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PubMed1983

Deposition of polymeric IgA1 in idiopathic mesangial IgA-glomerulonephritis.

IgA deposits in kidney and skin biopsies from patients with idiopathic mesangial IgA-glomerulonephritis were characterized with immunofluorescence microscopy using monoclonal antibodies against the IgA subclasses IgA1 and IgA2. IgA1 was the major constituent in all biopsy specimens. Double immunofluorescence microscopy showed that IgA deposits were constantly associated with J-chain. Secretory component was never found in the deposited material. In vitro fixation of free secretory component, however, was observed in some biopsies. These findings indicate that most if not all of the deposited IgA in patients with idiopathic IgA-glomerulonephritis is polymeric in nature.

Adolescent↗
PubMed2005

NF-kappaB in tracheal lavage fluid from intubated premature infants: association with inflammation, oxygen, and outcome.

OBJECTIVES: To determine if tracheal lavage concentrations of the transcription factor NF-kappaB, which is activated by risk factors associated with bronchopulmonary dysplasia (BPD) and induces expression of cytokines associated with BPD, is related to BPD in premature infants. DESIGN: Serial tracheal lavage samples from intubated premature infants were analysed for cell count and concentrations of interleukin (IL)8 and NF-kappaB, corrected for dilution by secretory component concentrations. SETTING: Level III university hospital neonatal intensive care unit. PATIENTS: Thirty three intubated infants (mean (SD) birth weight 903 (258) g, median gestation 27 weeks (range 24-31)) in the first 14 days of life. MAIN OUTCOME MEASURES: Tracheal effluent NF-kappaB, IL8, and cell counts, corrected for dilution by secretory component measurement. RESULTS: Square root transformed NF-kappaB concentrations were significantly related to signs of inflammation (cell count, p = 0.002; IL8, p = 0.019) and to simultaneous fraction of inspired oxygen in samples from the first 3 days of life (r = 0.512, p<0.003). Of the 32 subjects with samples in the first 3 days of life, the half who either died or had BPD had higher NF-kappaB concentrations than those without BPD (square root concentration 0.097 (0.043) v 0.062 (0.036) microg/microg protein/microg secretory component, p = 0.018). CONCLUSIONS: Tracheobronchial lavage NF-kappaB concentrations are related to lung inflammation, oxygen exposure, and pulmonary outcome in intubated preterm infants. NF-kappaB activation may be an early critical step leading to BPD.

Biomarkers↗
PubMed1986

Chromogranin A, B and C immunoreactivities of mammalian endocrine cells. Distribution, distinction from costored hormones/prohormones and relationship with the argyrophil component of secretory granules.

Antibodies specific for chromogranin A, B or C have been used to detect immunohistochemically these three anionic proteins. Pancreatic A, B and PP cells, gut argentaffin EC, argyrophil ECL and gastrin G cells, thyroid C cells, parathyroid cells, adrenal medullary cells, pituitary TSH, FSH and LH cells as well as some axons of visceral nerves have been found to react with chromogranin A antibodies. Pancreatic A, gut EC and G, adrenal medullary and pituitary cells as well as some gut nerve fibers showed chromogranin B immunoreactivity. Chromogranin C immunoreactivity has been detected in pancreatic A, pyloric D1, intestinal L, thyroid C, adrenal medullary and pituitary cells, as well as in some gut neurons and nerve fibers. No crossreactivity has been found in immunohistochemical tests between chromogranins A, B or C and costored monoamines or peptide hormones/prohormones, from which chromogranins can be separated by selective extraction during fixation. On both morphological and chemical grounds a relationship seems to exist between chromogranin A and Grimelius' argyrophilia. Sialooligosaccharide chains of chromogranin A and, possibly, chromogranins' phosphoserine/phosphothreonine groups, seem to interact with guanidyl, amino, and/or imidazole groups of non-chromogranin components to form silver complexing sites accounting for granules' argyrophilia, which can be removed or blocked without affecting chromogranin immunoreactivities. The abundant anionic groups of the three proteins should contribute substantially to granules' basophilia, the partly "masked" pattern of which supports the existence of a close interaction of such groups with other components of secretory granules, including monoamines and peptide hormones or prohormones. Chromogranins could play a rôle in hormone postranslational biosynthesis and intragranular packaging.

