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PubMed1976

Secretory component deficiency. A disorder of the IgA immune system.

We studied a 15-year-old boy with chronic intestinal candidiasis who had normal serum IgA levels without IgA in his secretions. There was an elevated number of peripheral blood lymphocytes bearing surface IgA. In addition, the lymphocytes cultured in vitro with pokeweed mitogen produced IgA as well as other immunoglubulins. Despite this evidence of normal IgA synthetic capacity, the patient had greatly diminished levels of IgA in the saliva and jejunal fluid, and, as estimated by 14C-L-leucine incorporation, could not synthesize IgA locally at intestinal-mucosal sites. Finally, the patient had no detectable free secretory component in saliva or jejunal fluid in contrast to normal persons and to patients with IgA deficiency. The basis of this disorder is probably a defect in the homing of IgA precursor cells to secretory sites or in the selective proliferation/differentiation of IgA cells at such sites.

Adolescent↗
PubMed1996

Investigation of activation markers demonstrates significant overexpression of the secretory component on salivary glands epithelial cells in Sjögren's syndrome.

Labial salivary glands biopsies (LSG) performed to support clinical anomalies suggestive of Sjögren's syndrome (SS) sometimes fail to confirm the diagnosis. Here we investigated whether epithelial activation markers could provide further information. Frozen cut sections of LSG from 40 patients, including 23 confirmed SS, were examined in immunofluorescence for the expression of HLA class II molecules, the protector of apoptosis bcl-2, the intercellular adhesion molecule 1 (ICAM-1) and secretory component (SC). Class II molecules were highly expressed on epithelial cells in SS patients (DR > DP > DQ). Bcl2 was expressed in infiltrating cells which were more numerous in the group of SS patients. ICAM-1 was present on endothelial and infiltrating cells of a few patients in both groups. Epithelial cells produced SC in 83% of SS patients samples vs four cases of non-SS patients (P = 0.0002). Investigation of the expression of SC on glandular epithelial cells could therefore be proposed as a marker of SS.

Adult↗
PubMed1991

Glucocorticoid regulation of the humoral immune system. Dexamethasone stimulation of secretory component in serum, saliva, and bile.

Dexamethasone, a potent synthetic glucocorticoid, has been shown to increase polymeric immunoglobulin A (IgA) and antigen-specific IgA antibody levels in serum. This response coincided with a decline in IgA and IgG levels in saliva and vaginal secretions after dexamethasone treatment. To investigate the mechanism(s) of glucocorticoid action responsible for the accumulation of polymeric IgA in serum, we undertook in the present study to determine whether dexamethasone alters the production of secretory component (SC). SC is the receptor responsible for transporting IgA from blood and tissues into bile and external secretions. Dexamethasone administered in vivo increased SC levels in serum in a dose- and time-dependent manner. When bile and saliva samples were analyzed, dexamethasone treatment increased saliva SC levels and the production rate of SC by the liver, but had a pronounced inhibitory effect on both bile and salivary levels of IgA. As judged by HPLC, the majority of SC in blood was associated with polymeric IgA and not with monomeric IgA. Immunoblots showed the presence of a 29/27K doublet band of SC in serum from control- and dexamethasone-stimulated rats. These findings indicate that the elevation of polymeric IgA levels in serum after dexamethasone treatment may be due to decreased clearance of IgA into bile. Further, it demonstrates that liver production rate of SC as well as saliva and serum SC levels increase with glucocorticoid treatment. This findings suggests that glucocorticoids, which are known to stimulate hepatocyte SC synthesis in vitro, increase SC levels in blood, possibly as SC fragments that are capable of binding polymeric IgA and retarding its clearance from blood to bile.

Animals↗
PubMed1985

In vivo proteolytic activity of the mammary gland. Contribution to the origin of secretory component, beta 2-microglobulin and bovine-associated mucoprotein (BAMP) in cows milk.

Milk samples were collected from Holstein-Friesian cows at various times after milking (10-30 min; 30 min-10 hr) and treated with a protease inhibitor or control solution. Samples were then fractionated into whole, skimmed and cell-free skimmed milk aliquots. Some animals were treated with E. coli endotoxin prior to sample collection. The concentrations of three membrane-associated proteins (MAP), beta 2-microglobulin (beta 2M), secretory component (SC) and bovine-associated mucoprotein (BAMP) as well as albumin were measured in each aliquot to determine if in vivo proteolysis of milk elements could explain the origin of these MAP in milk. All three MAP could be localized on milk fat globules (MFG) and alveolar epithelial cells of the gland. Data revealed that all BAMP in milk can be accounted for by in vivo proteolytic degradation of MFG while most beta 2M is derived by similar degradation, from cellular elements in milk, presumably monocytes. Experiments with endotoxin which elevate PMN levels, failed to influence the release of any MAP while elevating albumin levels by greater than 10-fold. Based on these studies, SC release into milk cannot be ascribed to a protease-dependent mechanism.

