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PubMed1990

Synergistic effect of IL-4 and IFN-gamma on the expression of polymeric Ig receptor (secretory component) and IgA binding by human epithelial cells.

The expression of secretory component (SC), the epithelial receptor for polymeric Ig, was enhanced by the addition of human rIFN-gamma or rIL-4, as revealed by the binding of radiolabeled polymeric, J chain-containing IgA or anti-SC antisera to the human colonic adenocarcinoma epithelial cell line HT-29. In combination, these cytokines exhibited a synergistic effect, and the potentiating effect of IL-4 was inhibitable by polyclonal anti-IL-4 antisera. Because the binding of radiolabeled polymeric IgA (pIgA) to HT-29 cells was inhibited by unlabeled pIgA or a polyclonal anti-SC reagent, but not by IgG, monomeric IgA, or Fab alpha fragments, we conclude that the receptor involved in the increased binding of pIgA is indeed SC. These data suggest that the expression of SC on human epithelial cells and the subsequent binding of pIgA (produced in mucosal tissues and glands by subepithelial plasma cells) is regulated by lymphokines such as IL-4 and IFN-gamma that are presumably derived from T cells found in abundant numbers in these tissues. These findings demonstrate a novel pathway of interaction between T cell products and epithelial cells that may result in enhanced translocation of large amounts of locally produced pIgA through epithelial cells into external secretions.

Biological Factors↗
PubMed1994

Evaluation of the secretory component as a prognostic variable in colorectal carcinoma.

Expression of the secretory component (SC) of IgA was investigated in normal colonic mucosa, in adenomas and in 188 colon carcinomas. Of the carcinoma patients, 149 underwent potentially curative surgical treatment. In particular, it was of interest to determine whether pathohistological or clinical parameters showed any association with the mode of SC expression in carcinomas. Irrespective of anatomical site, normal colon mucosa was generally SC-positive. Normal epithelium, however, displayed microheterogeneity in SC content, which was related to columnar and goblet-cell type and microtopographical site, implying a subtle regulatory mechanism. In contrast to adenomas, which were evenly SC-positive and showed focally weak SC expression in only 2 out of 20 cases, carcinomas were rather heterogeneous in their SC-expression pattern. In all, 48 carcinomas were entirely positive, 48 were completely negative and the remaining 92 showed various patterns of heterogeneous SC expression. The mode of SC expression was correlated with tumor staging, i.e., complete absence of SC was more often found in Dukes' C and D groups. In addition, the presence of SC in carcinomas was statistically correlated with the mucinous type. The mode of SC expression was not correlated with tumor grading and tumor location. The rate of disease-free survival and the risk of tumor-related death revealed a significant correlation with the mode of SC expression when patients who had received potentially curative or non-curative treatment were included in the log-rank test. Absence or low levels of SC expression were more frequent in the group that suffered a tumor relapse than in the recurrence-free cohort. Tumor-related death was more frequent when primaries were characterized by absence or low levels of SC expression. We conclude that absence or low levels of SC expression are an unfavorable prognostic variable in colorectal carcinoma.

Colon↗
PubMed1978

Secretory component of epithelial cells is a surface receptor for polymeric immunoglobulins.

Epithelial cells of human fetal intestines and of a colonic carcinoma cell line (HT-29) exhibited intracellular and surface binding of polymeric immunoglobulins of IgA and IgM classes; monomeric IgA and IgG did not bind to these cells. Secretory component was identified as the receptor involved in the immunoglobulin binding. This conclusion was confirmed by the following experiments: trypsin abrogated the surface binding of polymeric immunoglobulin, reappearance of surface secretory component (SC) restored immunoglobulin binding; the appearance of SC in developing fetal tissues coincided with their potential to bind polymeric immunoglobulin; anti-SC reagents inhibited the binding of immunoglobulins to epithelial cells; and SC-containing secretory IgA did not bind to the surface of HT-29 cells.

