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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↗
PubMed1982

Structures of the carbohydrate moieties of secretory component purified from human milk.

Secretory component purified from human milk contains four asparagine-linked sugar chains in one molecule. The sugar chains were released from the polypeptide portion of secretory component by hydrazinolysis as oligosaccharides and fractionated by paper electrophoresis and paper chromatography. The sugar chains of secretory component show an extraordinarily high multiplicity. By sequential exoglycosidase digestion in combination with methylation analysis, more than 40 structurally different sugar chains were found. They were all of biantennary complex type with either Man alpha 1 leads to 6(Man alpha 1 leads to 3)Man beta 1 leads to 4GlcNac beta 1 leads to 4GlcNAc or Man alpha 1 leads to 6(Man alpha 1 leads to 3)Man beta 1 leads to 4GlcNAc beta 1 leads to 4(Fuc alpha 1 leads to 6)GlcNAc as their core portions and the multiplicity is produced by variety of the two outer chain moieties. The structures of outer chains found are GlcNAc beta 1 leads to 2, +/- NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNAc beta 1 leads to 2, Gal beta 1 leads to 4(Fuc alpha 1 leads to 3)GlcNAc beta 1 leads to 2, GL beta 1 leads to 4GlcNAc beta 1 leads to 3Gal beta 1 leads to 4(+/- Fuc alpha 1 leads to 3)GlcNAc beta 1 leads to 2, NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNAc beta 1 leads to 3 Gal beta 1 leads to 4GlcNAc beta 1 leads to 2, Gal beta 1 leads to 4(Fuc alpha 1 leads to 3)GlcNAc beta 1 leads to 3Gal beta 1 leads to 4(Fuc alpha 1 leads to 3)GlcNAc beta 1 leads to 2, and NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNAc beta 1 leads to 3Gal beta 1 leads to 4(Fuc alpha 1 leads to 3)GlcNAc beta 1 leads to 2.

Carbohydrate Sequence↗
PubMed1981

Fixation techniques for secretory component in human lacrimal gland and conjunctiva.

We compared biopsy specimens of human lacrimal gland and conjunctiva preserved by alcohol-acetic acid with the same tissues preserved by freezing to find secretory component. Secretory component was found in lacrimal gland preserved both by alcohol-acetic acid and by freezing. The structure of the tissue was better preserved with the alcohol-acetic acid fixation. Three of eight conjunctival specimens preserved by alcohol-acetic acid showed weak staining for secretory component in a few superficial epithelial cells. We found nonspecific staining of the conjunctiva with the control antiserum, rhodamine-labeled goat antibovine serum. Two specimens preserved by freezing were unreadable; four of the remaining six stained nonspecifically with the remaining two specimens stained with neither the control nor the experimental antiserum; the second may have had more staining with the experimental antiserum than with the control. We found no evidence for including the conjunctiva in the secretory IgA immune system.

Conjunctiva↗
PubMed1984

Localization and serum concentration of secretory component during massive necrosis of human liver.

The serum concentration of secretory component was monitored in 9 patients with massive liver necrosis. During acute cytolysis, no increase in serum secretory component levels was observed. Later on, patients with fulminant evolution displayed minor elevations. Values as high as those usually found in acute hepatitis were only observed in cases with delayed liver failure. In these patients, levels were elevated before failure, dropped as liver failure developed, and rose again during recovery. This evolution of serum secretory component level cannot be accounted for by a defective liver clearance of circulating secretory component. It rather suggests a release into the blood of secretory component produced in the liver by cells other than damaged hepatocytes, possibly during liver regeneration. In 3 cases, secretory component localization in the liver was demonstrated by immunocytochemistry and was compared with that in normal liver and in obstructive jaundice. In normal liver, it was restricted to portal bile duct cells and lumens. In obstructive jaundice, additional secretory component staining was found in bile canaliculi. After fatal liver necrosis, secretory component was localized to portal ducts and to a variable proportion of the cholangiocytelike cells belonging to the numerous extraportal proliferating ducts. In these structures, 0.1%, 21%, and 4% of the cells were stained 3, 8, and 30 days after maximal cytolysis, respectively. Remaining hepatocytes and bile canaliculi or bile plugs were unstained. Therefore, portal cholangiocytes and extraportal cholangiocytelike cells are probably essential sources of secretory component in human liver. We propose that proliferation of extraportal cholangiocytelike cells, expression of secretory component synthesis by these cells, and their inability to secrete secretory component in a disorganized biliary tree result in the elevated serum concentration of secretory component observed after acute liver necrosis.

