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PubMed1995

Immunobiology of the human penile urethra.

The human penile urethra contains numerous IgA and J chain-positive plasma cells, and the epithelium expresses secretory component, the transport molecule for polymeric IgA, indicating that this region is an active site of secretory IgA-mediated immune defense. At the distal tip, the mucosae of the meatus and fossa navicularis contain intraepithelial dendritic cells but few macrophages, whereas the urethra proper contains many macrophages within the lamina propria and epithelium, but no dendritic cells. T lymphocytes are abundant and ubiquitous in all regions of the urethra. Both CD8+ and CD4+ subpopulations of T lymphocytes are present in the lamina propria and epithelium, although CD8+ cells predominate. The majority of T lymphocytes are positive for CD45RO (memory marker), and many are also positive for the alpha E beta 7 integrin (mucosal-associated antigen). These data indicate that the human urethra is a highly dynamic immunocompetent tissue possessing all the necessary elements for antigen presentation and both humoral and cellular mucosal immune responses. Furthermore, the urethra resembles other mucosal surfaces in terms of lymphocyte subpopulations, segregation of phenotypes and expression of antigenic determinants characteristic of mucosal lymphocytes. It is likely that this region plays a dominant role in protecting the male urogenital tract against ascending infections, and should be targeted in vaccination strategies directed against sexually transmitted diseases.

Adult↗
PubMed2004

Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway.

Most clinical isolates of Streptococcus pneumoniae consist of heterogeneous populations of at least two colony phenotypes, opaque and transparent, selected for in the bloodstream and nasopharynx, respectively. Microarray analysis revealed 24 orfs that demonstrated differences in expression greater than twofold between variants of independent strains. Twenty-one of these showed increased expression in the transparent variants, including 11 predicted to be involved in sugar metabolism. A single genomic region contains seven of these loci including the gene that encodes the neuraminidase, NanA. In contrast to previous studies, there was no contribution of NanA to adherence of S. pneumoniae to epithelial cells or colonization in an animal model. However, we observed NanA-dependent desialylation of human airway components that bind to the organism and may mediate bacterial clearance. Targets of desialylation included human lactoferrin, secretory component, and IgA2 that were shown to be present on the surface of the pneumococcus in vivo during pneumococcal pneumonia. The efficiency of desialylation was increased in the transparent variants and enhanced for host proteins binding to the surface of S. pneumoniae. Because deglycosylation affects the function of many host proteins, NanA may contribute to a protease-independent mechanism to modify bound targets and facilitate enhanced survival of the bacterium.

Animals↗
PubMed1992

Ontogenetic aspects of the intestinal immune system in man.

The development of the mucosal immune system in the human fetus has been studied in some detail. Aggregates of T and B cells form early Peyer's patches by 16 weeks gestation and by 19 weeks organised Peyer's patches with T and B cell zones are seen. T cells populate the mucosal lamina propria and epithelium from 11 weeks gestation and increase in number thereafter. As in the adult, most intraepithelial lymphocytes are CD8+ and most lamina propria T cells are CD4+. By 20 weeks, villus epithelial cells are HLA-DR+ and secretory component is also expressed. In the absence of lumenal stimulation in the fetus there is no intestinal secretory IgA antibody response. A few IgA plasma cells are present in fetal salivary glands but the number does not dramatically increase until after birth.

Embryonic and Fetal Development↗
PubMed1981

Demonstration of 11S IgA antibody to spermatozoa in human seminal fluid.

Spontaneous sperm agglutination was observed in the ejaculate of a 39-year-old male (patient Z). Using an enzyme-linked immunosorbent assay (ELISA) with spermatozoa fixed to wells of a microtitre plate it was determined that IgA was associated with patient Z's spermatozoa but not with a pooled sample of spermatozoa from fertile men Z's seminal fluid agglutinated human spermatozoa (titre 1:16). In contrast, no sperm-agglutinating or immobilizing activity was present in the patient's serum. Agglutination was prevented by preincubation of the seminal fluid with anti-IgA antibody but not with anti-IgA antibody. IgG from Z's seminal fluid readily bound to human spermatozoa, as determined by the ELISA assay. IgA from a pool of seminal fluids from fertile men or from 18 human sera bound to spermatozoa to a much lesser extent. By sucrose-gradient velocity centrifugation it was demonstrated that the anti-sperm IgA in patient Z's seminal fluid was 11S. Finally, antibody to secretory component removed the anti-sperm IgA from Z's seminal fluid. These data provide evidence that secretory IgA with anti-sperm activity is produced in the male genital tract. Furthermore, a new methodology is presented for the determination of antibodies to spermatozoa.