Cell Membrane↗
PubMed1983

Immunohistochemistry of gastric carcinomas and associated diseases: novel distribution of carcinoembryonic antigen and secretory component on the surface of gastric cancer cells.

Carcinoembryonic antigen (CEA) and secretory component (SC) were localized by peroxidase-labeled antibody immunocytochemistry in normal and abnormal human gastric mucosa. In normal epithelium, both glycoproteins were absent or only faintly present, but in intestinal metaplasia and carcinoma both were prominently present. CEA and SC on the surfaces of metaplastic epithelial cells were polarized. That is, CEA was expressed only on the microvillous surface and SC was expressed only on the basolateral surface. In gastric cancer, CEA and SC were distributed over the entire surface of the neoplastic cells. Thus, deviations from the normal differentiation and maturation of gastric epithelial cells were accompanied by abnormalities in surface expression of CEA and SC. These observations, together with compatible observations previously made in colonic neoplasia (DJ Ahnen, PK Nakane, and WR Brown, Cancer 49:2077, 1982), suggest that loss of polarity of surface membrane components is a characteristic of neoplastic epithelial cells.

Carcinoembryonic Antigen↗
PubMed1987

Structural variability of rabbit secretory components. Allotype-associated differences in the third, fourth, and fifth domains.

We have previously shown (Frutiger, S., Hughes, G. J., Hanly, W. C., Kingzette, M., and Jaton, J.-C. (1986) J. Biol. Chem. 261, 16673-16681) that limited tryptic digestion of the high Mr form of rabbit secretory component of allotypes t61, t62, and t63 generates two major fragments, the NH2-terminal domain and a 40-kDa fragment encompassing domains 3, 4, and 5. Similarly, from the low Mr form of secretory component, (SC) the NH2-terminal domain, together with a 30-kDa fragment containing domains 4 and 5, were released. These fragments were used as inhibitors in a sensitive competitive binding radioimmunoassay with noncross-reactive rabbit alloantisera to study the distribution and localization of the major allotype-specific allotopes within the SC polypeptide. The 40-kDa fragments were shown to inhibit the 125I-labeled intact SC/anti-SC allotype reaction to the extent of 90%, i.e. nearly as well as the intact homologous high Mr SC form. In contrast, the NH2-terminal fragments (domain 1) were not inhibitory. The low Mr SC of each allotype was less inhibitory on a molar basis than the homologous high Mr SC polypeptide, an observation compatible with the deletion of domains 2 and 3 in the smaller polypeptide (Deitcher, D. L., and Mostov, K. E. (1986) Mol. Cell. Biol. 6, 2712-2715; Frutiger, S., Hughes, G. J., Fonck, Ch., and Jaton, J.-C. (1987) J. Biol. Chem. 262, 1712-1715). The structural correlates of the allotypic specificities were evaluated by comparative peptide mapping of the 40-kDa fragments (allotypes t61, t62, and t63). The data suggest that the t61 allotype structure differs significantly from the t62 and t63 structures, the latter two being much more related to each other than to t61. These findings are in full agreement with the serological data. The inhibition results suggest that the major allotype-specific, noncross-reactive allotopes of SC are distributed throughout domains 3, 4, and 5, even though domain 4 appears to be more conserved than domains 3 and 5 between the allotypes t61 and t63. Seven amino acid substitutions between t61 and t63 have been detected within domains 3, 4, and 5.

Amino Acid Sequence↗
PubMed1983

Secretory component and IgA in endometrial adenocarcinomas. An immunohistochemical study.

The localization of secretory component (SC) and IgA was immunohistochemically studied in 6 normal endometrium and 55 endometrial adenocarcinomas including 34 well, 11 moderately and 10 poorly differentiated ones. In normal endometrium, SC localization was found in the cytoplasm of epithelial cells and luminal contents of the gland. IgA showed similar localization of SC. Secretory phase endometrium contained proportionally larger numbers of positive cells for SC and IgA than proliferative phase endometrium. SC localization was found in all cases of well and moderately differentiated carcinomas, while it was found only in 4 cases out of 10 poorly differentiated carcinomas. IgA localization was similar to that of SC and this condition was thought to reveal the binding of IgA to SC existing in the tumor cells. The present immunohistochemical study revealed that the staining intensity of SC well correlated with the histological grade of differentiation of the tumors.

