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Immunohistochemical demonstration of IgA and secretory component in relation to epithelial cell differentiation in normal colorectal mucosa and metaplastic polyp: a semiquantitative study.

The metaplastic polyp is a non-neoplastic epithelial lesion found within the human colorectum. Although not regarded as precancerous, recent studies have demonstrated the expression of multiple cancer-associated phenotypes. This might indicate a possible indirect relationship between metaplastic polyps and colorectal cancer. Epithelial secretory component and IgA were demonstrated by the immunoperoxidase technique and staining intensities were assessed semiquantitatively. The findings were related to cellular differentiation in normal colorectal epithelium as compared to the metaplastic polyp. The crypt base cells and also the surface epithelial cells stained with similar intensity in both types of epithelium. However, the expected increase in staining characterizing normal lower and upper crypt columnar cells and reduction in staining associated with the switch from crypt to surface columnar cell was not observed in the metaplastic polyp. Metaplastic crypt columnar cells showed significantly reduced staining for both IgA and secretory component as compared to their normal counterparts. There was also a significant reduction in the number of IgA-secreting plasma cells in the lamina propria of the metaplastic polyp. These findings are consistent with the concept of a premature switch to mature surface cell characteristics within the metaplastic polyp. They are discussed in the light of other changes in phenotype associated with this lesion.

Colon↗

Elevated cerebrospinal fluid IgA in humans and rats is not associated with secretory component.

Immunoglobulin A (IgA) is transported across mucosal tissue membranes covalently bound to secretory component (SC). To determine if this receptor-mediated process also occurs at central nervous system (CNS) boundaries, cerebrospinal fluid (CSF) and serum from patients with CNS neuroinflammatory disease were analyzed for IgA and SC. Excess CSF IgA was detected in six of 24 patients, but no significant CSF SC was detected. In a parallel study using a rat model with normal brain barriers, inactivated lymphocytic choriomeningitis virus was microinfused into CSF. Elevated CSF IgA was detected in four of six rats, yet the proportion of secretory IgA was again insignificant compared to normal exocrine fluids (bile, semen). There does not appear to be a secretory IgA immune system at CNS boundaries and elevated CSF IgA is attributed to intrathecal synthesis.

Animals↗

A monoclonal antibody which differentiates between bound and free human secretory component.

In this study a mouse monoclonal antibody ( LICR -LON- LC28 ) to human secretory component (SC) is reported. This antibody binds to free SC or to SC associated with IgA or IgM. It exhibits a 10-fold higher affinity for SC bound to IgA than for free SC. The affinity of the antibody for SC associated with IgM is equivalent to that seen for free SC. LICR -LON- LC28 appears to be species specific and does not cross-react with other human milk proteins.

Antibodies, Monoclonal↗

Intracellular and transcellular transport of secretory component and albumin in rat hepatocytes.

The intra- and transcellular transports of hepatic secretory and membrane proteins were studied in rats in vivo using [3H]fucose and [35S]cysteine as metabolic precursors. Incorporated radioactivity in plasma, bile, and liver subcellular fractions was measured and the labeled proteins of the Golgi complex, bile, and plasma were separated by SDS PAGE and identified by fluorography. 3H-radioactivity in Golgi fractions peaked at 10 min postinjection (p.i.) and then declined concomitantly with the appearance of labeled glycoproteins in plasma. Maximal secretion of secretory fucoproteins from Golgi occurred between 10 and 20 min p.i. In contrast, the clearance of labeled proteins from Golgi membrane subfractions occurred past 30 min p.i., indicating that membrane proteins leave the Golgi complex at least 30 min later than the bulk of content proteins. A major 80,000-dalton form of secretory component (SC) was identified in the bile by co-precipitation with (IgA)2 by an anti-IgA antibody. An antibody (raised in rabbit) against the biliary 80,000-dalton peptide recognized two larger forms (116,000 and 94,000 dalton), presumably precursors, in Golgi membranes. A comparative study of kinetics of transport of 35S-SC and 35S-albumin showed that albumin peaked in bile at approximately 45 min p.i., whereas the SC peak occurred at 80 min p.i., suggesting that the transit time differs for plasma and membrane proteins that are delivered to the bile canaliculus.

Albumins↗

Role of local cytokines in increased gastric expression of the secretory component in Helicobacter pylori infection.