Adrenal Medulla↗
PubMed1996

Immunologic responses to gene transfer into mice via the polymeric immunoglobulin receptor.

The respiratory epithelium is the primary target tissue for gene therapy of cystic fibrosis, and several methods of gene transfer permit the introduction of the gene encoding the normal cystic fibrosis transmembrane conductance regulator into cells of the respiratory tract in animals. DNA complexes based on Fab antibodies to secretory component have been used to mediate the delivery and uptake of expression plasmids into the respiratory tract via the polymeric immunoglobulin receptor both in vitro and in vivo. We evaluated the efficacy of gene transfer after several administrations of the DNA complexes, and examined the immunogenicity and toxicity of repetitive administration of anti-secretory component Fab-based complexes. Mice received single or multiple injections of the DNA complexes containing the plasmid pGL2 every 21 days after the initial treatment, and lysates from the lung and liver were assayed for luciferase expression. Luciferase activity was detected in the lungs of mice that received a single injection of the DNA complexes, whereas transgene expression was significantly lower in the mice that received three injections of the DNA complexes (17338 +/- 5469 integrated light units/mg and 3771 +/- 1778 integrated light units/mg, respectively). Serum samples from animals that underwent single or multiple injections were analyzed for a serologic response against the conjugate-DNA complexes by ELISA. No anticomplex antibodies were detected in the mice after a single injection. An escalating antibody response was noted with increasing number of treatments with the conjugate-DNA complexes. This serologic response was directed exclusively against the rabbit-derived, anti-secretory component (anti-SC) Fab antibody, and not against either the plasmid DNA or poly-L-lysine. Single injection of the conjugate-DNA complexes did not result in the consumption of circulating complement. Using direct immunofluorescence, perivascular deposits of immunoglobulin G were found in the liver of animals that received three treatments; no such deposition was detected in the lungs or kidneys. No increase in inflammatory cell infiltrates was observed in tissues after single and repeated injections of the DNA complexes. Thus, we conclude that repeated injections of the anti-SC Fab-based complexes evoked a humoral immune response against the heterologous Fab portion of the complex that was associated with reduced efficiency of gene transfer.

Animals↗
PubMed1998

Secretory immunoglobulin A in pancreatic juice and pancreatic tissue of patients with chronic pancreatitis.

BACKGROUND: The predominance of secretory IgA (S-IgA) in intestinal secretions compared with blood is well established, but concentrations of this protein in pancreatic juice and its origin, especially in chronic pancreatitis, are unknown. AIMS: To investigate the role of S-IgA in chronic pancreatitis. PATIENTS: Twenty one patients with chronic pancreatitis (group I), three patients with proven malignancies (group II), and 12 patients without pancreatic disease (group III). METHODS: Pure human pancreatic juice was collected endoscopically in four fractions after consecutive stimulation with secretin and cholecystokinin (CCK). Samples were analysed for S-IgA, protein, trypsinogen, and proteolytic activity. RESULTS: The S-IgA level was significant increased in fraction 1 of pancreatic juice of group I (1210 (1411) ng/ml) compared with controls (33 (70) ng/ml). Protein concentrations and trypsinogen content were lower in group I than in the other groups. Proteolytic activity could be observed in 53% of all 133 pancreatic juice samples, but in 87% of fraction 1. In pancreatic tissue of three patients with chronic pancreatitis both IgA and secretory component were detected by immunohistology. Expression of the secretory component by human pancreatic epithelial cells was increased in patients with chronic pancreatitis compared with normal controls. The concentration of S-IgA in pancreatic juice did not correlate with the serum S-IgA level. In contrast, serum levels of S-IgA were decreased in patients with chronic pancreatitis. CONCLUSION: There are high levels of S-IgA in human pancreatic juice following chronic inflammation and a protective role is suggested for this immunoglobulin.

Adult↗
PubMed1986

The kinetics of intestinal calcium absorption in the rat: an analytical and model building study.

The experimental data obtained from in vivo single pass perfusion of duodenal, jejunal, and ileal intestinal segments of 33- and 50-day-old rats have been used to test a series of models for calcium absorption. Each model was checked for the statistical validity and goodness-of-fit with the experimental data. The model adopted for the duodenum and jejunum had two major components, one saturable and the other nonsaturable, and a minor secretory component. This model was not applicable to ileal calcium absorption. Here the secretory component appeared to be much more important, and the absorption parameters varied in such a manner as to suggest that this intestinal segment was capable of short term autoregulation of dietary calcium absorption.