Adult↗
PubMed2000

Role of J chain in secretory immunoglobulin formation.

The joining (J) chain is a small polypeptide, expressed by mucosal and glandular plasma cells, which regulates polymer formation of immunoglobulin (Ig)A and IgM. J-chain incorporation into polymeric IgA (pIgA, mainly dimers) and pentameric IgM endows these antibodies with several salient features. First, a high valency of antigen-binding sites, which makes them suitable for agglutinating bacteria and viruses; little or no complement-activating potential, which allows them to operate in a noninflammatory fashion; and, most importantly, only J-chain-containing polymers show high affinity for the polymeric Ig receptor (pIgR), also known as transmembrane secretory component (SC). This epithelial glycoprotein mediates active external transfer of pIgA and pentameric IgM to exocrine secretions. Thus, secretory IgA (SIgA) and SIgM, as well as free SC, are generated by endoproteolytic cleavage of the pIgR extracellular domain. The secretory antibodies form the 'first line' of defence against pathogens and noxious substances that favour the mucosae as their portal of entry. The J chain is involved in creating the binding site for pIgR/SC in the Ig polymers, not only by determining the polymeric quaternary structure but apparently also by interacting directly with the receptor protein. Therefore, both the J chain and the pIgR/SC are key proteins in secretory immunity.

Amino Acid Motifs↗
PubMed1981

IGA in human bile and liver.

Hepatic bile IgA from 6 patients was measured by radioimmunoassay and characterized immunochemically. The concentration of IgA was 0.14 to 0.88 mg/ml. IgA associated with secretory component (SC) as well as unassociated with SC was demonstrated in all 6 samples; The proportion associated with SC (secretory IgA) was 72% to 95%. IgA and SC were localized immunocytochemically in liver and bile duct tissues by the peroxidase-labeled antibody method. Evidence favoring endocytic, SC-mediated transfer of IgA by intrahepatic and extrahepatic biliary epithelium, but not by hepatocytes, was found.

Bile↗
PubMedDate not supplied

Intestinal secretion of IgA and IgM: a hypothetical model.

The secretory component (SC) has recently been found to be associated with IgM in external secretions, although in a less stable complex than secretory IgA. Moreover, SC combines spontaneously in vitro with both IgA and IgM. A prerequisite is that the immunoglobulins contain the J chain, which is present only in dimers and polymers. This polypeptide is essential for the formation of an SC-binding site which appears already at the cytoplasmic level in IgA- and IgM-producing immunocytes. Locally formed J-chain-containing immunoglobulins are therefore readily available for complexing with SC present in the membranes of columnar secretory epithelial cells of glandular sites. This complexing initiates pinocytosis and external transport. Immunohistochemically the gland cells are shown to contain SC, IgA and IgM in identical locations, except that SC alone appears in the Golgi zone. Locally formed IgA and IgM antibodies are thus efficiently transferred to the mucosal surface where they exert an immunological exclusion of antigens. Conversely, IgG antibodies, which are not actively drained away from the lamina propria, may rather become engaged in complement activation and cell-mediated cytotoxicity with potentially deleterious effects on the tissue. Secondary to severe inflammatory reactions, secretory epithelium may show decreased production of SC; the selective external transport of SC-stabilized secretory IgA and IgM is thus jeopardized, and a vicious circle may be set up in the mucosa.

Animals↗
PubMed1999

Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice.