Using immunohistochemical staining, we examined the presence of secretory component (SC) on epithelial cells in gastric and duodenal biopsy specimens collected from Helicobacter pylori-infected individuals and healthy controls. Gastric epithelial cells from healthy volunteers expressed low, but detectable, levels of SC. In contrast, significantly higher level of expression of SC (P < 0.001) was observed on epithelial cells in the antra of H. pylori-infected individuals. The antral SC expression correlated with staining for gamma interferon of intraepithelial and lamina propria lymphocytes (r(s) = 0.76 and 0.69, respectively, P < 0.001) and correlated weakly with production of tumor necrosis factor alpha (r(s) = 0.43, P < 0.05), but it did not correlate at all with interleukin-4 production.

Adult↗

Salivary and gastric fluid secretory immunoglobulin A and free secretory component concentrations in children with Helicobacter pylori-positive gastritis.

The concentrations of secretory IgA (sIgA) in the saliva and the concentrations of free secretory components (FSC) both in the saliva and gastric fluid of patients with Helicobacter pylori HP-positive gastritis and of a control group with functional recurrent abdominal pain (RAP) were measured in order to determine whether there is a deficiency of these non-specific local defence factors in children with HP infection. Eighteen patients with HP-positive gastritis and 12 children with RAP were included in the study and sIgA and FSC concentrations were analysed using the radial immunodiffusion technique. In contrast to our initial hypothesis, the concentrations of FSC in saliva and gastric fluid and sIgA in saliva of patients with HP infection showed no significant difference when compared with children who do not have an organic disease and HP infection. It is suggested that these local defence factors are not involved in the pathogenesis of HP-positive gastritis.

Abdominal Pain↗

Secretory component and immunoglobulin in human gastric carcinoma: an immunohistochemical study.

The occurrence of secretory component (SC), IgA, IgG and IgM within tumor cells was immunohistochemically examined in a total of 101 gastric carcinomas comprising 50 early cancers and 51 advanced cancers. In advanced cancers, the frequency of SC was significantly higher in well-differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. The frequency of IgA did not differ with stage of cancer, but the frequencies of IgG and IgM were significantly higher in advanced cancer than in early cancer. The immunoglobulin-producing plasma cells in the stroma of advanced cancer were chiefly IgG, followed by IgA and IgM producers. The intensity of IgA plasma cell infiltration correlated with presence of IgA in tumor cells. No correlation was noted between serum immunoglobulin value and immunoglobulin in tumor cells. The survival rate indicated a tendency for IgG-containing advanced cancers which were infiltrated with many IgG plasma cells to have a better prognosis.

Adenocarcinoma↗

Secretory component and IgA in the endolymphatic sac.

Immunohistochemical methods were used to investigate secretory component (SC) and immunoglobulin A within the inner ears of Sprague Dawley rats and BALB/c mice. Utilizing specific antisera against SC and IgA, the distribution and localization of SC and IgA were studied in normal, non-immunized ears of both animal species. The kinetics of SC and IgA were also investigated during a secondary immune response following keyhole limpet hemocyanin (KLH) challenge of murine inner ears. In the non-immunized murine inner ear, neither SC or IgA were found. In contrast, SC was localized within the epithelial cells and lumen of the endolymphatic sac (ES) in non-immunized rats and faint luminal IgA staining was seen in one-third of the animals, as well as an occasional IgA-bearing cell in the ES. In the inner ear secondary immune response, SC was found only within the endolymphatic sac of approximately 50% of the immunized mice 14 days after KLH challenge. IgA-bearing cells were also observed within the ES 2 to 3 weeks following KLH challenge. We conclude that there are species differences in the distribution of SC and IgA within the inner ear, and that under pathological conditions the endolymphatic sac may be a site of IgA and SC induction.

Animals↗

Helicobacter pylori infection produces expression of a secretory component in gastric mucous cells.

Helicobacter pylori infection induces the expression of a secretory component (SC) in gastric epithelial cells. We investigated the cell lineage of the SC- and immunoglobulin (Ig) A-expressing epithelial cells in H. pylori-infected gastric mucosa. Materials were obtained by means of gastric biopsy from H. pylori-infected patients (24 cases) before and after the eradication of H. pylori, from five normal uninfected volunteers, and from three gastrectomy cases. Acetic acid-ethanol-fixed and paraffin-embedded specimens were examined using histochemical staining for gastric mucins (periodic acid oxidation-thionine Schiff reaction-concanavalin A-horse radish peroxidase staining) by means of immunostaining for gastric mucins (45M1 and HIK1083), intestinal cells (MUC2 and CD10), Ki67, H. pylori, SC, and IgA. The SC and IgA were not found in normal gastric mucosa. The expressions of the SC and IgA in gastric surface mucous cells and mucous neck cells in the generating zone of the gastric mucosa of H. pylori-infected patients were significantly higher before eradication of H. pylori than after the eradication. These mucous cells have the potential for SC-mediated translocation of IgA into the gastric lumen, and this may act as part of the antibacterial defense system against H. pylori infection in the gastric generating zone.

