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PubMed1980

Immunohistochemistry of epithelial cell markers in normal and pathological colon mucosa. Comparison of results based on routine formalin- and cold ethanol-fixation methods.

The purpose of this study was to examine whether formal-dehyde-fixed tissue may afford reproducible and reliable immunhistochemical results when carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA are evaluated semiquantitatively in normal and pathological colon specimens. Proximate tissue samples were processed by routine formalin fixation and by a cold-ethanol fixation method, respectively, and the immunofluorescence intensities obtained for the three antigens were scored. After formalin fixation SC and epithelial IgA were generally undetectable and also the staining for CEA was markedly reduced compared with that seen after ethanol fixation. Significant antigenic "unmasking" was obtained by enzyme treatment of the formalin-fixed tissue sections--resulting in enhanced staining for SC and epithelial IgA but not consistently so for CEA. With this modification scores from duplicate tissue samples processed by the two methods showed significant correlations for all the three epithelial markers; small amounts of CEA and epithelial IgA, and especially SC, nevertheless remained undetectable after formalin fixation. This result should be taken into account when epithelial markers are applied in studies of premalignant lesions of the colon where minor changes in the antigen pattern may be of diagnostic importance.

Carcinoembryonic Antigen↗
PubMed1997

Free-flow electrophoretic analysis of endosome subpopulations of rat hepatocytes.

The separation of functional early and late endosomes from other cellular compartments by free-flow electrophoresis (FFE) has been previously demonstrated in nonpolarized cells. Here, using 125I-labeled anti-secretory component antibodies ([125I]SC Ab) and FITC-labeled asialoorosomucoid (FITC-ASOR) as markers of the transcytotic and lysosomal pathway, respectively, we demonstrate the separation of three distinct endosome subpopulations from polarized rat hepatocytes. Internalization of both markers at 16 degrees C resulted in their accumulation in a common endosome compartment, indicating that both the transcytotic and the lysosomal pathways are arrested in the sorting early endosome at temperatures below 20 degrees C. After chase of the markers from early endosomes into the transcytotic or the degradative route at 37 degrees C, transcytotic endosomes carrying [125I]SC Ab migrated with an electrophoretic motility between early and late endosomes while late endosomes labeled with FITC-ASOR were deflected more towards the anode than early endosomes. These data indicate that in rat hepatocytes, the transcytotic and lysosomal pathways utilize a common (i.e. early endosomes) and two distinct endosome subpopulations (i.e. transcytotic endosomes, late endosomes) prior to delivering proteins for biliary secretion or lysosomal degradation, respectively.

Animals↗
PubMedDate not supplied

Lymphoid-epithelial secretory immune system in human fetuses in the second trimester of gestation.

The development of the secretory immune system (SIS) in the respiratory, digestive, and urogenital tracts and other organs of fetuses in the second trimester of gestation is described. Tissues of all internal organs of human fetuses (n = 36) that had died between 13 and 25 weeks of gestation were studied immunohistochemically for the presence of secretory component (SC), J chain, IgA, IgM, IgG, macrophages, and different subsets of lymphocytes. We found protein elements of the SIS in fetuses during the entire second trimester in the epithelium of the digestive, respiratory, and urinary tracts; in hepatocytes; in the epithelium of the bile duct, renal tubules, and all the urinary tract; in the salivary glands, pancreas, and thyroid; in the epithelium of the Fallopian tubes and uterus; in the epididymis and the rete testes; in the skin; and in other organs. Immunocompetent cells, including IgA- and IgM-secreting cells, were located in these organs under the epithelium and sometimes between epithelial cells. In fetuses with acute infection, the number of immunocompetent cells was higher, reflecting a whole-immune system reaction, including the SIS. We conclude that the fetal SIS is a ramified, defensive immune system that is distributed throughout most organs of epithelial origin in second-trimester fetuses, and that it reacts against intrafetal infiltration by foreign antigens.