Adenocarcinoma↗
PubMed1984

Immunoreactive secretory component of IgA in human tissues and tumors.

Secretory component (SC) of IgA is known to be produced by many glandular epithelial cells. To assess the usefulness of this antigen as a glandular tumor differentiation marker, the authors evaluated its normal body distribution and tested a variety of glandular neoplasms. The known normal distribution of SC was confirmed and extended to include the prostate. Immunoreactive SC was detected only in epithelial and glandular tumors. Many types of well-differentiated adenocarcinomas, (ovary, prostate, small bowel, pancreas, stomach, biliary) however, contained little or no immunoreactive SC. Therefore, the authors conclude that immunoreactive SC cannot be used as a general differentiation marker in tumors of glandular derivation. A high frequency of antigenic expression was found in adenocarcinomas of the lung (4/10), breast (5/10), and colon (24/27). No correlation between expression and tumor differentiation was observed in pulmonary or mammary tumors. Only in colonic neoplasia was such a relationship detected. SC expression in colonic tumors was not related to mucin content but was associated with the presence of a visible brush border.

Adenocarcinoma↗
PubMed1984

Evaluation of nine different fixatives. 2. Preservation of IgG, IgA and secretory component in an artificial immunohistochemical test substrate.

An artificial substrate was developed for quantitative testing of the ability of various fixatives to preserve the reactivity of IgG and IgA isotypes (gamma and alpha chains) and the secretory component (SC) of secretory IgA as model antigens. Polymerized normal rabbit serum was used as matrix and defined amounts (10-0.1 g/l) of antigen were incorporated into it by diffusion before fixation and paraffin embedding. The various fixatives comprised alcohol, routine formalin, glutaraldehyde(1%)-formalin, Baker's formol calcium, formol sublimate, acetic acid(2%)-formol saline, Bouin's fluid, Susa fixative, and carbodiimide. The detection sensitivity afforded by these fixatives was defined as the immunofluorescence staining end point. Compared to the reference value obtained with alcohol (gamma and alpha chains, 0.06 g/l of IgG and IgA; SC, 0.12 g/l of colostral IgA), an antigen concentration at least 8 times higher was necessary for detection with most of the cross-linking fixatives. Bouin's and Susa fixatives were peculiar in that they required more than 150 times higher antigen concentration for detection of IgG but only 3-8 times higher for IgA. The determined sensitivities were compared with the immunofluorescence performance results obtained on human tissues prepared with the same fixatives; excepting carbodiimide (which produced unacceptable autofluorescence of the substrate matrix) a remarkably good correlation was found with regard to IgG- and IgA-producing cells (especially of the former isotype) and secretory epithelium (IgA and SC). However, the latter result depended on pronase treatment of the tissue sections to unmask epithelial antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Comparison of secretory component for immunoglobulin A with albumin as reference proteins in tracheal aspirate from preterm infants.

