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PubMed1989

Molecular cloning of the human transmembrane secretory component (poly-Ig receptor) and its mRNA expression in human tissues.

A 2.5 kilobase (kb) cDNA clone containing 92% of the coding region for human transmembrane secretory component (SC) or poly-Ig receptor, was isolated from a mammary gland cDNA library. The cDNA clone encoded a protein of 693 amino acids which showed 99% homology with the primary amino acid sequence of human free SC as reported by Eiffert et al. (1), and 54% homology with the deduced amino acid sequence of rabbit transmembrane SC for which cDNA was cloned by Mostov et al. (2). Northern blot analysis showed mRNA expression in various human exocrine tissues in good agreement with our previous immunohistochemical studies of SC.

Amino Acid Sequence↗
PubMed1985

Secretory IgA and secretory component in women affected by recidivant vaginal candidiasis.

Local immunity was evaluated in 47 patients affected by recidivant vaginal candidiasis and 33 control women. IgG, IgA, IgM and secretory component (SC) were determined by single radial immunodiffusion in samples of cervicovaginal secretion. IgG in dosable levels was detected in 17/47 samples (36.2%) and IgA in 15/47 patients (31.9%) whereas in the controls, the incidence was 31/33 (93.9%) for IgG and 24/33 (72.7%) for IgA. The difference was significative (P less than 0.001) for both immunoglobulins. Significant differences were not obtained for IgM. The SC was detected in 4/47 cervicovaginal secretions of patients affected by candidiasis (8.5%) whereas in the control samples the incidence was 21/33 (63.6%) (P less than 0.001). In only 2/15 patients with dosable levels of IgA (13%) the secretory nature of this immunoglobulin could be shown by its reaction with anti-SC serum. In the control group, secretory IgA was detected in 19/24 cases (79%) (P less than 0.001). Serum immunoglobulins levels were normal. The lack of secretory IgA and SC in the secretion could be related to the adherence capacity of the Candida albicans to epithelial cells.

Adhesiveness↗
PubMed1986

Human IgA as a heterovalent ligand: switching from the asialoglycoprotein receptor to secretory component during transport across the rat hepatocyte.

Asialoglycoproteins are taken up by the rat liver for degradation; rat polymeric IgA is taken up via a separate receptor, secretory component (SC), for quantitative delivery to bile. There is negligible uptake of these ligands by the converse receptor, and only a low level of missorting of ligands to opposite destinations. The two pathways are not cross-inhibitable and operate independently (Schiff, J.M., M. M. Fisher, and B. J. Underdown, 1984, J. Cell Biol., 98:79-89). We report here that when human IgA is presented as a ligand in the rat, it is processed using elements of both pathways. To study this in detail, different IgA fractions were prepared using two radiolabeling methods that provide separate probes for degradation or re-secretion. Behavior of intravenously injected human polymeric IgA in the rat depended on its binding properties. If deprived of SC binding activity by affinity adsorption or by reduction and alkylation, greater than 80% of human IgA was degraded in hepatic lysosomes; radioactive catabolites were released into bile by a leupeptin-inhibitable process. If prevented from binding to the asialoglycoprotein receptor by competition or by treatment with galactose oxidase, human IgA was cleared and transported to bile directly via SC, but its uptake was about fivefold slower than rat IgA. Untreated human IgA was taken up rapidly by the asialoglycoprotein receptor, but depended on SC binding to get to bile: the proportion secreted correlated 1:1 with SC binding activity determined in vitro, and the IgA was released into bile with SC still attached. These results demonstrate that human IgA is normally heterovalent: it is first captured from blood by the asialoglycoprotein receptor, but escapes the usual fate of asialoglycoproteins by switching to SC during transport. Since the biliary transit times of native human and rat IgA are the same, it is probable that the receptor switching event occurs en route. This implies that the two receptors briefly share a common intracellular compartment.

Animals↗
PubMed1985

Ontogenic changes in secretory component expression by villous and crypt cells of rat small intestine.