Adult↗
PubMed1998

Lack of SC/pIgR-mediated epithelial transport of a human polymeric IgA devoid of J chain: in vitro and in vivo studies.

Three human polymeric IgA (pIgA) myeloma proteins of tetrameric size were compared for their J-chain content, their in vitro secretory component (SC)-binding ability, and their capacity to be transcytosed by polymeric immunoglobulin receptor (pIgR)-expressing epithelial cells in vitro and rat hepatocytes in vivo. One of the three pIgA preparations, pIgA-L, was shown to lack J chain and was unable to combine with purified free human and rat SC, whereas pIgA-G and pIgA-C contained J chain and combined readily with SC. Furthermore, pIgA-L was not transferred into rat bile after intravenous injection, and was hardly transported apically by polarized Madin-Darbey canine kidney cell monolayers expressing the human pIgR, whereas pIgA-G and pIgA-C were efficiently transported in both test systems. Together with our recent demonstration that antibodies to human J chain block the SC/pIgR-mediated epithelial transport of pIgA, these data unanimously confirm the proposed key role of J chain in the epithelial transport of polymeric immunoglobulins into exocrine secretions.

Animals↗
PubMed1999

The first exon of the human sc gene contains an androgen responsive unit and an interferon regulatory factor element.

Secretory component (SC) plays a key role in the transport of IgA and IgM to the lumina of many glands. The gene is constitutively expressed, but can be modulated by hormonal and immunological stimuli. Recently, the promoter and the first exon of the human sc gene have been cloned. The first exon contains a putative androgen/glucocorticoid response element (ARE/GRE) and an Interferon Regulatory Factor Element (IRF-E). Here we show that the ARE/GRE can bind the DNA-binding domain (DBD) of both the androgen (AR) and glucocorticoid receptor (GR) with a preference for the AR-DBD. In transient transfection experiments, this element confers higher responsiveness to androgens than to glucocorticoids. The IRF-E can function as an IRF-2, but surprisingly not as an IRF-I responsive element. We postulate that these two regulatory elements play a key role in the complex regulation of the sc gene in vivo.

Androgens↗
PubMed1985

Low level transport of IgA to bile via the asialoglycoprotein receptor.

The rat and rabbit transport IgA from blood to bile by a highly efficient transcellular pathway mediated by secretory component (SC). Other mammals do not express SC on liver hepatocytes, but they do transport a small amount of IgA to bile. In the first part of this study, human polymeric IgA was radiolabeled and depleted of SC binding activity by successive affinity adsorption. Transport of this preparation intact to rat bile was 4%, but was reduced to 2% when 50 mg unlabeled asialoglycoprotein was preadministered. The 2% decline corresponds to the percent of asialo-orosomucoid diverted to bile from the lysosomal pathway. In guinea-pigs, missorting of asialo-orosomucoid intact to bile was 10% of the injected dose. Transport of normal human IgA to bile was 1-2%, even though guinea-pigs do not express SC in the liver. Excess unlabeled asialofetuin reduced the transport of asialo-orosomucoid by 10-fold and IgA by 6-fold. This demonstrates that the asialoglycoprotein receptor can mediate transport of IgA to bile in small amounts, but that this transport may be only a biological artifact resulting from limited fidelity of intracellular protein sorting.

Animals↗
PubMedDate not supplied

Immunofluorescent study on middle ear mucosa.

To clarify the developmental course of the immunological defense system in the middle ear, immunoglobulin-forming cells of different classes and secretory proteins, such as secretory component (SC) and lactoferrin (Lf), were investigated in the middle ear mucosa of 20 developing and 5 normal adult guinea pigs by use of direct immunofluorescence technique. Changes in the middle ear mucosa were also observed after antigenic challenges directly to the tympanic cavity of 6 developing and 39 adult guinea pigs. IgA- and IgM-forming cells began to appear in the tubal mucosa at the seventh postnatal day, while it was scarcely possible to find IgG1- and IgG2-forming cells in developing guinea pigs. Immunoglobulin-forming cells of all classes increased in the middle ear mucosa after the antigenic stimuli. The injection of antigens to the tympanic cavity of developing animals induced the most striking accumulation of immunoglobulin-forming cells in the middle ear mucosa. Results of this study showed that local synthesis of IgA, as well as other classes, is latent in the middle ear, that the middle ear of immature animals is vulnerable to antigenic stimuli, and that the middle ear of developing animals possesses potential immune responsiveness.

