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PubMed2001

A novel NF-kappa B/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-alpha-induced transcription of the human polymeric Ig receptor.

Secretory Abs constitute the first line of specific immune defense at mucosal surfaces. Such Abs are generated by the active transport of polymeric Ig (pIg) across secretory epithelia mediated by the pIgR, also known as transmembrane secretory component (SC). The proinflammatory cytokine TNF-alpha is a key mediator of host responses to infections, and it can stimulate protein synthesis-dependent transcriptional up-regulation of pIgR/SC in the HT-29 intestinal adenocarcinoma cell line. By reporter gene assay we identified a novel TNF-alpha-responsive region located within a 748-bp fragment in intron 1 of the human pIgR/SC gene which depended on an NF-kappaB/Rel site for full responsiveness. EMSAs demonstrated preferential binding of the NF-kappaB/Rel family member p65 (RelA) to this DNA element after TNF-alpha stimulation, with weaker and more delayed binding of p50. Furthermore, the TNF-alpha-responsive region in intron 1 required cooperation with DNA elements located in the proximal promoter region of the gene. Mutational analysis demonstrated that an IFN-stimulated response element near the transcriptional start site in exon 1 was involved in the TNF-alpha responsiveness. Thus, DNA elements located >4 kb apart were found to cooperate in TNF-alpha-induced pIgR/SC up-regulation. The intronic TNF-alpha-responsive enhancer overlapped with a recently identified IL-4-responsive enhancer. Several intronic DNA elements found to be functionally important in the human gene are highly conserved between the human and mouse pIgR/SC genes, suggesting the presence of a conserved cytokine-responsive enhancer region.

Base Composition↗
PubMed1986

Estradiol regulation of the secretory immune system in the female reproductive tract: IgA in uterine and vaginal secretions of rats following portacaval anastomosis.

The uterine immune system is under the control of estradiol which acts to increase the levels of both IgA and secretory component (SC) in uterine secretions. The objective of the present study was to determine whether serum is the primary source of the IgA which enters uterine secretions in response to estradiol. To examine this, serum IgA levels in rats were surgically elevated by portacaval anastomosis which prevents hepatic clearance of IgA. Under these conditions, IgA levels in serum were 2- to 4-fold higher than those of intact or sham-operated animals. Levels of IgA in uterine secretions of portacaval animals, however, were significantly lower than those measured in controls when animals were ovariectomized and treated with estradiol. IgA in vaginal secretions of portacaval animals was greater than that in sham-operated or intact rats. To determine whether IgA had leaked from the uterus into vaginal secretions, a second group of animals had their uteri ligated at the utero-cervical junction prior to hormone treatment. Following estradiol stimulation, uterine IgA levels in portacaval animals were the same as those measured in intact and sham-operated animals. When free SC was measured in uterine secretions of ligated rats, levels were the same in all three groups. These studies indicate that elevated levels of serum IgA did not lead to a rise in uterine IgA. Further, since SC, which is thought to be a receptor for transporting IgA into mucosal secretions, remained unchanged, it appears unlikely that IgA movement into the uterine lumen was transport limited. These studies suggest that the presence of IgA in uterine and vaginal secretions is not due exclusively to serum contributions but may involve local synthesis of IgA.

Animals↗
PubMed1982

Plasma carcinoembryonic antigen concentrations and immunohistochemical patterns of epithelial marker antigens in patients with large bowel carcinoma.

Carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA were traced by paired immunofluorescence staining in 102 large bowel carcinomas from 99 patients. The immunohistochemical results were evaluated semiquantitatively in relation to histological tumour grade, clinicopathological stage, and preoperative plasma CEA concentration. CEA expression was significantly increased (p less than 0.05) in the following order: histologically normal colon mucosa, transitional mucosa adjacent to tumours, neoplastic epithelium; the reverse was true for the expression of SC and epithelial IgA (p less than 0.01). CEA was significantly more abundant in the moderately and poorly differentiated tumors than in the well differentiated ones (p less than 0.05), whereas the latter showed better expression of SC (p less than 0.05) and epithelial IgA (p approximately 0.06). In the transitional mucosa, CEA staining tended to be inversely related to histological tumour grade, whereas SC and epithelial IgA were significantly better seen in this zone when the adjacent tumour was well differentiated than when it was moderately or poorly differentiated (p less than 0.01). Furthermore, the expression of SC and epithelial IgA in the transitional mucosa decreased with increasing invasiveness of the tumours, whereas the opposite relation was indicated for CEA expression. Plasma CEA concentrations were not clearly correlated with histological levels than the localised well differentiated tumours tended to be associated with lower levels than the localised moderately differentiated ones (p approximately 0.06). Moreover, the latter variety was associated with lower plasma CEA concentrations than disseminated tumours of comparable differentiation (p less than 0.01).

Adenocarcinoma↗
PubMed2001

Lymphocyte homing and Ig secretion in the murine mammary gland.

In mice the majority of the immunoglobulins (Ig) in milk belongs to the IgA class. Prior to its transepithelial transportation into the milk, dimeric IgA (dIgA) is bound to the transmembrane form of the secretory component or polymeric Ig receptor (SC/pIgR). The latter is synthesized in the epithelial cells lining the ducts and alveoli of the mammary gland. A candidate for playing the role of adhesion molecule to primed lymphocytes present in the murine mammary gland might be the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). We studied the correlation between the levels of IgA in colostrum and milk, the number of IgA producing plasma cells in the mammary gland and the expression of MAdCAM-1 in mammary gland endothelial cells during pregnancy and lactation. The relation between the IgA levels in the milk and the expression levels of pIgR in mammary gland epithelial cells was also investigated. We found that the expression of MAdCAM-1 and pIgR starts in early-mid pregnancy; the number of IgA-producing plasma cells and the IgA concentration in milk increase from early lactation onwards. The MAdCAM-1 expression declines during lactation whereas the pIgR levels and IgA-producing plasma cell numbers rise until the end of lactation. Because the MAdCAM-1 level starts to rise several days before the rise of the IgA-producing plasma cell level, MAdCAM-1 cannot be the rate determining factor governing extravasation of primed B cells to the mammary gland. We also conclude that the pIgR is present in sufficient amounts to enable increasing S-IgA secretion into the milk during lactation.

Animals↗
PubMedDate not supplied

Polymeric IgA antibody to gliadin in the serum of patients with coeliac disease.

Secretory component (SC) binding assays which detect polymeric IgA (pIgA) in serum were used to measure serum antigliadin pIgA and total pIgA in patients with coeliac disease. Total IgA antigliadin antibody in serum and intestinal fluid was measured by enzyme linked immunosorbent assay (ELISA). The relationship of pIgA antibody to dietary gluten and the antigliadin IgA antibody in intestinal fluid was examined. Twenty-nine serum samples were assayed, twelve from patients ingesting gluten and seventeen from patients who had excluded gluten from their diet for 6 months. Eight of these were paired samples from 4 adults on and off gluten. In addition, paired samples of both intestinal fluid and serum were obtained from 7 children on and off gluten. Polymeric IgA antibody to gliadin was detected in 11 of 12 subjects on gluten but in only 3 of 17 who had excluded gluten. Three of the four adults from whom paired serum samples were obtained had pIgA antigliadin, but only while on gluten. Three of the seven children in whom intestinal and serum antibody were assayed had pIgA to gliadin, which could not be detected after exclusion of gluten, although their intestinal antibody level remained elevated. There was no change in total pIgA levels with diet although the levels were higher than those seen in normal subjects. We conclude that pIgA antibody to gliadin is frequently found in the serum of coeliac patients ingesting gluten. It disappears with gluten elimination at a time when the IgA antigliadin antibody in intestinal fluid has not altered.