Animals↗
PubMed1997

Characterization of a novel monoclonal antibody which identifies chicken secretory component.

A mouse monoclonal antibody (MAb) produced against chicken biliary IgA (bIgA) was characterized. This MAb, designated A63, reacted with purified chicken biliary IgA (bIgA) but not with serum IgA in ELISA. In Western blot analysis, it recognized an 80-kDa protein associated with bIgA. MAb A63, but not a chicken IgA-specific MAb, reacted strongly with chicken embryo allantoic fluid, a rich source of SC, in immunoblots. In immunohistostained sections of chicken intestines A63 stained intracytoplasmic vacuoles in the enterocytes consistent with goblet cells, whereas the IgA-specific MAb predominantly stained plasma cells in the lamina propria. Whereas the IgA-specific MAb only reacted with the homologous IgA, MAb A63 reacted with bile samples of chicken, turkey, and quail but not of duck or pheasant. These data collectively indicated that MAb A63 recognized an avian secretory component (sc).

Animals↗
PubMed1991

Transforming growth factor-beta enhances secretory component and major histocompatibility complex class I antigen expression on rat IEC-6 intestinal epithelial cells.

Transforming growth factor-beta (TGF-beta) has been implicated as having a role in inflammatory responses by inducing cellular infiltration and the release of inflammatory cytokines. In this study, the IEC-6 rat intestinal epithelial cell line was used as a model to assess the effect of TGF-beta 1 on the expression of various plasma membrane determinants. TGF-beta 1 induced a dose-dependent increase in the percentage of cells expressing surface secretory component (SC) and class I major histocompatibility (MHC) antigens. However, the expression of class II MHC was unaffected. In contrast, epidermal growth factor had no effect on any of the surface proteins studied. The TGF-beta 1-enhanced expression of SC was accompanied by an enhanced binding of polymeric, but not monomeric, immunoglobulin A (IgA). Preincubation of the TGF-beta 1-treated cells with an anti-human beta-galactosyltransferase (beta-GT) antiserum did not block the binding of the anti-SC antibody, indicating that the TGF-beta-induced increase in SC staining was due to SC expression and not the polymeric immunoglobulin-binding enzyme, beta-GT. These results indicate that TGF-beta 1 may be important in immune functions involving intestinal epithelial cells by enhancing the expression of surface class I MHC antigens and SC, a protein responsible for the transport of polymeric IgA into the intestinal lumen.

Animals↗
PubMed2003

IgA and secretory component (SC) in the third eyelid of domestic animals: a comparative study.

OBJECTIVE: The third eyelid of domestic animals is important for the production and distribution of tears, in removing ocular debris and in protection of the globe, and has significant immunologic functions. Although it is known that tears contain antibodies of the immunoglobulin A (IgA) isotype which are produced mainly by plasma cells of the lacrimal gland, very little is known about the antibody repertoires in the third eyelid of domestic animals. To assess whether IgA is derived from local synthesis, we analyzed the location of IgA-producing cells and the cellular distribution of secretory component (SC) in the third eyelid of domestic animals in a comparative study. ANIMAL STUDIED: A total of 83 third eyelids of dogs, cats, pigs, cows, sheep, goats and horses were investigated in the course of this study. PROCEDURES: Third eyelids were obtained immediately after death, cut length-wise, fixed overnight and processed for immunohistochemical detection of IgA and SC by the ABC technique. RESULTS: The results show that IgA-producing plasma cells are densely populated in subepithelial spaces of the surface epithelium as well as in the nictitating gland in a species-specific manner. In contrast, the SC could be demonstrated exclusively in glandular acinar and ductal epithelial cells and in different cell types of the surface epithelium, preferentially located on the bulbar side of the nictitating membrane. CONCLUSION: It is suggested that most of the SC is locally produced by resident plasma cells and subsequently transferred through the surface epithelium and glandular duct cells by transcytosis. This indicates that the third eyelid is an important member of the secretory immune system in domestic animals.

Animals↗
PubMed1982

Immunoglobulin classes, secretory component, and sperm agglutinins in semen after vasovasostomy.