Animals↗
PubMed1977

Immunohistochemical changes in morphologically involved and uninvolved colonic mucosa of patients with idiopathic proctitis.

Alterations in secretory component, IgA, IgG, and IgM were studied by immunofluorescent techniques in mucosal biopsy specimens obtained at colonoscopy from inflamed and grossly uninvolved colonic mucosa from 12 patients with idiopathic proctitis. Parotid-salivary secretory component and IgA and serum immunoglobulins were also investigated. Decreased secretory IgA was observed in the epithelium of all grossly involved rectal mucosa and in 40% of proximal normal mucosa. Salivary secretory IgA was not diminished. These observations suggest that a local immune defect may be pathogenetically related to idiopathic proctitis.

Adult↗
PubMed1990

Immunoglobulin and anti-Escherichia coli antibody in lower respiratory tract secretions from infants weighing less than 1500 g at birth.

Concentrations of immunoglobulins and anti-Escherichia coli antibody were studied longitudinally in tracheobronchial aspirates from 33 premature intubated neonates, median gestational age 27 weeks. Aspirates collected at birth contained IgG, IgA, and IgM in 100%, 93%, and 79% of samples, respectively. The median IgA concentration at birth was 0.7 micrograms/mg total protein and increased to 5.8 micrograms/mg protein by the sixth week. IgG and IgM antibodies to E coli were present in 90% and 30%, respectively, of tracheobronchial aspirates collected at birth. Samples from three of 28 neonates (11%) contained IgA anti-E coli antibody at birth, and the proportion with IgA antibody rose to 50% during the sixth week. Secretory component associated IgA and IgM were detectable in samples tested at birth and at 4 weeks of age, and secretory component associated anti-E coli antibody was present in aspirates from three of nine neonates studied at 4 weeks of age, but had not been detectable at birth.

Antibodies, Bacterial↗
PubMed1998

Opposite sorting and transcytosis of the polymeric immunoglobulin receptor in transfected endothelial and epithelial cells.

We have transfected a polarised endothelial cell line, ECV 304, and an epithelial cell line, MDCK, with a well characterised epithelial protein, the rat polymeric immunoglobulin receptor (pIgR), in order to study the protein sorting and transcytosis in endothelial cells. The expressed protein was normally processed and the steady state distribution between apical and basolateral surfaces was similar in both cell types. MDCK cells, however, showed a marked polarity in the delivery of newly synthesised pIgR to the cell surface, and in the release of secretory component. 88% of newly synthesised pIgR in MDCK cells was first delivered to the basolateral surface and 99% of secretory component was released from the apical surface. In contrast the basolateral targeting signal of pIgR was only partially recognised in endothelial cells, with 63% of the newly synthesised pIgR being first delivered to the basolateral surface. At steady state only 43% of the pIgR was found on the basolateral membrane. The direction of dimeric IgA transcytosis in endothelial cells was from apical to basolateral surfaces, opposite to that in MDCK cells. These data suggest that endothelial cells poorly recognise the targeting signals of proteins from epithelial cells, and that the direction of transcytosis is linked to the biological role of the cells.

Animals↗
PubMed2006

Human milk glycoproteins inhibit the adherence of Salmonella typhimurium to HeLa cells.

The ability of human milk, as well as its protein fractions, to inhibit the adhesion and invasion of Salmonella typhimurium to HeLa cells was investigated. The results revealed that milk secretory immunoglobulin A (sIgA) inhibited neither the adherence nor the bacterial invasion; however, free secretory component and lactoferrin inhibited the bacterial adhesion and interacted with several bacterial proteins. Our data indicated that glycoproteins such as free secretory component and lactoferrin could act as protective compounds against infant enteric diseases, possibly binding to bacterial surface and blocking adhesion, the primordial step of S. typhimurium infection.

Bacterial Adhesion↗
PubMed1983

Monoclonal antibodies recognizing the secreted and membrane domains of the IgA dimer receptor.