In order to determine whether the rat small intestine exhibits quantitative changes in the synthesis of the secretory component (SC) during growth, epithelial villus and crypt cells were isolated from jejunal segments at intervals after birth up to adulthood. SC concentration was measured in each cell fraction by immunoradiometric assay and compared to sucrase activity, an enzyme marker of the differentiated villus enterocyte. The following results were observed. (i) Adult rats showed a characteristic decreasing concentration gradient of SC from the crypts (mean concentration in crypt cells: 636 +/- 173 ng/mg protein) to the villus tip (mean concentration in villus cells: 152 +/- 17 ng/mg protein). This gradient was the reverse of that found for sucrase activity. (ii) In young sucklings (10 days old), SC was virtually absent in both villus and crypt cells, but its concentration progressively increased in weanling rats and reached adult levels by day 40 postpartum. (iii) The crypt to villus cell gradient of SC, absent in sucklings up to day 20, developed during the fourth postnatal week. (iv) Treatment of 10-day-old suckling pups with pharmacological doses of either corticosterone or L-thyroxine for 3 consecutive days failed to induce the precocious synthesis of SC by jejunal enterocytes, but produced significant (P less than 0.01) decreases in concentration. Under the same conditions, sucrase activity was markedly enhanced. In conclusion, major changes in the ability of the immature crypt cell to produce the specific receptor for transepithelial transport of polymeric immunoglobulins occur during the fourth week of rat life. The initiation of this ontogenic process is not triggered by the dietary and hormonal changes known to control the maturation of other functions linked to the differenciated villus cell, such as sucrase activity.

Animals↗
PubMed2000

Species-specific binding of human secretory component to SpsA protein of Streptococcus pneumoniae via a hexapeptide motif.

SpsA, a pneumococcal surface protein belonging to the family of choline-binding proteins, interacts specifically with secretory immunglobulin A (SIgA) via the secretory component (SC). SIgA and free SC from mouse, rat, rabbit and guinea-pig failed to interact with SpsA indicating species-specific binding to human SIgA and SC. SpsA is the only pneumococcal receptor molecule for SIgA and SC as confirmed by complete loss of SIgA and SC binding to a spsA mutant. Analysis of recombinant SpsA fusion proteins showed that the binding domain is located in the N-terminal region of SpsA. By the use of different truncated N-terminal SpsA fusion proteins, the minimum binding domain was shown to be composed of 112 amino acids (residues 172-283). The sequence of this 112-amino-acids domain was used to spot synthesize 34 overlapping peptides, consisting of 15 amino acids each, with an offset of three amino acids on a cellulose membrane. One of the peptides reacted specifically with both SIgA and SC. By using a second membrane with immobilized synthetic peptides of decreasing length containing parts of the identified 15-amino-acid motif a hexapeptide, YRNYPT was identified as the binding motif for SC and SIgA. SpsA proteins with a size smaller than the assay-positive domain of 112 amino acids were able to inhibit the interaction of SIgA and pneumococci provided they contained the binding motif. The results indicated that the hexapeptide YRNYPT located in SpsA of pneumococcal strain type 1 (ATCC 33400) between amino acids 198 and 203 is involved in SIgA and SC binding. Because synthetic peptides containing only parts of the hexapeptide also assayed positive, these results further suggest that at least the amino acids YPT of the identified hexapeptide are critical for binding to SC and SIgA. Amino acid substitutions in the identified putative binding motif abolished SC-/SIgA-binding activity of the mutated SpsA protein, confirming the functional activity of this hexapeptide and the critical role of the amino acids YPT in SC and SIgA binding. Identification of this motif, which is highly conserved in SpsA protein among different serotypes, might contribute towards a new peptide based vaccine strategy.

Amino Acid Sequence↗
PubMed1991

Determination of the molecular structure of the human free secretory component.

Here, we present the experimental data, leading to determination of the primary structure, the linkage of the carbohydrates and the arrangements of the disulfide bonds of the human free secretory component. Methods of protein chemistry were used. The protein can be divided into five homology regions and is a member of the immunoglobulin superfamily.

Amino Acid Sequence↗
PubMed1975

Secretory component and sudden-infant-death syndrome.

Post-mortem specimens of blood, respiratory-tract washings, bronchopulmonary tissue, spleen, and thymus were examined for respiratory viruses, immunoglobulins, and secretory component (S.C.) in eight infants with sudden-infant-death syndrome (S.I.D.S) and in eight other (control) infants with an identifiable cause of death. Serum-immunoglobulin levels were similar in infants with S.I.D.S. and in control infants. In some S.I.D.S. cases serum-IgM was slightly raised. Respiratory syncytial virus was found in the pulmonary tissues of five S.I.D.S. patients but no viruses were isolated from other subjects. However, in one control subject parainfluenza type-3 viral antigen was detected in the bronchial tissue. In all patients with S.I.D.S., immunological reactions and fluorescent antibody staining for S.C. in the broncho-pulmonary epithelium were absent or grossly reduced. The levels of IgG and IgM in bronchial washings were unremarkable. These observations suggest a possible defect in respiratory mucosal defence in patients with S.I.D.S.