Celiac Disease↗
PubMed1997

Clonal versus polyclonal Epstein-Barr virus infection in nasopharyngeal carcinoma cell lines.

In most nasopharyngeal carcinoma (NPC) biopsy specimens, the Epstein-Barr virus (EBV), particularly in the terminal repeat region genomic structure, reveals a clonal pattern. To evaluate this phenomenon in vitro, we infected EBV-negative NPC cell lines, which express secretory component (SC) protein on their cell surface, with EBV particles. The viral particles were obtained either from a subcloned single cell or from the original B95-8 cell line. EBV infection was performed by incubating IgA anti-EBV and EBV particles with NPC cells and confirmed by direct in situ PCR hybridization. Southern blot analysis of EBV terminal repeat in EBV-infected NPC cell lines was performed using a Xhol 1.9-kb DNA fragment from the right terminus of the EBV genome as a probe. We found that all four NPC cell lines (ie, NPC-TWO1; 03, 04, and 06) expressed SC protein on their surfaces and could be infected by EBV through the EBV IgA-SC complex. Southern blot analysis in the single cell-subcloned B95-8 cell line showed a clonal EBV terminal repeat with a higher molecular size; whereas the original B95-8 line revealed the polyclonal EBV DNA pattern. A similar clonal EBV genomic pattern with lower molecular size was seen in all EBV-infected NPC cell lines. For comparison, six NPC biopsy specimens were also examined; of these, five showed a single band, and the remaining showed one major band and several lower molecular-sized bands. The EBV genomic DNA in the infected cells was shown to be an episomal form. We conclude, therefore, that a single (clonal) form of EBV genome can be obtained from a mixed population of epithelial tumor cells, even when they are infected by multiple virions with single or multiple form(s) of the EBV genomic pattern.

Animals↗
PubMed1983

Structural and genetic heterogeneity of the receptor mediating translocation of immunoglobulin A dimer antibodies across epithelia in the rabbit.

Secretory component (SC), synthesized as a transmembrane protein, acts as the receptor that binds IgA dimers and mediates their transepithelial transport. Cleavage of the receptor (membrane SC) apparently occurs during transport and a fragment, the secreted form, is generated, which remains tightly bound to the IgA dimer. In the rabbit, variation in the size of membrane SC is observed with both a high and a low molecular weight family, each composed either of two or of four distinct polypeptides depending on the individual rabbit. The same degree of size heterogeneity is observed for secreted SC. Part of this size heterogeneity is related to genetic polymorphism. The milk of individual rabbits typed with anti-SC-allotype sera reveals three different banding patterns. The simplest pattern, found in t61/t61 and t62/t62 homozygotes, consists of an upper and a lower doublet. Since each band of these two doublets in the t62 allotype migrates slightly faster than its counterpart in the t61 allotype, a composite pattern is observed in the heterozygotes (t61/t62). Within a given allotypic group, all SC polypeptide chains expressed the identical allotypic specificity. The 2000 to 4000 difference in molecular weight between the two forms of a doublet probably reflects differences in the number of glycosylated asparagine residues, since individual bands of a doublet show identical peptide maps. High and low molecular weight families are also structurally related to each other as shown by one-dimensional peptide maps and identical NH2- and COOH-terminal amino acid sequences. These results indicate that the 25-kDa size difference between SC from the high and low molecular weight families reflects an intramolecular deletion.

Amino Acid Sequence↗
PubMed1980

Analysis of immunological responses in psoriatic lesions: (1) immunopathological studies on psoriatic lesions.