The receptor that mediates the specific uptake and intracellular transport of dimeric immunoglobulin A (IgA dimer) in mucosal and glandular epithelia is identical with a transmembrane precursor of secreted secretory component. During transport, the IgA dimer receptor (membrane SC) is cleaved into two domains, a membrane anchorage peptide and secreted secretory component. We have produced monoclonal antibodies with distinct specificity against both domains of the rabbit IgA dimer receptor. Two mouse hybridoma lines were obtained by fusion of SP2/0 myeloma cells with spleen cells from mice immunized with purified receptor from rabbit liver and by screening of culture supernatants in an immunoprecipitation assay with radiolabeled receptor. One antibody, designated anti-SC 303, reacts both with membrane and secreted SC and is therefore directed to a determinant on the secreted domain of the IgA dimer receptor. The other antibody, anti-SC 166, unable to interact with secreted SC, recognizes the membrane domain of the receptor. We discussed the unique precursor relationship between a cell-surface receptor and a secreted protein and its implications in the IgA dimer transport system.

Animals↗
PubMed2005

Structural requirements for the interaction of human IgA with the human polymeric Ig receptor.

Transport of polymeric IgA onto mucosal surfaces to become secretory IgA is mediated by the polymeric Ig receptor (pIgR). To study the interaction of human dimeric IgA (dIgA) (the predominant form of IgA polymer) with the human pIgR (hpIgR), we generated recombinant wild-type dIgA1 and dIgA2m(1) and various mutant dIgA1 and analyzed their interaction with a recombinant human secretory component and membrane-expressed hpIgR. We found that wild-type dIgA1 and dIgA2m(1) bound to recombinant human secretory component with similar affinity and were transcytosed by the hpIgR to the same extent. Mutation of the IgA Calpha2 domain residue Cys311 to Ser reduced binding to hpIgR, possibly through disruption of noncovalent interactions between the Calpha2 domain and domain 5 of the receptor. Within the Calpha3 domain of IgA1, we found that combined mutation of residues Phe411, Val413, and Thr414, which lie close to residues previously implicated in hpIgR binding, abolished interaction with the receptor. Mutation of residue Lys377, located very close to this same region, perturbed receptor interaction. In addition, 4 aa (Pro440-Phe443), which lie on a loop at the domain interface and form part of the binding site for human FcalphaRI, appear to contribute to hpIgR binding. Lastly, use of a monomeric IgA1 mutant lacking the tailpiece revealed that the tailpiece does not occlude hpIgR-binding residues in IgA1 monomers. This directed mutagenesis approach has thus identified motifs lying principally across the upper surface of the Calpha3 domain (i.e., that closest to Calpha2) critical for human pIgR binding and transcytosis.

Animals↗
PubMed1989

Molecular analysis of IgA in multiple sclerosis.

IgA plays an important role in immune-mediated and anti-viral responses, and is the major antibody in external mucosal secretions. We used enzyme-linked immunosorbent assay (ELISA) and immunoblot to examine IgA in tears and parotid saliva of 21 multiple sclerosis (MS) patients and 19 normal controls. No significant difference in absolute levels were noted and both groups showed a wide range in values. However, 16 of 21 MS patients had detectable changes in molecular form of their IgA. Monomeric IgA was found in 52% of MS tears (P less than 0.001) and 45% of MS parotid saliva (P less than 0.05). Among normals, monomeric IgA was noted in only two saliva samples. IgA in secretions consisted of both A1 and A2 subclasses, although 14% of the monomeric MS IgA samples were restricted to a single subclass. Free secretory component was found in the secretions of all subjects with the exception of a single MS patient. However, immunoblot staining of secretory component was decreased in MS patients compared to controls. This study notes changes in IgA in two distinct external secretions in MS patients compared to controls. These changes are consistent with local mucosal inflammation. Impaired mucosal barriers have important implications in MS with regard to susceptibility to infectious agents, environmental antigen processing, and lymphocyte activation.

Adult↗
PubMed1990

IgA subclass antibodies to gliadin in serum and intestinal juice of patients with coeliac disease.