Antigens, Viral↗
PubMed1988

Rabbit secretory components of different allotypes vary in their carbohydrate content and their sites of N-linked glycosylation.

The asparagine-linked glycosylation sites in rabbit high and low Mr secretory components (SC) have been determined for the three known allotypes, t61, t62, and t63. Purified SC polypeptides were subjected to mild periodate oxidation of terminal nonreducing sugars followed by selective reduction with [3H]sodium borohydride, SC polypeptides were further proteolytically cleaved, and the 3H-labeled peptides were isolated and characterized. Both high and low Mr SCs of the three allotypes possess a common glycosylation site at the asparagine residue position 400, whereas the second site, in the amino-terminal domain of SC, was found to be variable: the t61 and t63 allotypes contained a glycosylation site at positions 70 and 90, respectively. Moreover, although the t62 allotype was found to contain a triplet acceptor site (N-X-S) at positions 90-92, analyses showed that less than 30% of the t62 allotype peptides encompassing this region were glycosylated at residue 90. Furthermore, the amino acid sequence of the t61 SC in the region of residues 69-90 varies by 8 and 10 amino acid substitutions when compared with the t62 and t63 allotype sequences, respectively. However, neither the variation in amino acid sequence nor the variation in degree or site of glycosylation measurably affected the non-covalent binding of domain 1 to dimeric IgA.

Animals↗
PubMed1986

Immunoglobulin and secretory component regulation in the rat uterus at the time of decidualization.

To determine the effect of decidualization on uterine immunoglobulins (Igs), we measured the levels of IgG, IgA, and secretory component (SC) after induction of artificial decidual cell reactions (DCR) in hormonally primed ovariectomized rats. When progesterone-treated (2.5 mg/day, 3 days) rats received an intraluminal instillation of oil or a needle scratch stimulation in one uterine horn, the stimulated horn had an increase in wet weight and cytoplasmic protein relative to the contralateral horn. Under these conditions, IgG levels increased 10-fold in the lumen of the stimulated horn. This response was selective for IgG, because induction of DCR had no effect on accumulation of IgA or SC in the stimulated horn. The progesterone-induced accumulation of IgG after DCR was further enhanced by estradiol. The addition of a small amount of estradiol (0.2 microgram) on day 3 of a 4-day progesterone pretreatment resulted in further increases in both the wet weight of the stimulated horn and the concentration of IgG in the lumen. The amount of IgG in the lumen of the stimulated horn was 5-fold greater than that in the stimulated horn after progesterone alone. Levels of IgA and SC, however, remained unchanged with this treatment. These results indicate that movement of IgG into the uterine lumen occurs as a part of the DCR and that both an appropriate endocrine balance and physical stimulation are essential for maximal IgG accumulation. Further, they suggest that IgG may play a central role in early pregnancy, which results in the successful implantation of the blastocysts.

Animals↗
PubMed1994

Neuroendocrinimmune modulation of secretory component production by rat lacrimal, salivary, and intestinal epithelial cells.

PURPOSE: To evaluate the kinetics, receptor specificity, molecular basis, and site selectivity of the endocrine and neural regulation of secretory component (SC) synthesis by rat lacrimal gland acinar cells. METHODS: Acinar cells from the rat lacrimal and submandibular glands, as well as epithelial cells (IEC-6) from the rat small intestine, were cultured in supplemented, serum-free media and treated with dihydrotestosterone, cholera toxin, carbachol, vehicle, or other agents for varying time periods. Media SC levels were measured by radioimmunoassay. RESULTS: The authors' findings with lacrimal gland acinar cells demonstrate that: a significant, temporal delay exists between the initiation of stimulatory or inhibitory signals and the eventual cellular SC response to regulatory compounds; the parasympathetic analogue, carbachol, exerts a dual effect on SC output, i.e., an early stimulation (hours) followed by an extended suppression (days); the androgen and cholinergic control of SC is receptor-mediated; and the androgen modulation of SC may involve the induction of gene expression. In addition, the authors' results show that distinct, tissue-specific variations occur in the nature of SC regulation: Compounds that control SC output by lacrimal acinar cells do not necessarily alter SC production by epithelial cells from the rat submandibular gland or small intestine. CONCLUSIONS: These findings advance the authors' understanding of the neuroendocrine regulation of SC synthesis in acinar cells from the lacrimal gland. Moreover, the authors' results indicate that the nature of the neural, endocrine, and immune control of lacrimal SC may be unique.