Acute Disease↗
PubMed2000

The relationship of smoking, preeclampsia, and secretory component.

OBJECTIVE: We sought to determine whether total secretory component in serum is increased in women in whom preeclampsia subsequently develops. STUDY DESIGN: Serum samples were collected serially throughout pregnancy and post partum from nulliparous women (N = 1496). Serum concentrations of total secretory component were measured by an enzyme-linked immunosorbent assay in all women in whom preeclampsia developed (n = 71) and a randomly selected group of normotensive women (n = 83). RESULTS: Secretory component increased with smoking (P =.0003) and with gestation (P =.0001). In the whole group secretory component was not different in women with preeclampsia (P =.10), but there was a significant interaction of smoking, gravidity, and preeclampsia (P =.04). Among the women who smoked, secretory component was lower in women in whom preeclampsia subsequently developed compared with those who remained normotensive (P =.02). This difference was significant from 15 to 19 weeks' gestation. CONCLUSION: Very high serum concentrations of secretory component in smokers may protect against the development of preeclampsia and may indicate the involvement of mucosal tolerance.

Adult↗
PubMed1991

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↗
PubMed1987

Intracellular transport and processing of secretory component in cultured rat hepatocytes.

Membrane secretory component (mSC) mediates the transcellular transport of polymeric immunoglobulin A from the sinusoidal surface of rat hepatocytes to the bile, where it is released as a proteolytic fragment, fSC. We have examined the biosynthesis, posttranslational processing, transport, and cleavage of secretory component in cultured rat hepatocytes. Membrane secretory component is detected at the cell surface beginning 1.0-1.5 h after synthesis, whereas fSC is not found in the medium until 2.5-3 h after synthesis. Approximately 16% of metabolically labeled mSC is accessible at the cell surface at 4 degrees C. Surface accessible mSC labeled with 125I at 4 degrees C is internalized with a half-time of less than 5 min after warming to 37 degrees C and begins to be released as fSC after 20 min at 37 degrees C. Posttranslational processing and cleavage of mSC by cultured hepatocytes yields products that appear to be identical to those produced in vivo. Although the kinetics of some of these events are significantly slower than those observed in vivo, the major fraction of mSC accessible at the surface of cultured hepatocytes is internalized before cleavage to fSC, as occurs with mSC present on the sinusoidal domain of hepatocytes in vivo. Cultured hepatocytes provide a suitable model system for the examination of mSC transport and cleavage to fSC.

Animals↗
PubMed1976

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↗
PubMed1998

Interaction with secretory component stimulates effector functions of human eosinophils but not of neutrophils.

Eosinophils and their products are important in the pathophysiology of allergic inflammation in mucosal tissues. Secretory component bound to IgA mediates transepithelial transport of IgA and confers increased stability on the resultant secretory IgA; however, the effect of secretory component on the biologic activity of IgA is unknown. Here, we report that secretory IgA and secretory component preferentially activate human eosinophils. When eosinophils were stimulated with immobilized secretory IgA, degranulation and superoxide production were two- to threefold greater than when stimulated with serum IgA. In contrast, neutrophils responded similarly to secretory IgA and serum IgA. Flow cytometric analysis showed that eosinophils bound to purified secretory component. The binding of 125I-labeled secretory component was inhibited by unlabeled secretory component or secretory IgA but not by serum IgA. Superoxide production by eosinophils stimulated with cytokines or IgG was enhanced synergistically by immobilized secretory component; secretory component showed no effect on neutrophil activation. Finally, anti-CD18 mAb abolished eosinophil superoxide production stimulated with secretory IgA or secretory component but not with serum IgA, suggesting a crucial role for beta2 integrins in eosinophil interactions with secretory IgA or secretory component. Thus, secretory component plays important roles in activating eosinophil functions but not neutrophil functions. This preferential interaction between secretory component and eosinophils may provide a novel mechanism to regulate mucosal tissue inflammation.