In order to understand immunological responses in psoriatic lesions, immunofluorescent findings have been compared in early psoriatic lesions and fully developed plaque lesions. IgG and IgA were detected as the main antibodies in the horny layer by immunohistology. The IgA at the site of leukocyte accumulation in the horny layer seemed to be associated with secretory component (S-component) and joining chian. Regarding complement, the alternate pathway might be related to the immune reaction as the initial response, because deposits of C3, properdin and glycine rich beta-glycoprotein were found more frequently than C1q-deposit in the both lesions. In the dermis S-component was also detected at the dermal papillae adjacent to the dermoepidermal (D-E) junction of the lesions and no deposit of S-component was observed in uninvolved skin of psoriatic patients. This, however, is not a specific pattern in psoriatic lesions since deposits of S-component were found at the dermal papillae and D-E junction in other dermatoses. These findings might suggest that the immunological response was initiated by secretory IgA in horny layer, which was composed of dimeric IgA and S-component at the D-E junction and which passed easily through the epidermal cells.

Adolescent↗
PubMed1997

The intestinal epithelial cell: immunological aspects.

IECs likely play an important role in immunological defense mechanism. Apart from being a passive barrier against luminal bacteria, IECs secrete protective and microbiocidal products such as ITF, complement components and cryptdins into the lumen. Moreover, IECs produce secretory component that is essential for the transport of IgA from the lamina propria into the lumen. IECs also have regulatory functions. They express adhesion molecules important in the homing of T cells and other leukocytes, and likely modulate T cell functions in a paracrine way. Furthermore, IECs secrete cytokines, either constitutively or after bacterial challenge, and they express cytokine receptors. Lastly, IECs may play an important role as non-professional antigen-presenting cells by expressing classical MHC class I and class II and nonclassical MHC class I molecules on the cell surface. This aspect is particularly intriguing in that IECs also express a FcR that may have a function in luminal antigen sampling.

Animals↗
PubMed1995

Induction of IgA and IgG antibodies in vaginal fluid, serum and saliva following immunization of genital and gut associated lymphoid tissue.

Vaginal immunization with the Simian immunodeficiency virus (SIV) was investigated in macaques in order to study genital mucosal antibodies. A combined route of genital- and gut-associated lymphoid tissues was used to stimulate IgA and IgG antibodies in vaginal fluid, serum and saliva. Macaques were immunized with a recombinant, particulate SIV antigen (SIV gag P27), covalently linked to the mucosal adjuvant cholera toxin B subunit (CTB). The animals were immunized sequentially as follows: vaginal (x2) followed by oral (x3), or the reverse sequence of immunization. The results show that both vaginal followed by oral immunization or the reverse sequence induces specific p27 IgA and IgG antibodies in the vaginal fluid and serum. IgA antibodies were also detected in saliva. Vaginal IgA antibodies have the secretory component and J chain suggesting that they are of secretory origin.

Adjuvants, Immunologic↗
PubMed1986

Mixed hyperplastic and neoplastic polyp of the colon. An immunohistological study.

A small colonic polyp which was composed of equal parts of hyperplastic and adenomatous tissue sharing a common basement membrane, displayed a paradoxical distribution of immunohistological markers: In contrast with the neoplastic component, the hyperplastic tissue lacked signs of functional maturity (IgA, secretory component) and displayed markers associated with carcinoma (carcinoembryonic antigen, peanut-agglutinin binding).

Adenoma↗
PubMed2004

Characterization of the interaction of the pneumococcal surface protein SpsA with the human polymeric immunoglobulin receptor (hpIgR).

