile canalicular membranes. We have established a reconstituted system to examine the process of specific cleavage of mSC to yield fSC and to characterize the protease activity responsible. A membrane fraction highly enriched for endocytic vesicles was found to contain approximately 90% of the [35S]Cys-mSC from metabolically labeled rat liver slices but only 5% of the cellular protein. No cleavage activity was present in these vesicles. Highly enriched bile canalicular membranes were able to mediate cleavage of metabolically labeled mSC to a fragment indistinguishable from authentic fSC. In the absence of nonionic detergent, cleavage was dependent on the presence of polyethylene glycol, presumably to mediate fusion of mSC-enriched membranes with bile canalicular membranes. Following solubilization with nonionic detergent, cleavage was no longer dependent on the addition of polyethylene glycol. Cleavage of mSC was not observed with either intact or detergent-solubilized sinusoidal, microsomal, or lysosomal membranes. We have thus identified a proteolytic activity associated with bile canalicular membranes which has the properties of a membrane protein and is likely to be responsible for production of fSC in vivo. Its highly restricted localization to the bile canalicular membrane would account for the vectorial release of fSC into the bile.

Animals↗
PubMed1984

Demonstration of secretory component, IgA, and IgM by the peroxidase-antiperoxidase technique in inverted papillomas of the nasal cavities.

Fifteen inverted papillomas were examined by the peroxidase-antiperoxidase method for their ability to synthesize secretory component (SC) and to take up IgA and IgM. In each case, SC and IgA could be localized to the apical cytoplasm of some tumor cells. In addition, secretory component, IgA, and IgM were observed as the main constituents of hyaline globules lying in the intracytoplasmic lumina of one columnar cell variant of inverted papilloma, suggesting an intact transepithelial transport mechanism of polymeric immunoglobulins. Goblet cells, found only in the transitional cell variant of inverted papilloma, did not react with anti-SC, anti-IgA, or anti-IgM. Since SC can be utilized as a marker to differentiate columnar cells from goblet cells, transitional cell papillomas may originate from undifferentiated reserve cells, which retain their capacity to differentiate into both columnar cells and goblet cells. In contrast, in columnar cell papillomas only differentiated columnar cells are integrated into the neoplastic process.

Humans↗
PubMed1998

Binding of Clostridium difficile toxin A to human milk secretory component.

Toxigenic Clostridium difficile is isolated from a majority of healthy human infants. The exact mechanism of asymptomatic colonisation is unclear; however, previous studies in this laboratory have shown that components of both the immunoglobulin and non-immunoglobulin fractions of human milk bind to toxin A and prevent its interaction with hamster intestinal brush border membranes (BBMs). Secretory IgA (sIgA) is the primary immunoglobulin found in human milk. As sIgA resists digestion in the infant stomach and passes at high levels into the colon, its ability to bind toxin A was the subject of this investigation. Purified sIgA in concentrations at and below those found in human milk inhibited the binding of toxin A to purified BBM receptors. Heating sIgA to 100 degrees C for 5 min did not affect its inhibitory activity. IgM, IgG and serum IgA did not appreciably inhibit the binding of toxin A to BBM receptors. SDS-PAGE separated sIgA into three major bands: secretory component, heavy chains and light chains. Autoradiography with radiolabelled toxin A revealed that toxin A bound to the secretory component (SC) of sIgA. When the three purified subunits of sIgA were coated on to microtitration wells, SC bound significantly more toxin A than the heavy or light chains of sIgA. Purified SC also inhibited toxin binding to receptors in a dose-dependent fashion similar to sIgA. The heavy and light chains of sIgA did not inhibit toxin A receptor binding. Removing carbohydrates from sIgA and SC by enzymic digestion showed that toxin A binds much less to deglycosylated SC than to glycosylated SC. These data suggest that SC in human milk binds to toxin A and may function as a receptor analogue, protecting human infants against C. difficile-associated disease.

Animals↗
PubMed1986

The amino-terminal domain of rabbit secretory component is responsible for noncovalent binding to immunoglobulin A dimers.