Adult↗

Secretory IgA, free secretory component and IgD in saliva of newborn infants.

AIM: To determine levels of secretory IgA (sIgA), free secretory component (FSC) and IgD in saliva of newborn infants at the age of 1 day and to evaluate the detection patterns, the influence of saliva flow and the relation to serum derived proteins. METHODS: Seventy-three healthy newborn infants were studied. Saliva was obtained from the bottom of the mouth and buccal sulci using a sterile polyethylene tube connected to a syringe. SIgA, FSC, IgD and albumin were measured by radial immunodiffusion. RESULTS: SIgA was detected in 74.0% of all saliva samples, whereas detection rates for FSC and IgD were 94.5% and 75.3%, respectively. Investigation of detection patterns and their relation to saliva flow indicated that secretion of sIgA and FSC into the oral cavity is under similar regulation. Levels of IgD were found to be independent from saliva flow, as well as from concentrations of serum-derived proteins suggesting different regulative mechanisms compared to sIgA and FSC. The flow rate of unstimulated whole saliva in newborn infants was found to be 15 times lower compared to adolescents, emphasizing the role of saliva flow as a limiting factor for secretion of sIgA and FSC. CONCLUSION: SIgA, FSC and IgD can be determined in saliva of newborn infants even in the first day of life. The saliva flow rate has to be considered when evaluating the function and biological relevance of the oral mucosal immune system of newborn infants shortly after birth.

Cross-Sectional Studies↗

The gene encoding human transmembrane secretory component (locus PIGR) is linked to D1S58 on chromosome 1.

The human transmembrane secretory component (SC or poly-Ig receptor, PIGR) is expressed basolaterally on glandular epithelial cells and is responsible for the external translocation of polymeric IgA and IgM. SC is hence a key molecule in antibody protection of mucosal surfaces. The human SC gene (locus PIGR) is located on chromosome 1 (1q31-q41). Here we present the first genetic linkage study of PIGR versus syntenic markers, including D1S58 and F13B, which have been previously regionalized to 1q31-q32 and 1q31-q32.1, respectively. We found that PIGR is closely linked to D1S58 (lods + 5.06 at theta max = 0.06, without sex difference). PIGR versus F13B showed + 1.46 at theta max = 0.25 for both sexes combined. A recombination of 0.06 between F13B and D1S58 (lods + 2.24) was in contrast to a previously published study giving theta max = 0.22 (lods + 3.9), the combined lods being 5.6 at theta max = 0.20. The progeny of a triply heterozygotic female indicated that PIGR is the flanking locus, therefore suggesting a cen-F13B-D1S58-PIGR-qter gene sequence on human chromosome 1. Only negative lod scores to RH, C8@, and PGM1 on 1p, and FY on proximal 1q, were found. Current combined Norwegian allele frequencies were estimated for PIGR to be A1 = 0.63, A2 = 0.37 (370 chromosomes), and for D1S58 to be A1 = 0.44, A2 = 0.56 (218 chromosomes).

Chromosome Mapping↗

Cellular adaptation of the rat small intestine after proximal enterectomy: changes in microvillous enzymes and in the secretory component of immunoglobulins.

To investigate the adaptation of functions expressed by the villous and crypt cell of the intestinal mucosa after intestinal resection, a 50% proximal enterectomy or a single transection was performed in 16 growing rats weighing 175-200 g. Ten days following the enterectomy, we determined the mucosal mass parameters (weight, protein, and DNA content), the activity of microvillous enzymes (lactase, sucrase, and aminopeptidase) in villus cells, and the concentration of the secretory component of immunoglobulins in crypt cells isolated from the proximal intestinal remnant. Mucosal hyperplasia was attested by the finding that mucosal weight, protein, and DNA content per cm of intestinal length were significantly (p less than 0.01) higher (+29 to +48%) in the resected group than in transected controls. The specific activity of lactase, sucrase, and aminopeptidase were significantly (p less than 0.05) lower (-23 to -56%) in villous cells isolated from the intestinal remnant of resected rats compared to controls. Sucrase activity was depressed in each cell fraction of the entire villous-crypt unit resulting in a lower villous to crypt gradient of enzyme activity. Km for the enzyme determined in villous cells was similar in both groups but the Vmax was reduced proportionally to the enzyme activity in the resected group indicating less enzyme per cell. By contrast, the concentration of secretory component measured by an immunoradiometric assay in both villous and crypt cells was significantly (p less than 0.05) increased (+37 to 45%) following proximal enterectomy. Our data indicate that the response of the epithelial cell to intestinal resection varies according to the metabolic function and that the mechanism of adaptation at the cellular level is complex.