OBJECTIVES: To determine whether the concentration of secretory component (SC) in tracheal aspirate samples is less altered by changes in alveolar-capillary permeability and thus is a more reliable reference standard than albumin for the measurement of other components obtained by saline lavage in preterm infants. METHODS: A total of 1229 tracheal aspirate and 1530 blood samples were collected from 195 neonates to evaluate the effects of advancing postnatal and gestational age, resolution of acute respiratory distress syndrome (RDS), steroid therapy for chronic lung disease, and acute sepsis on tracheal aspirate SC and albumin levels. The tracheal aspirate and blood samples were analyzed by enzyme-linked immunosorbent assay techniques for SC and albumin concentrations. RESULTS: The mean values for the concentrations of aspirate and plasma SC did not vary significantly during an 8-week study period (n = 100) and did not vary with either gestational age (23 to 36 weeks) or postnatal age. Albumin concentration significantly decreased in aspirate samples from 1.67 +/- 0.77 mg/dl at week 1 to 0.41 +/- 0.21 mg/dl at week 8 (p < 0.001), whereas serum levels increased from 2.65 +/- 0.36 to 2.99 +/- 0.54 gm/dl (p < 0.001), suggesting a decrease in alveolar-capillary leakage with advancing postnatal age. The concentration of SC in aspirate samples from 51 infants who received dexamethasone remained constant during the first week of therapy, whereas the concentration of albumin decreased from 1.33 +/- 0.91 mg/dl at the initiation of therapy to 0.51 +/- 0.34 mg/dl on treatment day 7 (p < 0.001). The onset of sepsis (n = 40) was not accompanied by a significant change in either aspirate SC or albumin levels. However, in infants who had a deterioration in respiratory status concomitant with the onset of sepsis (n = 10), the levels of aspirate albumin increased whereas serum levels decreased (p < 0.001), suggesting an increase in alveolar-capillary leakage; the levels of aspirate SC remained unaltered. CONCLUSIONS: Secretory component may serve as a more valid reference protein for the standardization of tracheal aspirate collection in preterm infants during evaluation of changes in inflammatory mediators in disease states and therapeutic interventions that alter alveolar-capillary integrity.

Acute Disease↗
PubMed1977

Studies on translocation of immunoglobulins across intestinal epithelium. IV. Evidence for binding of IgA and IgM to secretory component in intestinal epithelium.

We conducted studies concerning the issue of whether secretory component (SC) is a specific receptor on intestinal epithelial cells for IgA and IgM. Initially, frozen sections of human intestinal mucosa were incubated with dimeric monoclonal human IgA, conjugated to horseradish peroxidase; adjacent sections were reacted with peroxidase-conjugated antibodies to SC. The conjugated IgA and anti-SC bound to similar sites in the epithelium, that is to basolateral margins and supranuclear cytoplasm of columnar epithelial cells, principally in gland crypts. In subsequent tests of binding specificity, binding of the dimeric IgA conjugate was inhibited by pretreating the tissues with unconjugated dimeric IgA or 19S IgM, pretreating the tissues with unconjugated antibodies to SC, or preincubating the dimeric IgA conjugate with free SC. Binding was not inhibited or only partially inhibited by pretreating the tissues with monomeric IgA or IgG, pretreating the tissues with antibodies to human or heterologous immunoglobulins, or preincubating the dimeric IgA conjugate with 11S secretory colostral IgA. The findings indicate that dimeric IgA and 19S IgM are capable of binding in vitro to specific sites on intestinal epithelial cells, most likely to SC. This supports the hypothesis that transport of these immunoglobulins into intestinal fluids involves their combination with SC in the epithelium.

Binding Sites, Antibody↗
PubMed1986

Both Fc alpha domains of human IgA are involved in in vitro interaction between secretory component and dimeric IgA.

The sites of interaction between 125I labelled human secretory component (SC) and dimeric IgA were located by studying the inhibitory effect of various antibodies to IgA. Several Fab' fragments were isolated from three sera of hyperimmunized rabbits. The specificity of these different antibody preparations, as determined by a RIA inhibition test or by ELISA, showed that two were directed against both domains of Fc alpha, two against C alpha 2, two against C alpha 3 and one against Fd alpha. A monoclonal antibody against C alpha 3 was also used. The results indicate that both the C alpha 2 and C alpha 3 domains are equally and independently involved in the interaction between SC and dimeric IgA.

Animals↗
PubMed1985

Nasopharyngeal carcinoma: immunohistochemical study for keratin, secretory component and leukocyte common antigen.