Rabbit secretory components (SC) constitute a family of markedly heterogeneous glycoproteins which are released in the secretions as free SC or as SC bound to polymeric immunoglobulins. The aim of this work was to determine the region of the SC polypeptides which is involved in IgA binding. The high and the low Mr forms of free SC (or IgA-dissociated bound SC) and the native secretory IgA complex were subjected to limited tryptic digestion. Chemically characterized peptides ranging in apparent size from 15 to 20 kDa, depending upon the allotype, were shown to be necessary and sufficient for efficient noncovalent binding to IgA dimers (subclass g). These fragments encompass the amino-terminal first domain of SC, i.e. residues 1-126, when aligned with the predicted amino acid sequence from a cDNA clone encoding the rabbit polymeric Ig receptor (Mostov, K.E., Friedlander, M., and Blobel, G. (1984) Nature 308, 37-43). The high and the low Mr forms of SC exhibited the same relative affinity for IgA dimers, suggesting that the postulated internal deletion in the smaller polypeptide (Kühn, L. C., Kocher, H.-P., Hanly, W.C., Cook, L., Jaton, J.-C., and Kraehenbuhl, J.-P. (1983) J. Biol. Chem. 258, 6653-6659) does not impair the IgA dimer recognition function.

Amino Acid Sequence↗
PubMed1999

Interleukin-4 and interferon-gamma synergistically increase secretory component gene expression, but are additive in stimulating secretory immunoglobulin A release by Calu-3 airway epithelial cells.

Interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) synergize to express polymeric immunoglobulin receptor (pIgR) but their combined effect, and that of IL-4 alone, on secretory immunoglobulin A (sIgA) release is unknown. Recently, we have developed an airway epithelial cell model that allows assessment of the integrated effect of a stimulus on pIgR gene and protein expression and sIgA release. With this model we show here that IL-4 and IFN-gamma dose-dependently increased pIgR mRNA and protein expression, and sIgA release. IFN-gamma and IL-4 induced similar maximal expression of pIgR, but IFN-gamma enhanced sIgA release more than IL-4. When added together, IL-4 and IFN-gamma synergistically increased pIgR mRNA and protein expression, but sIgA release was stimulated in an additive manner. Thus, IL-4 and IFN-gamma may be implicated in the increase of sIgA levels as found in mucosal inflammatory diseases. In addition, our results indicate that transport and release of empty pIgR is subject to regulatory mechanisms different from those of pIgR with bound dimeric IgA.

Cell Culture Techniques↗
PubMed1985

[Detection of secretory immunoglobulin A (S-IgA) and secretory component (SC) in cystic fluids from ovarian tumors and ovarian cysts].

Secretory immunoglobulin A (S-IgA) and secretory component (SC) were estimated by means of double radial immunodiffusion and single radial immunodiffusion in 22 cystic effusions from 22 patients with cystic ovarian tumours and ovarian cysts. For the quantitative estimations of S-IgA a S-IgA standard preparation was used. S-IgA and/or SC were demonstrable in all cases of the mucinous cystadenomas and also in the cystic effusions of an endometrioid adenocarcinoma and of a serous cystadenoma. The S-IgA values were estimated between 230 and 1330 mg/1. The estimation of S-IgA in cystic effusions is useful to support and extend the histological diagnosis of ovarian tumours.

Adenocarcinoma↗
PubMed1983

Distribution of secretory component in non-cancerous human gastric mucosa.

Immunological detection of secretory component (SC) in non-cancerous human gastric mucosa was carried out by the peroxidase-anti-peroxidase (PAP) method using several fixatives. SC was detected in the generative zone or mucous neck of normal gastric mucosa without intestinal metaplasia (IM) and in absorptive cells of IM of the stomach. The deep part of complete type IM showed a larger amount of SC than the superficial part. These findings suggested that the appearance of SC in gastric mucosa would be relevant to the immunity of glandular epithelium. In addition, SC was also detected in pyloric gland cells in specimens fixed with cold 95% ethanol. From these results, SC was considered to be a normal constituent and one of the developmental proteins in the gastric mucosa.

Gastric Mucosa↗
PubMed1997

Serologic assay for secretory component distinguishes mechanical from hepatocellular cholestasis in humans.

In rats, serum secretory component (SC) is elevated in mechanical but not hepatocellular cholestasis. To determine if serum SC might distinguish cholestatic syndromes in humans, serum samples were obtained from control subjects and patients with mechanical and hepatocellular cholestasis. Equal volumes of serum were assayed for SC by immunoblotting with an antibody specific for human SC. Quantitative densitometry of these immunoblots showed that in mechanically obstructed patients serum SC was reversibly elevated to a level approximately 10-fold higher than that of patients with hepatocellular cholestasis (P < 0.001). When comparing the two cholestatic groups, levels of serum alkaline phosphatase, but not bilirubin and alanine aminotransferase, were significantly higher in the group with mechanical cholestasis (P < 0.01). When comparing individual patients, serum SC was more reliable than alkaline phosphatase in distinguishing the two cholestatic syndromes (P < 0.05). Thus, serum SC may distinguish mechanical from hepatocellular cholestasis in humans.