Adaptation, Biological↗

Biliary and pancreatic secretory component of the migrating myoelectric complex in the pig. Effect on intraduodenal pH.

The aim of the present study in the pig was to describe the biliary and pancreatic secretory component of the migrating myoelectric complex (MMC) during the interdigestive period and after feeding, and to examine the effects of the extracorporal diversion of biliary or pancreatic secretions on the MMC and on the cyclical variation of intraduodenal pH. In a first trial six pigs (50.6 +/- 1.6 kg) were fitted with a permanent catheter in the common bile duct (3 pigs) or in the pancreatic duct (3 pigs) to control the flow of these secretions. They also had a duodenal catheter to return the secretions, and antral and duodenal electrodes for simultaneous recording of motility in fasting conditions. In a second trial ten pigs (50.8 +/- 1.5 kg) underwent a similar surgical preparation (5 bile duct and 5 pancreatic duct fistulations). They had, in addition, a duodenal T-shaped cannula (19 cm distal to the pylorus) allowing continuous intraluminal pH recording parallel to the motility recording. Experiments included 4 situations: secretions returned under fed or fasted conditions; by-passed secretions in fed or fasted pigs. The flow of bile and pancreatic juice was very high during irregular spiking activity phases (ISA), peaking at the beginning of regular spiking activity phases (RSA); it was minimal during quiescent phases. The duration of the duodenal MMC and of its 3 constitutive phases was not modified by total extracorporal diversion of bile or pancreatic secretion either in the fed or fasted state. During the interdigestive period the pH was significantly reduced under bile diversion (quiescence: 6.17 vs 7.15; ISA: 4.91 vs 5.94; RSA: 5.40 vs 6.52) as well as under pancreatic juice diversion (quiescence: 5.56 vs 7.18; ISA: 4.21 vs 5.97; RSA: 5.14 vs 6.72). In fed pigs only bile diversion resulted in a small acidification during the postprandial pattern (5.07 vs 5.44) and the consecutive MMC cycles (quiescence: 5.81 vs 6.61; ISA: 4.66 vs 4.92; RSA: 5.11 vs 5.78). Nevertheless the periodicity of pH variation along the MMC cycle was unaffected in bile or pancreatic juice-deprived animals. It is concluded that a true biliary and pancreatic secretory component of MMC exists in the pig, and that these 2 secretions strongly contribute to the neutralization of the duodenal contents. However, the major determinant of the cyclical variation of the intraduodenal pH appears to be the periodicity of the acid gastric outflow.

Animals↗

Secretory component and IgA expression by epithelial cells in sow mammary gland and mammary secretions.

Secretory component (SC) and IgA expression of epithelial cells were studied in the mammary tissue and mammary secretions of sows. In mammary tissue, SC was not detected until day 105 of gestation. From the time of delivery (day 115) to the time of established lactation, the proportion of epithelial cells containing SC rose from 20 per cent to nearly 100 per cent. There was no IgA in alveolar epithelial cells until day 105 of gestation; on day 115, IgA positive epithelial cells were present in 10 per cent of the alveoli, which increased to 80 per cent during lactation. Epithelial cells represented more than 20 per cent of the total cells in colostrum, and predominated over leucocytes in milk. In colostrum, these epithelial cells (9 to 15 microns) showed weakly positive membrane, SC, contained cytoplasmic SC and had a limited capacity for in vitro proliferation. Ten per cent of epithelial cells contained intracytroplasmic IgA. In milk, the epithelial cells were larger (15 to 40 microns) with a higher expression of both membrane and intracytoplasmic SC; 66 per cent of these cells expressed intracytoplasmic IgA. These data showed that the capacity of mammary epithelium to process IgA to secretory IgA was complete at the end of mammary gland organisation, and established that the epithelial cells of milk contribute to the transfer of IgA to neonates.