BACKGROUND & OBJECTIVES: The polymeric immunoglobulin receptor (pIgR) is produced by mucosal epithelial cells and plays a crucial role in mucosal immunity. At the basolateral surface of mucosal cells, the pIgR binds predominantly polymeric immunoglobulins, such as dimeric IgA and polymeric IgA (pIgA) and mediates their transport across the polarized cells. This results in apical release of secretory component (SC), either free or bound covalently to IgA, forming secretory IgA (SIgA). The choline-binding protein (Cbp) SpsA, also called PspC and CbpA, has been shown to interact with the pIgR. A hexapeptide motif in SpsA was identified as the minimal binding motif required for binding specifically to pIgR and SC. The present study was carried out to show that the hexapeptide motif in SpsA is crucial for the interaction of pneumococci and pIgR-expressing cells. METHODS: Streptococcus pneumoniae were cultured to mid-log phase. Calu-3 cells and MDCK epithelial cells, stably transfected with the hpIgR cDNA in pCB6 were used in in vitro infection experiments. Pneumococcal adherence to and invasion of epithelial cells were assayed. RESULTS: By the use of the N-terminal domain of SpsA and SpsA(201), which exhibits a single amino acid substitution in the pIgR-binding motif, in vitro assays indicated the association of the identified hexapeptide motif, located between amino acid 198 and 203 in SpsA, with pneumococcal adherence to and invasion of hpIgR-expressing cells. INTERPRETATION & CONCLUSION: The present findings demonstrated not only the crucial role of the hexapeptide of SpsA, not only for the SpsA-pIgR interaction, but also for adherence and invasion of hpIgR-expressing cells.

Bacterial Adhesion↗
PubMed1983

Histochemical properties of the respiratory tract epithelium in different species.

The comparative composition of secretory components and cell surface moieties is described in this review on epithelial cells of the respiratory tract in mouse, rat, and humans. The discussion concerns mainly the nature of the carbohydrate-rich secretory substances and glycocalyx components present in the various types of epithelial cells in the 3 species. Older methods for characterizing acid groups and vicinal glycols of the complex carbohydrates and more recent methods for identifying specific terminal and internal sugars with labeled lectins are outlined, including techniques for both light and electron microscopic examination. Knowledge derived from the application of these methods is detailed for the surface glycocalyx of secretory cells lining the proximal and distal airways and alveoli, as well as for the glycocalyx of ciliated cells and membranous pneumocytes in each species. Histochemically derived knowledge of the composition of substances in secretory granules of surface epithelial cells is also summarized. The review concerns as well the nature of secretory products in serous and mucous cells of the glands in the lamina propria of trachea and bronchi. The available data delineate major differences between serous cell secretions compared with mucous cell secretions as well as differences between species for each cell type. In addition, ABO blood group dependent differences have been demonstrated in the human glands.

Animals↗
PubMed1988

Secretory IgA against herpes simplex virus in cervical secretions.

A recently developed method to recover proteins from cervical secretions was combined with methods to detect minute concentrations of herpes simplex virus (HSV) type specific antibodies to measure the concentrations of locally produced antibodies in women with genital infections. Forty nine women attending a sexually transmitted disease (STD) clinic were included. Cervical secretions were obtained by suction into a plastic catheter. Soluble proteins were recovered from the secretions by elution with hyperosmolar sodium chloride. A rabbit antibody to human secretory component, which was conjugated to horseradish peroxidase, was used to measure secretory IgA (S-IgA) that was HSV type specific. For comparison, HSV type specific IgG was measured in serum samples from the patients. Of the 49 women, 16 yielded detectable HSV type 2 (HSV 2) S-IgA in secretions. Twelve of them also reacted to the HSV type common antigen, but only five had HSV 2 IgG detectable in their serum. S-IgA against HSV was found in significantly more women with a clinical diagnosis of acute cervicitis than in others. This could be explained by a general increase in local antibody production and immunity triggered by previous contacts with HSV. It is concluded that local mucosal immunity to HSV 2 can be detected in women who do not have a specific humoral antibody response to the virus. For seroepidemiological studies of infection with HSV 2 this local immunity may be considered to be a factor that gives an underestimation of the true incidence of HSV 2 infection.

Acute Disease↗
PubMed1985

The ocular secretory immune system of the rat.