Animals↗
PubMed1985

Immunohistochemical study of so-called sclerosing haemangioma of the lung.

To elucidate the histogenesis of sclerosis haemangioma of the lung, we examined 7 cases with the immunoperoxidase method using antibodies against several useful marker antigens; secretory component (SC), cytokeratins, epithelial membrane antigen (EMA) for epithelial cells, factor VIII related antigens (factor VIII) for endothelial cells, vimentin and desmin for mesenchymal cells. The results were compared with those of histologically normal lung tissues. Both the characteristic round cells arranged in sheets, which are present predominantly in the solid area and are reported to be neoplastic, and the flattened cells lining blood lakes show positive staining for EMA only, with negative staining for the other marker antigens. These observations suggest that these cells are derived from epithelium rather than mesothelium or from endothelium, and are analogous to type I pneumocytes. This conclusion is supported by their immunohistochemical characteristics, in comparison with the localization patterns of the marker antigens in normal lung tissues. However, the lining epithelial cells of papillary projections in the papillary area and of ducts in the solid area stained for SC and cytokeratins as well as EMA, and their immunohistochemical characteristics are analogous to those of bronchiolar epithelial cells or type II pneumocytes in normal lung tissues.

Adult↗
PubMed1999

Over-expression of the murine polymeric immunoglobulin receptor gene in the mammary gland of transgenic mice.

The polymeric immunoglobulin receptor (pIgR), a transmembrane protein, transports dimeric IgA (dIgA) across the epithelial cells of the mucosal surfaces into the external secretions, for example milk from the mammary glands. The pIgR is consumed during the transcytosis of dIgA and is cleaved at the apical side of the epithelial cells, regardless of the binding to its ligand (dIgA), to form secretory component (SC). We hypothesize that the expression level of the endogenous murine pIgR gene in the epithelial cells is rate-limiting for the transport of dIgA across the epithelial cells into the secretions. We address this key issue by generating transgenic mice over-expressing the pIgR gene in their mammary glands in order to examine the effect on dIgA levels in the milk. Here we report on the generation of transgenic mice and analysis of the expression level of pIgR in their mammary glands. We cloned and characterized the murine pIgR gene and constructed an expression cassette bearing the pIgR gene under the control of the regulatory sequences of the bovine alpha s1-casein gene. Four transgenic lines were made, expressing the pIgR construct at RNA and protein level only in their mammary glands. The levels of the SC protein in the milk ranged from 0.1 to 2.7 mg/ml during mid-lactation. These levels are 10-270 times higher than wild-type SC levels (0.01 mg/ml).

Animals↗
PubMedDate not supplied

[Immunopathomorphology of the human placental barrier in the first trimester of pregnancy complicated by the inflammation of the birth-ways].

The effect of ascending infection of birth-ways on transport of maternal immunoglobulins (Igs) through the placental barrier in humans during the first trimester of pregnancy was studied. The transport of Igs is seen already in 3.5-to 5-week-old embryos, and different cellular and biochemical compounds participate at each stage of this process. Transport of Igs through the trophoblast is carried out due to the secretory component (SC) and, perhaps, to some other receptors. Monocytes together with Igs penetrate into capillaries between the endothelial cells and are transported with the blood all over the body. It seems that SC and other receptors help Igs to penetrate into capillaries through the endothelium. Further, Igs are transported with erythroblasts. In the development without infection the transport of IgG was seen in all cases studied. Inflammation of the birth-ways is accompanied by an increase in transport of all Igs, already in early embryogenesis. Three groups were distinguished: 1) abortions without inflammation; 2) cases with signs of moderate inflammation (endometritis, deciduitis); 3) cases with intensive inflammation with necrosis and leucocytic infiltration. Transport of Igs was seen in 77.8% cases of the first group and in all cases of groups 2 and 3. Transport of IgM was not found in the first group, but was seen in 50% cases of group 2 and 66.7% of group 3.