Animals↗

Quantitation of secretory component levels in cyst fluids, ascitic fluids, and sera from ovarian adenocarcinoma patients.

A secretory component (SC) was detected by radioimmunoassay in the cyst fluids, ascitic fluids, and sera from patients with ovarian adenocarcinomas. Serous cyst fluids and ascitic fluids showed lower levels (expressed as means +/- SE) of SC (1.37 +/- 0.37 and 1.24 +/- 0.24 microgram/ml, respectively) than mucinous cyst fluids (181.50 +/- 50.40 microgram/ml). SC levels in the sera of all patients with ovarian adenocarcinoma were high (12.67 +/- 1.43 microgram/ml) when compared to SC levels in the sera of normal individuals (2.34 +/- 0.41 microgram/ml). Sera from patients with ovarian cancers diagnosed as serous, mucinous, papillary, and poorly differentiated adenocarcinomas showed SC levels of 9.93 +/- 1.68, 22.44 +/- 3.24, 7.35 +/- 1.13, and 10.10 +/- 1.58 microgram/ml, respectively.

Adenocarcinoma↗

Abnormal expression of secretory component in term newborns with bowel perforation--a report of two cases.

Expression of secretory component (SC) in intestinal resection specimens from two term newborns with bowel perforation due to necrotizing enterocolitis (NEC) or and NEC-like syndrome was determined and compared with the SC immunoreactivity in a panel of intestinal tissues from fetuses at different ages of gestation. Expression of SC was absent in one patient, whereas in the other patient, SC immunoreactivity was observed in the basal cell part of colonic epithelium only. SC was normally expressed in a follow-up biopsy on one of these patients. In contrast, SC was present in the apical plasma membrane and brush border of colonic epithelium from 32 weeks of gestation onwards in fetuses without demonstrable intestinal disease. From these findings we conclude that the expression of SC was impaired in our patients, thus possibly playing a role in the development of the bowel perforation in these full-term newborns with an NEC-like syndrome or resulting from its pathogenesis.

Enterocolitis, Pseudomembranous↗

Immunohistochemical localization of secretory component in the liver of guinea pigs and dogs versus rats, rabbits, and mice.

Secretory component (SC) was localized in the liver of guinea pigs, dogs, rabbits, rats, and mice. In rabbits, rats, and mice SC localized predominantly in bile canaliculi and on hepatocyte sinusoidal membranes but was doubtful in cholangiocytes . In dogs and guinea pigs SC-staining was not detected in/on hepatocytes and canaliculi but was strong in/on cholangiocytes , as reported for humans. In guinea pigs IgA biliary output was small (0.23 mg/kg/day), as for dogs and humans, and below IgG output (1.4 mg), in contrast to rats, whose IgA biliary output (38 mg/kg/day) was much larger than IgG output (2mg). Biliary obstruction in guinea pigs induced only minor increases in serum IgA (+ 26% over 24 h), as reported for dogs and humans, in contrast to rats (+ 800% over 24h) and rabbits. Hepatocyte SC expression correlates with IgA hepatobiliary excretion, being low in guinea pigs, dogs, and humans but high in rats, rabbits, and mice.

Animals↗

Endocrine, neural, and immune control of secretory component output by lacrimal gland acinar cells.

Androgens regulate the synthesis and secretion of secretory component (SC), the IgA antibody receptor, by acinar cells from the lacrimal gland. However, this hormone action may be susceptible to significant modification by other agents from the endocrine, nervous, or immune systems. To investigate the nature of this neuroimmunoendocrine interaction, the present study examined the impact of hormones, neurotransmitters, and lymphokines on basal and androgen-induced SC production by lacrimal gland acinar cells in vitro. Our results demonstrated that vasoactive intestinal peptide, the beta-adrenergic agonist, isoproterenol, PGE2, IL-1 alpha, IL-1 beta, and TNF-alpha significantly increased media SC levels in control or androgen-containing cell cultures. In contrast, the cholinergic agonist, carbachol, significantly decreased cellular SC output. These effects may be mediated through the agents' known capacity to alter intracellular cAMP levels. In support of this hypothesis, exposure of acinar cells to stimulators or analogues of cAMP resulted in a significant enhancement of SC production. Thus, these findings indicate that SC output in lacrimal tissue may be modulated by interactions between the endocrine, nervous and immune systems.

1-Methyl-3-isobutylxanthine↗