The immunoglobulin classes of the sperm-agglutinating antibodies in the seminal fluid and serum from four vasovasostomized men, as well as in operatively obtained testis-epididymis fluid from two of them, were investigated by specific solid-phase absorption of IgG, IgM, and IgA. In two patients the major part of the seminal agglutinins was IgA, and in one IgG, indicating that both local production and diffusion of sperm agglutinins from serum to the testis-epididymis compartment may take place. The total levels of immunoglobulins in seminal fluid generally increased after the operation, and IgM was present in two postvasovasostomy samples. This suggests a pathotopic potentiation effect of the vasectomy on the epithelial lining of the testis-epididymis compartment. Comparison of the results of solid-phase absorption with anti-IgA and anti-secretory component (SC) pointed to the presence of "free" SC in postvasovasostomy seminal fluid.

Agglutinins↗
PubMed1990

Immunohistochemical analysis of the binding of human IgM to secretory component present in normal adult colon epithelia, but not in colon cancer and fetal colon epithelia.

We have analysed the binding of human IgM to fetal, normal adult and malignant colo-rectal tissues. Using an indirect immunoperoxidase technique on sections of frozen tissues human IgM binds to all normal adult colo-rectal epithelia (n = 15) tested. By contrast, 9 out of 25 colo-rectal adenocarcinomas were negative, and in the remaining 16 the staining reaction varied from staining of all the cancer areas to focal staining of a few areas. Human IgM did not bind to 14 samples of fetal intestinal epithelium (gestational age of 6-14 weeks). The binding of IgM was found to be mediated by secretory component (SC) as anti-SC antibody (anti-SC) showed a similar staining pattern as IgM and the IgM binding could be blocked by anti-SC. SC was also demonstrated in glandular epithelia of sections of all normal breast epithelia but only in 10 out of 15 breast adenocarcinomas. The loss of IgM binding and SC could not be correlated to the morphology of the adenocarcinomas. The observations on fetal, normal adult and malignant tissue suggest that IgM binding and SC may be gradually lost during dedifferentiation of normal cells, to malignant colo-rectal or breast epithelia.

Adenocarcinoma↗
PubMed1999

Covalent homodimers of murine secretory component induced by epitope substitution unravel the capacity of the polymeric Ig receptor to dimerize noncovalently in the absence of IgA ligand.

Recombinant secretory immunoglobulin A containing a bacterial epitope in domain I of the secretory component (SC) moiety can serve as a mucosal delivery vehicle triggering both mucosal and systemic responses (Corthésy, B., Kaufmann, M., Phalipon, A., Peitsch, M., Neutra, M. R., and Kraehenbuhl, J.-P. (1996) J. Biol. Chem. 271, 33670-33677). To load recombinant secretory IgA with multiple B and T epitopes and extend its biological functions, we selected, based on molecular modeling, five surface-exposed sites in domains II and III of murine SC. Loops predicted to be exposed at the surface of SC domains were replaced with the DYKDDDDK octapeptide (FLAG). Another two mutants were obtained with the FLAG inserted in between domains II and III or at the carboxyl terminus of SC. As shown by mass spectrometry, internal substitution of the FLAG into four of the mutants induced the formation of disulfide-linked homodimers. Three of the dimers and two of the monomers from SC mutants could be affinity-purified using an antibody to the FLAG, mapping them as candidates for insertion. FLAG-induced dimerization also occurred with the polymeric immunoglobulin receptor (pIgR) and might reflect the so-far nondemonstrated capacity of the receptor to oligomerize. By co-expressing in COS-7 cells and epithelial Caco-2 cells two pIgR constructs tagged at the carboxyl terminus with hexahistidine or FLAG, we provide the strongest evidence reported to date that the pIgR dimerizes noncovalently in the plasma membrane in the absence of polymeric IgA ligand. The implication of this finding is discussed in terms of IgA transport and specific antibody response at mucosal surfaces.

Animals↗
PubMed1982

Secretory component and serum immunoglobulin A deficiencies with intestinal autoantibody formation and autoimmune disease: a family study.

A teenage boy with both secretory component deficiency and selective serum immunoglobulin A deficiency also developed pernicious anemia, insulin-dependent diabetes mellitus, pancreatic insufficiency, lymphopenia, intestinal candidiasis, and anti-intestinal antibody. The patient's father had pernicious anemia and diabetes mellitus while the paternal grandfather also had pernicious anemia. Because the patient had inherited the paternal grandmother's human leukocyte antigen complex, there was no direct association between pernicious anemia and the genetic markers. The presence of multiple immunologic abnormalities in a single patient supports the concept of an underlying defect in immune regulation as a central factor in the pathogenesis of these disorders.

Adolescent↗
PubMed1975

Localization of secretory IgA, secretory component, and alpha chain in the mammary gland of lactating rabbits by immunoelectron microscopy.