Alanine Transaminase↗
PubMed1993

Interferon-gamma stimulation of messenger RNA for human secretory component (poly-Ig receptor) depends on continuous intermediate protein synthesis.

Secretory component (SC or poly-Ig receptor) plays a key role in mucosal external body fluids. The aim of this study was to elucidate the molecular events underlying IFN-gamma-dependent up-regulation of SC. Using a human SC cDNA clone isolated by our laboratory, we found that IFN-gamma up-regulated SC mRNA levels in a time- and concentration-dependent manner. Moreover, in situ hybridization showed a striking increase of SC mRNA-positive HT-29 cells after IFN-gamma treatment. Inhibition with 5,6-dichloro-1-beta-ribofuranosyl-benzimidazole (DRB) indicated a half-life for IFN-gamma-induced SC mRNA of approximately 1 h. Cycloheximide (CHX) abolished the IFN-gamma-induced accumulation of SC mRNA in a reversible manner; the time-course suggested that de novo synthesis of protein factor(s) with a turnover time shorter than 6 h was required for accumulation of SC message. IFN-gamma-stimulated up-regulation of SC expression therefore appears to depend on molecular events similar to those taking place for the activation of several other genes in the Ig supergene family.

Colonic Neoplasms↗
PubMed2003

Free secretory component from cystic fibrosis sputa displays the cystic fibrosis glycosylation phenotype.

Secretory IgA contributes to humoral defense mechanisms against pathogens targeting mucosal surfaces, and secretory component (SC) fulfills multiple roles in this defense. The aims of this study were to quantify total SC and to analyze the form of free SC in sputa from normal subjects, subjects with asthma, and subjects with cystic fibrosis (CF). Significantly higher levels of SC were detected in CF compared with both other groups. Gel filtration chromatography revealed that SC in CF was relatively degraded. Free SC normally binds interleukin (IL)-8 and inhibits its function. However, in CF sputa, IL-8 binding to intact SC was reduced. Analysis of the total carbohydrate content of free SC signified overglycosylation in CF compared with normal subjects and subjects with asthma. Monosaccharide composition analysis of free SC from CF subjects revealed overfucosylation and undersialylation, in agreement with the reported CF glycosylation phenotype. SC binding to IL-8 did not interfere with the binding of IL-8 to heparin, indicating distinct binding sites on IL-8 for negative regulation of function by SC and heparin. We suggest that defective structure and function of SC contribute to the characteristic sustained inflammatory response in the CF airways.

Adult↗
PubMed1995

Urinary secretory immunoglobulin A and free secretory component in pyelonephritis.

The immune defense mechanisms of mucosal surfaces involve secretory immunoglobulin A (sIgA) antibodies and, to a lesser degree, other specific and nonspecific immune factors. These antibodies are dependent on a secretory component (SC) for their transmission through the epithelium. This SC is also secreted without Ig as free SC (FSC). The kidney does produce these proteins; however, the ability of the lower urinary tract to secrete them has not been shown. Thus, an upper urinary tract infection should produce more urinary sIg and possibly more FSC than a lower tract infection. To demonstrate this, urine was obtained from normal controls (N = 33), cystitis patients (N = 22), and pyelonephritis patients (N = 27). Monoclonal antibodies binding to specific conformational epitopes were used in an enzyme-linked immunosorbent assay to detect the levels of sIgA and FSC in these groups. Previous sIgA measurements have been hampered by lack of specificity of the capture antibody. Urine creatinine was obtained to correct for the effect of diuresis. A one-tailed Student's t-test for nonparametric populations was performed to assess differences. The sIgA levels in the normal and cystitis groups were equivalent (1.4 micrograms/mg/mL and 1.3 micrograms/mg/mL, respectively; P = 0.32). When these two groups were compared with the pyelonephritis group (24.1 micrograms/mg/mL), a statistically significant difference was seen (P = 0.012 and P = 0.011, respectively), with no overlap. There was a statistical difference in the levels of FSC in these same groups, but a large degree of overlap.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