Biological Transport↗
PubMed1990

Epithelial polymeric immunoglobulin receptors.

The secretory immune system, which leads to secretion of polymeric immunoglobulins along mucosal surfaces, has not been shown to have any definite role in cutaneous immunology, although the polymeric immunoglobulin receptor, secretory component (SC), has been found in sweat glands and possibly in the epidermis. The purpose of this study is to examine normal human skin and cultured human keratinocytes for the presence of SC. Positive staining for SC was found in sections of normal human skin along the basement membrane zone with use of a polyclonal antibody to SC and focally on the surfaces of epidermal cells with use of a monoclonal antibody to SC. Granular cell-surface fluorescence of an intensity far less than that of the positive control HT 29 cells was seen when cultured human keratinocytes were stained for SC by indirect immunofluorescence (IF). Study of lysates of both HT 29 cells and HK by immunoblotting have been negative, perhaps due to destruction of the protein or loss of antigenicity during the extraction process. If human keratinocytes are capable of expression of SC, and the receptor can interact with IgA and IgM, this might be a mechanism for protection of the skin from microbial agent or foreign antigens and might be relevant to the deposition of IgA seen in certain skin diseases.

Antibodies, Monoclonal↗
PubMed1985

A role for the spleen in the appearance of IgM in the bile of rats injected intravenously with horse erythrocytes.

The i.v. injection of the particulate antigens horse red blood cells (HRBC) and Salmonella enteritidis into rats results in the appearance of high levels of IgM agglutinating antibody in the serum and bile. This is in contrast to the appearance of specific IgA antibodies in bile after the injection of antigen into the Peyer's patches. At the height of the response, a fivefold to 10-fold increase in total IgM was found in bile, whereas there was no increase in IgA or in total protein levels. The biliary IgM was not associated with secretory component. Studies aimed at revealing the source of the IgM showed that neither immunized nor nonimmunized rats were able to transport 131I-rat IgM, but both groups were equally efficient at transporting 125I-rat IgA. Furthermore, specific anti-HRBC antibody could not be detected in the bile of rats that were injected with a high titer serum, indicating that blood is unlikely to be the source. Splenectomy of rats at the time of the injection of antigen, at 3 days after immunization had abrogated the biliary response, and at 5 days resulted in rapid decline in existing specific antibody level. Involvement of the spleen was additionally implicated when it was shown that injection of animals with immune spleen cells gave rise to specific antibodies in serum and bile. On the basis of these experiments, it is proposed that antigen entering the blood stream can stimulate a population of cells in the spleen that emigrates to the liver, where the cells localize and secrete IgM into bile.

Animals↗
PubMed1990

Immunoglobulin A (IgA) polymerization sites in human immunocytes: immunoelectron microscopic study.

The cytoplasmic affinity of polymeric IgA for secretory component (SC) and the expression of joining (J) chain were examined in pokeweek mitogen (PWM)-stimulated human peripheral blood lymphocytes (PBL) to determine, on the ultrastructural level, the polymerization sites of human IgA. SC-binding was found in 5.7% of transformed PBL on day 7 of culture; SC-binding was observed in a high proportion of IgA-producing cells. A low proportion of IgM-producing cells also bound to SC, while there was virtually no SC-binding by IgG-producing cells. A high proportion of IgA- and IgM-producing cells expressed intracellular J chain, while approximately half of the IgG-producing cells were positive for J chain. The number of J chain-positive cells exceeded the number of SC-binding cells among transformed PBL on day 7 of culture. Immunoelectron microscopic study of the sites of SC-binding, and of IgA and J chain expression, revealed that polymerization of human IgA and the addition of J chain occur in the perinuclear space and endoplasmic reticulum, prior to immunoglobulin secretion.