Ocular tissues and tears of adult male rats were examined for the presence of immunoglobulins (Ig) and secretory component (SC). By immunofluorescent analysis, we found the highest density of Ig-containing cells in the exorbital (lacrimal) gland. In contrast, few if any Ig-containing cells were observed in the conjunctiva or Harder's gland. IgA was the most frequent cell-associated isotype identified in the exorbital gland, and the number of IgA-containing cells was much greater than that of IgM- or IgG-containing cells. With respect to IgG, cell counts were fairly evenly distributed among the various subclasses. No IgE-containing cells were detected in ocular tissues. SC was identified exclusively within the acinar cells of the exorbital gland. In tears, IgA was the predominant isotype and occurred almost entirely in the polymeric form. Of the IgG subclasses, IgG 2a was present in the greatest concentration. Only trace amounts of IgG 2b were found, and IgG 1, IgG 2c and IgM could not be detected. The level of free SC in tears was relatively high, compared to the concentration of free SC reported in other mucosal secretions. These results suggest that the exorbital gland is the primary tissue associated with the ocular secretory immune system of the rat. Furthermore, our findings indicate that rat tears contain components that may provide immune defense for the ocular surface.

Animals↗
PubMed1990

Identification and characterization of IgA and Vicia villosa-binding T cell subsets in rheumatoid arthritis.

Autoimmunity may be due to augmentation of immune responses by human CD8 cells which bind the lectin Vicia villosa (VV). We have investigated T cells in rheumatoid arthritis (RA) by double immunofluorescence flow cytometry, in order to assess VV-binding CD8 and CD4 cells from the peripheral blood and synovial fluid. A significant increase in CD8+VV adherent (P less than 0.0001) and CD4+VV adherent cells (P less than 0.001) was found in synovial fluid, as compared with peripheral blood from patients with RA. A significant increase in VV-binding CD8+ or CD4+ cells was, however, not found in the blood of patients with RA, as compared with controls. We suggest that the lack of VV-binding T cells separated from blood, in contrast to those from synovial fluid, may be due to an inhibiting agent expressing N-acetyl D-galactosamine. Indeed, IgA1 is rich in N-acetyl D-galactosamine, it inhibits VV binding to T cells and is significantly bound to CD8 cells (P less than 0.001). The IgA1 was then characterized and in about half the patients J chains and secretory component was found, suggesting that the IgA1 is of the polymeric and secretory variety. IgA bound to the T cells engaged the Fc alpha receptors and a significant decrease in the Fc alpha receptors was found in CD8 cells (P less than 0.0001) and CD4 cells (P less than 0.01). Desorption studies were then carried out on CD8 and CD4 cells which showed that a loss of cell-bound IgA1 was associated with an increase in VV binding. Conversely, adsorption of IgA to T cells was associated with a loss in VV binding. The results suggest that the failure of VV binding to CD8+ and CD4+ cells from peripheral blood of patients with RA can be ascribed to cell-bound IgA1. Cytophilic IgA1 may inhibit the function of CD8+VV binding cells, thereby preventing augmentation of the systemic immune response, consistent with the lack of extra-articular disease in these patients with RA.

Adult↗
PubMed1999

The B-cell system of human mucosae and exocrine glands.

The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80-90% of all immunoglobulin (Ig)-producing cells. The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional justification for the J chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a "spin-off" from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin alpha 4 beta 7 and MAdCAM-1) that explain the "gut-seeking" properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgG1, IgG2) production patterns shown by local immunocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.

Animals↗
PubMed1981

Qualitative changes in saliva composition after short-term administration of imipramine and zimelidine in healthy volunteers.

Ten healthy volunteers participated in a double-blind controlled, randomized, cross-over trial, where the effects of the antidepressant drugs imipramine (75 mg/day) and zimelidine (100 mg/day and 200 mg/day) on saliva secretion rate and saliva composition were tested. The saliva secretion decreased and qualitative changes were found. Imipramine (75 mg/day) and zimelidine (200 mg/day), but not zimelidine (100 mg/day), increased buffer capacity and the components of the salivary glycoproteins (sialic acid, fucose, hexoses). Total proteins, amylase, secretory component and electrolytes (Na+, K+, Ca++, PO43-) did not change significantly.

Adult↗