Mucosal surfaces are protected specifically by secretory immunoglobulin A (SIgA) and SIgM generated through external translocation of locally produced dimeric IgA and pentameric IgM. Their active transport is mediated by the epithelial polymeric Ig receptor (pIgR), also called the transmembrane secretory component. Paracellular passive external transfer of systemic and locally produced antibodies also provides mucosal protection, making the biological importance of secretory immunity difficult to assess. Here we report complete lack of active external IgA and IgM translocation in pIgR knockout mice, indicating no redundancy in epithelial transport mechanisms. The knockout mice were of normal size and fertility but had increased serum IgG levels, including antibodies to Escherichia coli, suggesting undue triggering of systemic immunity. Deterioration of their epithelial barrier function in the absence of SIgA (and SIgM) was further attested to by elevated levels of albumin in their saliva and feces, reflecting leakage of serum proteins. Thus, SIgA did not appear to be essential for health under the antigen exposure conditions of these experimental animals. Nevertheless, our results showed that SIgA contributes to maintenance of mucosal homeostasis. Production of SIgA might therefore be a variable in the initiation of human immunopathology such as inflammatory bowel disease or gluten-sensitive enteropathy.

Animals↗
PubMed1997

Mucosal immunity in the female genital tract.

Immunoglobulin (Ig)-producing cells in mucosal tissues represent quantitatively the most important humoral immune system of the body. All exocrine tissue sites contain immunocytes (B-cell blasts and plasma cells) that mainly synthesize dimers and larger polymers of IgA (collectively called pIgA) with incorporated J chain. Such pIgA is actively transported to external secretions as secretory IgA (SIgA) by the polymeric Ig receptor (pIgR), a transmembrane epithelial glycoprotein also called the secretory component (SC). The same transport mechanism includes pentameric IgM to generate SIgM. Although the most active SIgA system occurs in the gut, secretory immunity also operates in the female genital tract, with considerable pIgA production in the cervical mucosa and fallopian tubes. The origin of these local IgA immunocytes remains undefined. In mice, both lymphoid tissue in the large bowel (GALT) and nasopharynx (NALT) have been suggested as inductive sites for B cells homing to the urogenital tract. It is well established that integrin alpha 4 beta 7 is used by primed lymphoid cells to enter the intestinal lamina propria through interactions with mucosal addressin cell adhesion molecule (MAdCAM)-1 expressed on venule endothelium. However, alpha 4 beta 7 does not appear to be an important homing molecule in the airways, and the same might be true for the urogenital tract; this could explain that high levels of IgA antibodies occur in cervicovaginal secretions of mice after nasal immunization. The endometrium can likewise perform pIgR-mediated external translocation of pIgA that in this tissue appears to be mainly derived from serum, partly under hormonal regulation. In addition, paracellular diffusion of serum-derived and locally produced IgG through epithelia is an important part of humoral immunity in the female genital tract.

Animals↗
PubMed1985

Degradative intracellular transport of antisecretory component in cultured hepatocytes. An alternate pathway for the immunoglobulin A receptor.

The liver efficiently transports dimeric immunoglobulin A (dIgA) from blood to bile in a direct, nonlysosomal pathway involving smooth-surfaced vesicles. Secretory component (SC), the plasma membrane receptor for dIgA, is released into bile still bound to its ligand by disulfide bridges. Rabbit IgG antirat SC binds specifically to plasma membrane SC, yet the biliary secretion of anti-SC is markedly lower than that of dIgA, suggesting that the IgG antibodies utilize an alternate transhepatocellular pathway. Uptake of commercially available antihuman SC conjugated to horseradish peroxidase was examined by quantitative electron microscopic immunocytochemistry using primary rat hepatocyte monolayer cultures. Coincubation with human polymeric IgA, rabbit antiserum to rat SC, free human SC, human secretory IgA, and rat bile, all significantly suppressed uptake of anti-SC-horseradish peroxidase, thus demonstrating the specificity of the labeled antibody. Coated vesicles accounted for greater than 70% of the total uptake of either the anti-SC-horseradish peroxidase preparation or colloidal gold-labeled IgG antirat SC. Both compounds could also be observed in other structures associated with the degradative pathway, i.e., multivesicular bodies and lysosomes. Moreover, the extent to which 125I-anti-SC was degraded was significantly greater than that of 125I-dIgA. These data demonstrate that dIgA and anti-SC utilize different intracellular pathways, with anti-SC undergoing lysosomal degradation.