Adult↗
PubMed2001

The J chain is essential for polymeric Ig receptor-mediated epithelial transport of IgA.

Local production of secretory (S)IgA provides adaptive immunologic protection of mucosal surfaces, but SIgA is also protective when administered passively, such as in breast milk. Therefore, SIgA is a potential candidate for therapeutic administration, but its complex structure with four different polypeptide chains produced by two distinct cell types complicates recombinant production. The J chain is critical in the structure of SIgA because it is required for efficient polymerization of IgA and for the affinity of such polymers to the secretory component (SC)/polymeric (p)IgR. To better understand the role of the J chain in SIgA production, we have generated various mutant forms of the human J chain and analyzed the function of these mutants when coexpressed with IgA. We found that the C terminus of the J chain was not required for the formation of IgA polymers, but was essential for the binding of pIgA to SC. Likewise, we found that two of the intrachain disulfide bridges (Cys(13):Cys(101) and Cys(109):Cys(134)) were also required for the binding of pIgA to SC but, interestingly, not for IgA polymerization. Conversely, the last intrachain disulfide bridge (Cys(72):Cys(92)) was not essential for either of these two J chain functions. Finally, we demonstrated that the presence of only Cys(15) or Cys(69) was sufficient to support polymerization of IgA, but that these polymers were mostly noncovalently stabilized. Nevertheless, these polymers bound free SC with nearly the same affinity as pIgA containing wild-type J chain, but were transcytosed by pIgR-expressing polarized epithelial cells at a reduced efficiency.

Animals↗
PubMed1986

Adenosine deaminase complexing protein (ADCP) immunoreactivity in colorectal adenocarcinoma.

Immunoreactive adenosine deaminase complexing protein (ADCP) was studied in 91 human colorectal adenocarcinomas. The expression of ADCP was correlated with that of secretory component (SC) and carcinoembryonic antigen (CEA), with the histological grade and the Dukes' stage of the carcinomas. The histological grade was scored semi-quantitatively according to 5 structural and 4 cytological variables. ADCP expression was observed in 3 different staining patterns, namely: (1) diffuse cytoplasmic (77% of the carcinomas); (2) granular cytoplasmic (13%); and (3) membrane-associated (66%). These patterns were observed alone or in combination. Eleven percent of the carcinomas exhibited no ADCP immunoreactivity. Linear regression analysis showed that the expression of ADCP correlates with that of SC and CEA. However, no significant correlation emerged between the histological parameters or the Dukes' stage and any of the immunohistological parameters. Comparison of the histological characteristics of carcinomas exhibiting little or no ADCP immunoreactivity with those showing extensive immunoreactivity, showed that membranous ADCP immunoreactivity occurs more frequently in well-differentiated carcinomas. Structural parameters showed a better correlation with membranous ADCP expression than the cytological variables. It is concluded that membranous expression of ADCP and CEA are indicators of a high level of differentiation as reflected primarily in the structural characteristics of the tumor.

Adenocarcinoma↗
PubMed1993

Maturation of villus and crypt cell functions in rat small intestine. Role of dietary polyamines.