CD18 Antigens↗
PubMed1991

Serum and bile secretory immunoglobulins and secretory component during the early postoperative course after liver transplantation.

Secretory component was assayed in serum and bile from 34 patients within 40 days after a first or a second (three cases) liver transplantation. Levels of serum secretory IgA and IgM and of a serum component referred to as immunoreactive free secretory component, identified by its reactivity with monoclonal and polyclonal antibodies specific to secretory component, were significantly elevated in all posttransplant patients compared with 45 healthy subjects and 10 kidney transplant patients (p less than 0.0001). The highest serum levels of bound secretory component and of immunoreactive free secretory component were observed in patients with acute rejection. The elevation of immunoreactive free secretory component was significantly higher in patients with rejection as compared with patients with a graft ischemia (p = 0.002) or an uncomplicated postoperative evolution (p = 0.01). The highest levels of immunoreactive free secretory component and secretory IgM were observed in a transplant patient with selective IgA deficiency. No significant difference was seen between the levels of serum immunoreactive free secretory component observed in patients with rejection and those of patients with cytomegalovirus hepatitis or sepsis. Immunoreactive free secretory component, secretory IgA and secretory IgM levels measured in the serum of three patients with primary nonfunction were lower than those observed in the other groups. Immunoreactive free secretory component bile/serum ratios calculated from 16 patients were significantly higher in patients with acute rejection than in infected patients. This study provides new insight into the mechanisms of increase of serum immunoreactive free secretory component, secretory IgA and secretory IgM in various types of liver dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

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↗
PubMed1987

The sites of tryptic cleavage in bovine secretory component: structural and functional implications.

Tryptic fragments from bovine secretory component and sIgA have been separated by HPLC and/or SDS polyacrylamide gel electrophoresis and electroblotting. Their N-terminal amino acid sequences have been determined and their positions in the secretory component molecule deduced by homology with the amino acid sequences of human secretory component and rabbit polyimmunoglobulin receptor. Taken in conjunction with the known binding affinities of the tryptic fragments, the results imply that the three most N-terminal domains of secretory component are directly involved in binding IgM and IgA dimers. The results also favour the concept of an extended 'zig-zag' structure for the secretory component molecule.

Amino Acid Sequence↗
PubMed2005

In vitro refolding of recombinant human free secretory component using equilibrium gradient dialysis.

Human secretory component (SC) is associated with secretory immunoglobulins (IgA and IgM) and serves to protect the immunoglobulin in the harsh mucosal environment. SC is derived from the polymeric immunoglobulin receptor (pIgR) which transports polymeric immunoglobulins across epithelial cells into secretions. In this present study, we describe the first cloning, expression, in vitro refolding and purification of a free form of human secretory component (rSC) containing the five functional ligand binding domains using Escherichia coli BL21 (DE3). Free rSC was refolded from inclusion bodies by equilibrium dialysis after purification by nickel affinity chromatography under denaturing conditions. Refolded rSC was purified by gel filtration chromatography. Surface plasmon resonance and dot blot association analysis have shown that purified rSC binds IgM with a physiological equilibrium dissociation constant (KD) of 4.6x10(-8) M and shares structural similarity to native SC. This provides an important step in the elucidation of the structure of this immunologically important receptor.

Binding Sites, Antibody↗
PubMed1993

The covalent linkage of secretory component to IgA. Structure of sIgA.