Immunohistochemical studies using antisera to keratin and secretory component (SC) and monoclonal antibody against leukocyte common antigen (LCA) were performed on 92 biopsy and autopsy specimens taken from 65 patients with nasopharyngeal carcinoma. Five biopsy specimens from malignant lymphoma of the nasopharynx and tonsil, and 20 biopsy specimens of nasopharyngeal epithelium were also included in the study. Keratin was positively stained in all squamous cell carcinomas and nonkeratinizing carcinomas, and 38 of 46 undifferentiated carcinomas (82.6%), but in no malignant lymphomas. LCA was intensely stained in all malignant lymphoma, but in no nasopharyngeal carcinomas. SC was positively stained in two of the 46 undifferentiated carcinomas (4.3%). Nasopharyngeal carcinoma is a definite malignant epithelial neoplasm and can be distinguished from malignant lymphoma by immunostaining for keratin and LCA. Some undifferentiated carcinoma may show cellular differentiation toward ciliated epithelium.

Adolescent↗
PubMed1987

Rabbit secretory components: identification of a third allotype, t63.

A third allotype of rabbit secretory component has been identified. The allotype previously referred to as t62 by our laboratory can now be subdivided into two allotypes, t62 and t63, with alloantisera capable of discriminating between the two. Results of family studies are consistent with a three allele system (t61, t62 and t63) at the t-locus. By SDS PAGE, electrophoretic mobilities of the multiple SC bands for each of the three allotypes are characteristic of the allotype; the apparent molecular sizes of the bands of the t62 allotype are 2 to 3 kDa lower than those for the t61 allotype. The banding patterns of the t61 and t63, although similar, are not identical to each other. Results of serologic cross-reaction studies and of tryptic peptide mapping studies suggest multiple structural differences between the allotypes as well as a closer relationship between t62 and t63 than between either of these allotypes and t61.

Alleles↗
PubMed1984

The value of secretory component (SC) immunoreactivity in diagnosis and prognosis of colorectal carcinomas.

Immunoreactivity of secretory component (SC) was tested in routinely processed tissue specimens of 314 colorectal cancer patients and correlated with clinicopathologic parameters, such as stage and histologic grade of the tumors as well as survival data of patients. In 22% of the carcinomas almost all tumor cells were SC positive, 36% of the tumors showed SC immunoreactivity in a focal, heterogeneous pattern, whereas in 42% of the carcinomas SC immunoreactivity did not occur. Uniformly SC positive carcinomas demonstrated a tendency to occur more frequently in the low stage and grade carcinomas, whereas uniformly SC negative neoplasms showed the reverse trend. These trends were only statistically significant for stage. Focal SC immunoreactivity (SC heterogeneous tumors) was not correlated with stage nor with grade. Furthermore, inclusion of SC heterogeneous tumors in the analysis of survival data obscured the statistical significance observed in the correlation of SC immunoreactivity status and patient survival in uniformly SC positive or negative tumors. It is concluded that the prognostic value of SC immunoreactivity patterns in colorectal carcinoma tissue appears to be limited due to the occurrence of a substantial proportion of tumors with heterogeneous SC expression and is of less significance than staging. Nevertheless, determination of the SC immunoreactivity status may be of additional value for the identification of a subpopulation of patients with a more favorable prognosis.

Cell Transformation, Neoplastic↗
PubMed1983

Steroid hormone regulation of free secretory component in the rat uterus.

The present studies analysed the uterine free secretory component (SC) response to steroid hormones, and correlated effects on SC with those on IgA. Administration of oestradiol for 3 days to ovariectomized rats significantly increased the levels of SC in uterine secretions, when compared to those in saline-injected controls. This response was dose-dependent and specific for oestrogens, since progesterone, testosterone and glucocorticoids had no effect. The oestradiol-induced elevation in SC levels occurred in parallel with that of IgA. Time course studies of SC and IgA in uterine secretions indicated that both proteins accumulated in nearly identical patterns following oestradiol administration. The oestradiol-stimulated accumulation of SC, however, appears to be independent of IgA since dexamethasone treatment with oestradiol decreased IgA but not SC levels in uterine secretions. In contrast to dexamethasone, progesterone antagonized the oestradiol effect on both uterine IgA and SC. The uterine SC response to oestradiol was also observed in vitro. Incubation of uterine tissue following oestradiol exposure in vivo resulted in a significant accumulation of SC in the culture medium, when compared to levels from control uteri. Addition of either cycloheximide or colchicine to uterine incubation media significantly decreased the effect of oestradiol on SC accumulation. These results suggest that oestrogen regulation of uterine SC may involve stimulation of its synthesis. In addition, our findings indicate that oestradiol control of SC in uterine secretions may be responsible for the movement of IgA from uterine tissues to lumen.