Animals↗
PubMed1987

Interferon-gamma enhances expression of secretory component, the epithelial receptor for polymeric immunoglobulins.

Recombinant interferon-gamma (IFN-gamma) increased in a dose-dependent manner the intracellular pool, the membrane expression, and the shedding of secretory component (SC) in human colonic adenocarcinoma cell line (HT-29). A similar dose-response relationship was observed when we examined the binding of polymeric IgA to HT-29 cells treated with IFN-gamma, thus reflecting expression of functional SC. Because IFN-gamma is produced by T cells during immune responses, activated T cells may be able to promote the external transport of dimeric IgA and pentameric IgM and thereby enhance the efferent limb of the secretory immune system. This is, therefore, the first observation indicating how the secretory transport capacity may be adjusted to increased local immunoglobulin production.

Adenocarcinoma↗
PubMedDate not supplied

Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulins.

J chain is a polypeptide of molecular weight (Mr) approximately 15,000 common to human dimeric IgA and pentameric IgM. These immunoglobulin polymers show a high affinity for secretory component (SC) in vitro, a feature that, in some studies, has been claimed to be a function of the J chain. SC is a glycoprotein of Mr approximately 80,000 which is expressed on the basolateral surfaces of secretory epithelial cells where, according to a current hypothesis, it may act as a receptor for dimeric IgA and pentameric IgM which are selectively transported through secretory epithelial cells into exocrine fluids. Previous studies, however, have not excluded the possibility that secretory cells express isotype-specific Fc receptors for IgA and IgM which may be involved in epithelial transport. We now report that the adsorption of immunoglobulin polymers to SC-expressing epithelial cells depends solely on a J chain-determined binding site. This finding lends biological significance to the striking J-chain expression shown by immunoglobulin-producing immunocytes in secretory tissues.

Biological Transport↗
PubMed1993

The human colon cancer cell line CaCo-2 produces secretory components during enterocytic differentiation.

A human colon cancer cell line CaCo-2 differentiates spontaneously by expressing enterocytic phenotypes after the confluence of the culture. The authors examined a production of secretory components (SC) by CaCo-2 in relation to its differentiation. The SC production showed an increase immediately after the cells came to confluence, and reached its peak production during the 6th to the 9th day after confluence of the culture. SC production decreased remarkably after the 10th day. On the other hand, the activity of alkaline phosphatase of CaCo-2 showed a gradual increase up to the 18th day after confluence. The production of SC was not affected by the presence of dimeric IgA in the culture. Interferon-gamma enhanced SC production of CaCo-2 with dose-dependent manner. These observations indicate that capability of SC production of CaCo-2 is enhanced in the early stage of differentiation but is reduced in the late stage. Moreover, CaCo-2 provides a useful model for studying the regulation of SC production in enterocytic differentiation.

Adenocarcinoma↗
PubMed1983

Immunohistochemical studies of ulcerative colitis. With special reference to localization of immunoglobulins, secretory component, and lysozyme in view of suffering periods.

Surgically resected large bowels with ulcerative colitis (UC) and biopsies specimens from UC patients were studied immunohistochemically in terms of localization of immunoglobulins, secretory component (SC), complement (C3), and lysozyme in relation to suffering periods. In the long-standing group (suffering periods more than nine months) of UC, marked decrease or absence of IgA as well as IgM was frequently observed in the columnar epithelial cells despite residue of SC positivity. However, in the short-standing group (suffering periods from one month to four months) both SC and IgA were well preserved in the apical portion of the epithelial cells in the similar manner as observed in the control group. There was moderate to marked increase of IgA-producing cells and slight to moderate increase of IgM-producing cells in the majority of the UC cases regardless of suffering periods. Lysozyme was not demonstrable in the normal epithelial cells of the large intestine but occasionally observed in those of UC cases.

Adolescent↗
PubMed1995

Androgen control of secretory component mRNA levels in the rat lacrimal gland.