Immunoglobulin A which is secreted into external fluids is synthesized in plasma cells as an (IgA)2-J-chain complex. This complex docks on to the polyimmunoglobulin receptor which is located at the basolateral surface of epithelial cells. After docking the (IgA)2-J-receptor complex is internalized and processed. The polyimmunoglobulin receptor loses its C-terminal tail and thus becomes the secretory component. This secretory component is then covalently linked to the (IgA)2-J-chain complex by a disulfide bond, and protects the so formed sIgA from denaturation and proteolysis in external fluids. In order to establish this disulfide bond between IgA and the secretory component, sIgA, purified from human colostrum, was subjected to several enzymatic and chemical fragmentation reactions. One of the resulting polypeptides allowed us to characterize the covalent linkage of the secretory component to IgA in sIgA. IgA was found to be covalently linked to the secretory piece by a single disulfide bond between Cys 311 of one alpha-chain and Cys 467 of the secretory component. Cys 501 of the secretory component and Cys 311 of the other alpha-chain are blocked by cysteines. With this last paper of a series the structure of an entire sIgA molecule has been elucidated.

Amino Acid Sequence↗
PubMed1975

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↗
PubMed1989

Assays for total and antigen-specific polymeric IgA in serum based on binding to secretory component.

Binding assays with secretory component (SC) were used to detect polymeric IgA antibody to E. coli lipopolysaccharide and to estimate total polymeric IgA in sera from 14 patients with alcoholic liver disease and eight normal controls. Radioiodinated human SC was shown to bind to polymeric IgA and IgM but not to monomeric IgA, secretory IgA or IgG. Serum aliquots (0.5 ml) were totally depleted of IgM using 2 ml anti-IgM affinity columns and the effluent sera were titrated in microtitre plates coated with lipopolysaccharide, the binding of polymeric IgA being detected by adding 10 ng radiolabelled SC. Total polymeric IgA was measured via its capacity to inhibit the binding of 5 ng labelled SC to IgM coated wells, quantitation being achieved by comparison with the inhibition produced by purified polymeric IgA. Total lipopolysaccharide-specific IgA antibody was detected by ELISA in sera from both patients and controls, 1185 +/- 793 and 56 +/- 19 U/100 microliters (mean +/- SD), respectively; but polymeric IgA antibody was detected only in patients' sera (131 +/- 214 U/100 microliters). The concentration of total polymeric IgA was higher in patients' sera than in control sera (488 +/- 333 and less than 120 micrograms/ml respectively).

Antibodies, Bacterial↗
PubMed1981

Secretory-component-producing lung cancer with hypergammaglobulinemia of secretory IgA.

Studies were made on a case of well-differentiated adenocarcinoma of the lung in which the serum levels of secretory IgA (sIgA) were very high. Immunofluorescent studies showed that secretory component (SC) was found to be diffusely distributed in cancer cells. The SC was detected in the supernatant of homogenates of cancer tissues from the primary site and lymph node with metastases. The SC extracted from cancer tissue and purified colostral SC were antigenically identical. The authors conclude that the adenocarcinoma cells produced SC and secreted it into the bloodstream and that the binding of SC with polymeric IgA resulted in the hypergammaglobulinemia of sIgA. This appears to be the first reported case of SC-producing lung cancer. The authors' findings suggest that the high serum levels of sIgA in cancer patients may be due to the production and secretion of SC by tumor cells themselves rather than the reabsorption of intraluminal sIgA into the circulation through a damaged epithelium.

Adenocarcinoma↗
PubMed1985

The secretory immune system in the uterus of the pregnant rat: production of secretory component by uterine tissues.

Secretory component (SC) was measured in amniotic fluid, fetal serum, and maternal serum and compared with SC production during in vitro culture of uterine tissue segments from pregnant rats. The concentrations of SC in amniotic fluid did not change between days 14 and 20 of pregnancy. Similarly, there was no change in maternal or fetal serum during pregnancy, although, the levels of SC in sera were consistently higher than those in amniotic fluid. When uterine segments were incubated in vitro, release of SC was greater in the absence of cycloheximide than in the presence of cycloheximide at all stages of pregnancy. In contrast to SC values in amniotic fluid, however, SC production by uterine tissue changed markedly during pregnancy. SC levels were low during early pregnancy (day 7 post coitus) and increased to levels found in non-pregnant diestrous rats just prior to parturition (day 20). The findings suggest that the endocrine balance during pregnancy may play a central role in regulation of the uterus immune system. The pattern of SC release may reflect a need both to ensure protection of the fetus from the IgA immune system in early pregnancy and to prevent maternal infection during parturition by reactivation of this system.

Amniotic Fluid↗