To evaluate the role of dietary polyamines in maturation of the rat small intestine, spermine was given orally twice daily to suckling pups from day 10 to day 14 postpartum at different doses: 0, 0.2, 0.5, 1, 2.5, and 5 mumol/dose. Compared to saline treated controls, spermine (5 mumol) produced significant increases in mucosal mass parameters (+12 to +57%, P < 0.05), induced prematurely an adult pattern of microvillous enzymes, and enhanced, respectively, by 19- and 3.5-fold (P < 0.01 vs controls) the concentration of the secretory component of p-immunoglobulins in villous and crypt cells. The response of microvillous enzymes (lactase, sucrase, maltase, and aminopeptidase) to spermine was dose-dependent and -specific since oral administration of arginine (5 mumol) or ornithine (5 mumol) was without effect. Intestinal changes were found to be significant (P < 0.05) for doses of spermine exceeding 1 mumol/day, which is in the range of the amount of polyamines provided by solid pellets at weaning (0.4 mumol/g). However, intestinal changes were undetectable at the physiological amounts of polyamines consumed by pups from rat milk during the suckling period (less than 0.3 mumol/day). Consistent with a direct effect of spermine on the intestinal cell, the cytosolic activity of ornithine decarboxylase was depressed by 27-fold (P < 0.005 vs controls) in the jejunum, while inhibition of ornithine decarboxylase by alpha-difluoromethylornithine did markedly decrease but did not suppress the cell response to spermine. Alternately, plasma corticosteronemia, which was virtually absent by day 14 in controls, ranged between 1.4 and 4.6 micrograms/dl in 60% (N = 9) of the spermine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

The mechanism of Epstein-Barr virus infection in nasopharyngeal carcinoma cells.

To investigate the relationship between Epstein-Barr virus (EBV) and nasopharyngeal carcinoma (NPC) cells, we examined the pathway of EBV infection in NPC cell lines. We used immunolocalization to investigate the EBV receptor (C3d-R) and polymeric immunoglobulin receptor [secretory component (SC) protein]. We incubated IgA anti-EBV and EBV particles with NPC cells and observed the EBV DNA signal by in situ polymerase chain reaction hybridization and polymerase chain reaction plus Southern blotting. We also colocalized SC protein and EBV RNA in NPC biopsy specimens. Results showed that: 1) NPC cells did not express the EBV receptor but did express SC protein in each line; 2) SC protein was also expressed in some tumor cells but not in untransformed squamous metaplastic epithelia in NPC biopsy specimens; 3) EBV could infect NPC cells through an EBV-IgA and SC complex and retained an EBV viral genome in their nuclei; SC expression could be down-regulated by EBV proteins; and 4) in biopsy specimens, a fraction of tumor cells showed SC protein expression; only a portion of tumor cells contained EBV, and of these cells only a few expressed SC protein. These findings indicate that EBV cannot infect untransformed nasopharyngeal squamous metaplastic epithelia but can enter NPC cells through IgA-mediated endocytosis.

Carcinoma↗
PubMed1992

Polymeric Ig receptor expression in hepatocellular carcinoma.

The cellular localisation of the polymeric Ig receptor (pIg-R) and carcinoembryonic antigen (CEA), hepatic and biliary cell markers, were investigated in patients with hepatocellular carcinoma (HCC) and high serum levels of secretory component. Serum SC were increased 6-20-fold in 8 HCC patients compared with normal subjects. Serum free SC was positively correlated bilirubin (r = 0.95, P less than 0.04). In normal liver tissue, cytokeratin (CK) 8 and 18 were localised in hepatocytes and biliary cells while pIg-R and CK 19 expression was restricted to biliary cells. In tumoral liver tissue, malignant cells expressed CK 8 and 18 weakly; pIg-R and CK 19 were not detected in tumoral cells. CEA was expressed by biliary cells in normal and proliferating ducts. In peritumoral fibrosis, proliferating biliary cells were strongly stained by anti-cytokeratins and anti-pIg-R antibodies. In one case, pIg-R was localised in isolated cells close to fibrosis without co-staining of anti-CK 19. Thus increased serum SC is not associated with pIg-R expression by tumoral cells, and pIg-R may be considered an additional marker of biliary cells. High SC might be explained either by reflux from bile to serum and/or release of unbound SC from the vascular pole of non-functional, proliferating biliary structures.

Carcinoembryonic Antigen↗