The purpose of this investigation was to determine whether the known gender-related differences in, and the endocrine control of, the production of secretory component (SC) by the rat lacrimal gland are associated with alterations in SC mRNA content. Levels of SC mRNA were measured in lacrimal tissues of intact, sham-operated, castrated, hypophysectomized, and testosterone-treated male and female adult rats by Northern blot procedures, which utilized a specific, [alpha-32P]-labelled rat SC cDNA probe. For control purposes, SC mRNA amounts were standardized to the beta-actin content in experimental blots. The location of SC mRNA in lacrimal glands was evaluated by in situ hybridization techniques, which involved exposure of tissue sections to sense or anti-sense [35S]-labelled SC RNA probes. Our results demonstrate that: (1) lacrimal glands of male rats contain a significantly greater amount of SC mRNA than those of female rats, and that this difference co-exists with distinct, gender-associated variations in the distribution of SC mRNA in lacrimal tissue; (2) orchiectomy or hypophysectomy, but not ovariectomy or sham surgery, leads to a marked decline in the lacrimal SC mRNA content; and (3) testosterone, but not placebo, administration to castrated male and female rats induces a significant increase in the SC mRNA levels in lacrimal tissue. Overall, these findings show that gender, androgens and the hypothalamic-pituitary axis exert a considerable influence on the SC mRNA content in the rat lacrimal gland.

Animals↗
PubMed1992

Secretory immune system of the male reproductive tract: effects of dihydrotestosterone and estradiol on IgA and secretory component levels.

Immunoglobulin A (IgA) is present at mucosal sites of the body which are exposed to the external environment. In this study we evaluated the levels of IgA and its transport protein secretory component (SC) in organs of the male reproductive tract of both intact and castrate-hormone-treated rats. Our goals were to determine whether these proteins are present in the male reproductive tract and whether sex hormones can influence the amounts of IgA and SC in selected organs. We found that in intact animals, IgA was present in the prostate, epididymis, vas deferens and testis and that SC levels in the prostate were 22-fold greater than in these same organs. Dihydrotestosterone (DHT) and/or estradiol, when administered to castrate animals, dramatically increased the levels of prostatic SC. In contrast, the levels of IgA were only minimally affected. DHT administration also resulted in a significant increase in SC found in the seminal vesicles. These studies demonstrate that IgA and SC are present in the male reproductive tract of the rat. Further, they show that androgens and estrogens act at selected sites in the male reproductive tract to play an important role in maintaining SC levels and thereby suggest that these hormones influence the movement of IgA from tissues into secretions.

Animals↗
PubMed1997

Human free secretory component is composed of the first 585 amino acid residues of the polymeric immunoglobulin receptor.

The main objective of this work was to unequivocally determine the C-terminal sequence of human milk free secretory component (SC). It was found to end at arginine-585, i.e. 33 amino acids downstream from the major heterogeneous C-terminal residue previously identified for colostrum SC. In contrast, our data showed that the C-terminal end of SC was found to be homogeneous. Conflicting assignments, Asp/Gln, a missing Asn-211, Asp/Asn, Glu/Gln were corrected and found to agree with the cDNA sequence. An Ala/Val substitution at position 562 (domain VI) was identified. Its genetic significance is uncertain at present.

Amino Acid Sequence↗
PubMed1984

Secretory component, alpha 1-antitrypsin and lysozyme in IgA deficient children. An immunohistochemical evaluation of intestinal mucosa.

Nine children with IgA deficiency were studied in order to evaluate by the immunoperoxidase technique the behaviour of secretory component (SC), alpha 1-antitrypsin (alpha 1-AT), lysozyme and esterase in biopsies of intestinal mucosa. In none of the studied patients was SC found to be lacking, suggesting that the epithelial transport mechanism of IgA across enterocytes was relatively normal. The distribution of SC activity in immunodeficient children differed however from that seen in control intestinal mucosa in its non-uniform distribution on the villus, abnormal retention in the Golgi region of enterocytes or exclusive activity confined to the proliferating compartment of the villus. The staining of alpha 1-AT in enterocytes was clearly obvious in all studied cases with no alteration in zonal distribution when compared with normal human mucosa. The lysozyme staining pattern was seen exclusively in Paneth cells. The non-specific esterase positive enterocytes observed in control mucosa failed to stain in biopsies from IgA deficient children. The results of this study of SC, alpha 1-AT, lysozyme and esterase may indicate that IgA deficiency is not related to a defect in enterocyte transport of immunoglobulins and confirms previously reported findings indicating the lymphoid B-cell compartment to be altered.

Biopsy↗