Animals↗
PubMed1995

Rheumatoid factor associated with a secretory component in rheumatoid arthritis.

The authors' objective was to study the serum secretory immunoglobulin A (S-IgA) concentration and the presence of rheumatoid factor (RF) complexed with a secretory component (SC) in rheumatoid arthritis (RA). Sixty-three RA patients were studied. There were 49 healthy subjects in the control group. The S-IgA concentration and the presence of IgA isotype RF were determined by ELISA in the serum. The presence of SC complexed to RF (SC-RF) was studied by a sandwich-type enzyme-linked immunosorbent assay with an antibody against the SC used to capture S-immunoglobulin, and associated anti-globulin activity was revealed with a peroxidase-conjugated human IgG Fc fragment. We observed a significant increase in S-IgA in RA (mean 76.8 micrograms/ml +/- 152.9 S.D.), as compared to controls (mean 13.6 micrograms/ml +/- 11.9 S.D.) (P < 0.01). Forty-one per cent of RA patients presented a S-IgA concentration above the upper threshold, but we did not observe any association with disease activity. S-IgA concentration was correlated with the presence of IgA-RF. Twenty-seven RA patients had a positive SC-RF versus one in the control group (P < 0.01). The presence of SC-RF was associated with an increased S-IgA concentration (P < 0.0001), and the presence of RF-IgA (P < 0.002). However, no association with disease activity was noted. Our study showed that serum S-IgA was increased in RA, and that part of the RF were complexed with SC. These results suggest contribution of mucosal lymphocytes in the pathogenesis of RA.

Adult↗
PubMed1992

Secretory component is bound to the paraproteins in sera of IgA and IgM gammopathies.

Secretory immunoglobulins A (SIgA) and M (SIgM) were investigated in 20 sera containing high levels of monoclonal polymeric IgM or IgA. In the sera of patients suffering from Waldenström's macroglobulinemia (WM), the level of SIgA was found to be low, whereas that of SIgM was extremely high. Reciprocally, in the multiple myeloma (MM) patients, SIgA were increased and SIgM were dramatically decreased. Electrophoretic analysis showed these SIgA and SIgM to have the same monoclonal pattern as the corresponding paraprotein. Hence these molecules must originate from the malignant clone. The most likely mechanism involved is an intravascular formation of the secretory-like immunoglobulins. Free secretory component (SC) could diffuse passively from the digestive lumen and bind the circulating myeloma polymeric immunoglobulins. Such a possibility of in vivo binding of free SC to IgM and IgA polymers leads to a reconsideration of the secretory origin of SIgM and SIgA in normal human serum.

Electrophoresis↗
PubMed1988

Immunoelectron microscopical localization of immunoglobulins, secretory component and J chain in the human minor salivary glands.

Localization of IgA, secretory component (SC) and J chain was investigated immunocytochemically in minor salivary glands of the lip and palate to define the mechanism involved in the transport of immunoglobulin A (sIgA) into the saliva from the minor salivary glands. SC synthesis was detected in mucous acinar cells and ductal epithelial cells. Free SC is secreted into the saliva through secretory granules in the mucous acinar cells. Dimeric IgA containing J chain is translocated through these cells as sIgA by a SC-mediated transport mechanism involving cytoplasmic vesicles.

Cell Membrane↗