Animals↗
PubMed1979

Reflux of billiary components into blood in experimental intrahepatic cholestasis induced in rats by treatment with alpha-naphthylisothiocyanate.

The sera of rats treated with alpha-naphthylisothiocyanate, an agent reported to cause intrahepatic cholestasis, and of rats treated with carbon tetrachloride, are examined for evidence of leakage of bile into blood. The levels of the four bile components assayed, namely IgA, free IgA secretory component, the biliary isoenzyme of 5'-nucleotidase and of direct reacting (conjugated) bilirubin, were all elevated in the sera of rats treated with alpha-naphthylisothiocyanate. No change in any of these components was found in rats treated with carbon tetrachloride, indicating that their appearance in serum is not an inevitable consequence of damage to hepatocytes. As the bile components assayed reach bile by three different routes. their rapid appearance in the sera of rats treated with alpha-naphthylisothiocyanate indicates reflux of bile into blood, presumably as a result of mechanical obstruction of intraheptic bile ducts.

1-Naphthylisothiocyanate↗
PubMed1992

Small cell (endocrine cell) carcinoma of the gallbladder with squamous and adenocarcinomatous components.

Small cell (endocrine cell) carcinoma of the gallbladder in a 62-year-old woman is reported. The palliative cholecystectomy specimen revealed a submucosally invading tumor with extensive hemorrhagic necrosis. At autopsy, performed five months after surgery, a huge tumor measuring 14 x 12 x 8 cm was located at the liver hilus. No signs or symptoms related to overproduction of hormones were recorded throughout her illness. Neither lung lesions nor gall stones were identified. Histologically, diffuse proliferation of small, spindle-shaped atypical tumor cells with numerous mitoses was evident. Intraepithelial tumor cell proliferation in the gallbladder mucosa was seen focally. The neuroendocrine nature of the tumor cells was confirmed by the histologic pattern of growth with pseudo-rosette formation, positive reaction for Grimelius' argyrophilia, neuron-specific enolase and Leu 7, and ultrastructural demonstration of neuroendocrine-type granules. Immunostaining for a variety of hormones was all negative. Characteristically, foci with squamous and adenocarcinomatous differentiation were identified in the tumor tissue. The glandular components were immunoreactive for carcinoembryonic antigen, secretory component, epithelial membrane antigen and CA19-9. The histogenesis and totipotentiality of the neoplasm were discussed.

Adenocarcinoma↗
PubMed1983

Experimental cholestasis promotes the deposition of glomerular IgA immune complexes.

Previous experimental and clinical studies support a role for the hepatobiliary system in the clearance of oligomeric IgA from serum, and alterations of this system have been associated with the deposition of IgA in the renal mesangium. The present studies in mice address the question of whether the mesangial deposition of IgA following cholestasis includes immune complexes. While bile duct ligation resulted in mesangial IgA deposition within several days in approximately 75% of animals, whether deliberately orally immunized, nonimmunized, or given injected immune complexes, mice that underwent sham operations had IgA deposits only if orally immunized. Moreover, mice that had been orally immunized or given injected immune complexes and whose bile ducts had been ligated contained deposits of specific IgA antibody and antigen. In the ligated mice some of the IgA was secretory IgA, as demonstrated by the presence of secretory component. Thus, bile duct ligation promotes the deposition of circulating IgA immune complexes, presumably by decreasing their clearance from serum, and gives rise to secretory IgA in the glomerular mesangium. The secretory immune system probably plays a role in the pathogenesis of idiopathic and cirrhosis-related human IgA nephropathy.

Animals↗
PubMed1994

[Histological analysis of craniopharyngiomas--with special reference to their histological origin and differentiation].