The different steps in the processing of secretory IgA (sIgA) of the mammary gland of lactating rabbits have been investigated with immunoelectron microscopy. The method employed consists of an indirect localization sequence, in which the immunologic reagents are allowed to diffuse into the fixed tissue prior to embedding and thin sectioning. In the first step, goat F(ab')2 fragments directed against sIgA, secretory component (SC), or alpha chain were used. To visualize the location of these first-step antibody fragments, a second Fab fragment directed against goat F(ab')2 antibody was prepared and coupled to a small heme octapeptide that possessed peroxidatic activity, the reaction product of which is visible by electron microscopy. Both the epithelial cell and the local plasmacytes of the mammary gland contain alpha chain, whereas SC is exclusively located in the epithelial cells. In the plasmacytes, both the cisternae of the rough endoplasmic reticulum and the saccules and vesicles of the Golgi complex contain alpha chain. In the epithelial cells, the elements of the Golgi complex and large apical vacuoles situated in the apical region of the cell. Based on these results, a model for processing of sIgA is proposed and discussed.

Animals↗
PubMed1986

The importance of the Fc receptors for IgA in the recognition of IgA by mouse liver cells: its comparison with carbohydrate and secretory component receptors.

The numbers of murine hepatocytes and Kupffer cells with receptors for human polymeric (pIgA) or monomeric IgA (mIgA) were determined by rosette formation with immunobeads coated with human pIgA or mIgA. About 63% of hepatocytes were found to express receptors for pIgA. Receptors for mIgA were also found in a significantly lower percentage of hepatocytes (50%). Only about 10% of Kupffer cells had this type of receptor. Blocking studies performed with purified human immunoglobulins suggested that both cells expressed a receptor that recognized the Fc portion of IgA (either pIgA or mIgA). In addition, murine multimeric MOPC-315 IgA strongly inhibited in a dose-dependent fashion the pIgA and mIgA rosette formation by both cells. When cells were incubated in the presence of a rabbit antiserum to secretory component (SC), only pIgA rosette-forming hepatocytes were partially inhibited. No such inhibition was seen when an antiserum to human IgG was used. Both galactose and mannose monosaccharides failed to inhibit the IgA rosette formation by either type of cell. These results show that murine hepatocytes, besides having SC receptors for polymeric IgA, also express receptors for the Fc portion of IgA. The carbohydrate receptors did not seem play any role in the recognition of IgA. The fact that Kupffer cells exclusively present Fc alpha R suggests that monomeric and polymeric IgA, either in form of immune complexes or not, are handled in a different manner by the liver cells.

Animals↗
PubMed1996

Lack of association of secretory component with IgA in J chain-deficient mice.

J chain has been proposed to play a role in the mucosal transport of polymeric Igs (pIg) by the polymeric Ig receptor (pIgR). We have previously reported the generation of J chain-deficient mice. These mice exhibited elevated serum IgA and depleted biliary and fecal IgA levels compared with wild-type mice. We report here that, unlike the IgA levels in bile and feces, IgA levels in local mucosal and glandular secretions were not depressed in J chain-deficient mice. Breast milk, intestinal mucosal surface, and nasal wash IgA levels in the mutant mice were similar to wild-type mice while bronchoalveolar lavage IgA levels were higher in the J chain-deficient animals. Western blot analysis with an Ab to secretory component (SC), the portion of the pIgR that remains bound to pig in secretions, and immunoprecipitation with Abs directed against IgA showed that secreted IgA was associated with SC in wild-type but not J chain-deficient mice. The IgA in wild-type secretions was polymeric while the secretions of J chain-deficient mice contained IgA monomers and other nonpolymeric IgA forms. Thus, J chain is not essential for IgA transport by intestinal, mammary, or respiratory epithelia but is necessary for the stable association of pIgA with SC. Further, we suggest that J chain-deficient IgA is transported into secretions by a different mechanism than wild-type IgA.

Animals↗
PubMed1998

Primary rat lacrimal cells undergo acinar-like morphogenesis on reconstituted basement membrane and express secretory component under androgen stimulation.