The histogenesis of craniopharyngiomas was immunohistochemically studied on the basis of cytokeratins (CK) expression, with special reference to histological subtype, i.e., the squamous type (Sq) and adamantinomatous type (Ad). Alcian-Blue staining and immunohistochemical expression of secretory component were also studied to assess secretory activity. Although combined expression of simple-, stratified-, and skin-type CK was detected in both Sq and Ad, the pattern of expression in Sq and Ad was different. Sq displayed epidermal differentiation of CK, and secretory activity was limited to the apical cells of Sq. Based on these findings, the histogenesis of Sq appeared to be from Rathke's pouch, but that of Ad remained obscure.

Adolescent↗
PubMed2003

Novel functions of the polymeric Ig receptor: well beyond transport of immunoglobulins.

The polymeric Ig receptor (pIgR) ensures efficient secretion of polymeric IgA (pIgA) at mucosal surfaces. On basal to apical transport across epithelial cells, the pIgR extracellular domain is cleaved, releasing secretory component (SC) in association with pIgA. This finds its raison d'être in the recent observation that SC is directly involved in the protective function of secretory IgA. In addition, free SC exhibits scavenger properties with respect to enteric pathogens. However, although pIgR dedicates its life to mucosal protection, it also seems to permit pathogen entrance through the epithelial barrier. The multiple mechanisms that they are involved in make pIgR and SC instrumental to mucosal immunity.

Animals↗
PubMed1982

Alpha heavy chain disease lacking secretory alpha chain, with cobblestone appearance of the small intestine and duodenal ulcer demonstrated by endoscopy.

Ultrastructural and immunohistochemical studies of the small intestine are described in a Japanese patient with alpha heavy chain disease who had a history of colonic ulcers. Endoscopic examinations revealed multiple gastric erosion, duodenal ulcer, and a thickened, cobblestone-like pattern composed of small nodules in the duodenum and jejunum, which was similar in appearance to Crohn's disease. An electron microscopic study showed that the numerous, infiltrated cells in the jejunal lamina propria were matured plasma cells with atypical structure of the organelles. These plasma cells had alpha heavy chain protein devoid of light chain. Although secretory component was demonstrated normally in the epithelial cells by immunofluorescent methods, no association of this component with alpha heavy chain protein could be observed in any of the plasma and epithelial cells of this case. These facts suggest the absence of secretory alpha chain or secretory IgA, and a deficiency of the mucosal secretory immune system in this patient.

Adult↗
PubMed1988

Mucosal antibody response to vaginal infection with herpes simplex virus in pre-vaccinated guinea-pigs.

The mucosal antibody response, in female guinea-pigs vaccinated with the Skinner herpes simplex virus vaccine, has been investigated. The HSV-specific secretory IgA response was assessed using the cross-reactivity of an antiserum raised against human secretory component. Animals vaccinated subcutaneously at a distant site were shown to respond to subsequent infection with HSV by the production of HSV-specific vaginal IgG and secretory IgA. No vaginal HSV-specific antibodies were found in infected, non-vaccinated animals.

Animals↗
PubMed1989

Immunohistological study of the epithelial components of Warthin's tumor.

In order to gain insight into the origin of Warthin's tumor, 10 cases of Warthin's tumor were compared immunohistologically with macroscopically and microscopically normal areas of the same glands, using 6 types of functional markers; carcinoembryonic antigen, secretory component, lactoferrin, keratin, S-100 protein and glial fibrillary acidic protein. It was shown that in normal parotid glands, the cells of acini, the intercalated ducts, the striated ducts, and the excretory ducts, as well as myoepithelial cells differed from each other in intensity and distribution of reaction products with antisera against those markers. Although the differences were rather subtle, the results suggested that those markers could differentiate the cell types of the salivary glands. In Warthin's tumors with double-layered tumor epithelia, the staining characteristics of the luminal and basal epithelia differed from each other. Epithelial cells on the luminal side showed immunological characteristics similar to striated duct cells of the parotid gland, while those of the basal side had characteristics similar to those of basal cells of the excretory duct. It is therefore suggested that the epithelia of Warthin's tumor may show differentiation into 2 different cell types.

Adenolymphoma↗