Single cells or small cell clusters, isolated from the rat lacrimal gland, were incubated on reconstituted basement membrane (matrigel) in a well-defined serum-free medium. During the first days of culture, cells reassociated and reorganized in structures resembling acini. These multicellular structures, maintained in culture for 2 weeks, consisted of well-polarized cuboidal cells surrounding a central lumen and exhibiting apically located microvilli. Myoepithelial cells were observed at the periphery of the acinar structures. Both in the native lacrimal and in the cultured aggregates, epithelial cells displayed strong immunoreactivity for cytokeratin 8, while myoepithelial cells were immunoreactive for vimentin and alpha-smooth muscle isoactin. These data indicate that the cultured aggregates closely mimic the in vivo architecture of lacrimal glands both by morphology and immunohistochemistry. We further demonstrated the presence of an intact androgen receptor and the ability of the cultured aggregates to respond to androgens with increased secretion of the secretory component. Comparable androgen responses were observed in lacrimal gland cultures of 5-week-old male and female rats. In conclusion, we report a morphologically and functionally differentiated culture system of primary rat lacrimal cells, in which androgen-regulated gene expression was observed. This culture model provides a unique experimental paradigm for studying the effects of hormones, cytokines, and growth factors on the morphogenesis, growth, and functional differentiation of lacrimal glands.

Actins↗
PubMed1989

Secretory component in differentiating normal epithelium, benign lesions and malignancy in the human breast as monitored by monoclonal antibodies.

An immunohistochemical study of the expression of the secretory component (SC) in human mammary gland epithelium at various stages of differentiation, as well as in benign and malignant breast tumours, was undertaken using three mouse monoclonal antibodies. Antibody RICEO-SC-05 (SC-05), raised against a partially purified preparation of human SC, and reacting with a reduction-resistant epitope present in both free and polymeric immunoglobulin-bound SC, was compared in immunoperoxidase and immunofluorescence studies on a diverse range of normal tissues, to 2 reference anti-SC antibodies (LICR-LONLC28 and RICEO-MFG-12). All three antibodies reacted with secretory epithelia only, consistent with known patterns of expression of SC in tissues, although there was an unexpected reaction by all anti-SC antibodies with some Hassal's corpuscles of the thymus. Staining patterns seen in the normal resting, pregnant, lactating and regressing (after weaning) breast provide evidence for differentiation-associated changes in the production of SC, and support the concept of terminal ductal lobular units (TDLUs) as functional compartments of the mammary gland. SC was detected in all but one benign breast lesion (n = 53) as compared to only 24% positive cases with heterogeneous expression of SC found among 176 primary and metastatic breast carcinomas examined. In a series of 40 primary breast carcinomas and their corresponding lymph node metastases, a good overall correlation was found between the expression of SC in the matched specimens; aside from 3 heterogeneously SC-positive carcinomas whose metastatic counterparts were SC-negative. Our results demonstrate a potential application for monoclonal antibodies to SC in the study of human mammary gland differentiation, but suggest that the value of an assay for SC in the diagnosis of breast carcinomas is questionable due to the generally low expression of SC by either primary or metastatic breast lesions.

Antibodies, Monoclonal↗
PubMed1990

The epithelium overlying rabbit bronchus-associated lymphoid tissue does not express the secretory component of immunoglobulin A.

The epithelium associated with lymphoid aggregates in the bronchial tract (BALT) was studied in rabbits by immunohistochemistry using monoclonal antibodies against the secretory component (SC) of IgA. The normal bronchus epithelium was intensely labelled. In contrast, epithelium overlying the central parts of the follicles was negative. This specialized epithelium cannot participate in the SC-mediated transport of IgA, which might be a basis for the adherence and transport of microorganisms into the lymphoid tissue, thus initiating immune responses of the BALT.

Animals↗
PubMed1985

Estradiol and progesterone regulation of immunoglobulin A and G and secretory component in cervicovaginal secretions of the rat.

The present study examined the influence of hormones on the levels of immunoglobulins A (IgA) and G (IgG) and secretory component (SC) in cervicovaginal secretions of ovariectomized rats. Administration of estradiol to ovariectomized rats resulted in a significant decline in cervicovaginal content of IgA, IgG and SC. This response was dose dependent and was not prevented by administration of dexamethasone, a potent synthetic glucocorticoid, with estradiol. Treatment of ovariectomized rats with progesterone also lowered the levels of IgA and SC in cervicovaginal secretions. In contrast, dexamethasone had no apparent vaginal effect. The action of estradiol on cervicovaginal IgA, IgG and SC appears to be independent of uterine influence. This conclusion is based upon our observation that estrogen treatment of rats with ligations at their uterocervical junction still have decreased cervicovaginal IgA and SC levels. In parallel with this inhibitory effect, estradiol administration stimulated the accumulation of IgA and SC in uterine secretions. These findings indicate that the sex hormones play a role in regulating IgA, IgG and SC content in cervicovaginal secretions. In addition, it suggests that hormonal balance in females may influence the immune response of the reproductive tract to infectious disease.

Animals↗