Serum IgA anti-gliadin antibodies (AGA) were positive in 25 (68%) of 37 untreated adults with coeliac disease belonging mostly to IgA1 subclass (88%) and only in a few cases to IgA2 (12%). Antisecretory component IgA AGA were present in serum of seven patients (28%) by immunofluorescence and in nine (36%) by ELISA. The search for IgA AGA in jejunal juice of eight untreated children with coeliac disease was positive in seven cases (88%), with consistent finding of antisecretory component IgA AGA. These antibodies belonged with equal proportion to IgA1 and IgA2 subclasses. This study shows that in intestinal secretions of untreated coeliac disease cases the IgA immune response to gliadin is confined to polymeric anti-secretory component IgA with the same prevalence of IgA1 and IgA2 subclasses, while in serum IgA AGA are largely monomeric, more frequently of IgA1 than of IgA2 subclass, and with a lower proportion of polymeric anti-secretory component IgA (20-36%). The finding of secretory IgA AGA in serum of patients with coeliac disease could result from a spill-over from the intestinal mucosal synthesis into the circulation.

Adolescent↗
PubMed2000

Conjunctiva-associated lymphoid tissue in the human eye.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) represents a part of the immune system located at mucosal surfaces. Its presence in the human eye is the point in question in the current study. Its occurrence, components, topography, and probable functional significance in the human conjunctiva and lacrimal drainage system were investigated. METHODS: Fifty-three complete conjunctival sacs were obtained from cadaveric eyes, prepared as flat wholemounts, stained, optically cleared, observed in total thickness, and sectioned for light microscopic histology, immunohistochemistry, and electron microscopy. Eight lacrimal sacs and adhering canaliculi were prepared accordingly. RESULTS: Lymphoid tissue was mainly observed in the palpebral conjunctiva, more pronounced in the upper than in the lower lid. It occurred in different forms: 1) In all specimens, diffuse lymphoid tissue of lymphocytes and plasma cells, most of which were IgA positive, formed a thin layer in the lamina propria. The overlying epithelium produced secretory component. 2) In approximately three fifths of the conjunctival sacs, organized follicular accumulations were embedded in this layer. They had a lenticular shape, were composed of B lymphocytes, and were apically covered by lymphoepithelium. 3) Both types could be associated with the conjunctival crypts. Lymphoid tissue with similar characteristics, including secondary follicles, was also observed inside the lacrimal drainage system. High endothelial venules were present in all types of lymphoid tissue. CONCLUSIONS: Human conjunctiva and lacrimal drainage system show an associated lymphoid tissue (suggesting the term conjunctiva-associated lymphoid tissue [CALT]) that contains all components necessary for a complete immune response. Expression of immunoglobulins and secretory component indicates that the conjunctiva belongs to the secretory immune system.

Aged↗
PubMed1994

Stimulation of transcytosis of the polymeric immunoglobulin receptor by dimeric IgA.

The polymeric immunoglobulin receptor (pIgR) is transcytosed from the basolateral to the apical surface of polarized epithelial cells. We have previously shown that phosphorylation of Ser-664 in the cytoplasmic domain of the pIgR is a signal for its transcytosis. We now report that binding of a physiological ligand, dimeric IgA, to pIgR stimulates pIgR transcytosis. This stimulation occurs in both the presence or absence of Ser-664 phosphorylation. We have used three methods to measure transcytosis of the pIgR. (i) The pIgR was biosynthetically labeled and its cleavage to secretory component after transcytosis was measured. (ii) The pIgR was labeled with biotin at the basolateral surface. After transcytosis, release of the biotin-labeled secretory component into the apical medium was measured. (iii) Transcytosis of a ligand bound to the pIgR was measured. All three methods indicated that dimeric IgA stimulates transcytosis of the pIgR.

Animals↗
PubMed1991

SDS-Minigel electrophoresis of human tears. Effect of sample treatment on protein patterns.

An automated Minigel electrophoresis system (PhastSystem, Pharmacia, Uppsala, Sweden) was tested for human tear protein analysis. Tear samples were treated under nonreducing or reducing conditions before sodium dodecyl sulphate polyacryl amide gel electrophoresis (SDS-PAGE). Micro-amounts of tears (2 microliters) were sufficient for analysis and separation and visualization of proteins were completed within 2 hr. Tear proteins were identified using purified control proteins and immunoblotting techniques, using antisera against immunoglobulin (Ig) A (alpha) heavy chains, Ig heavy and light chains, secretory components and lactoferrin. In nonreduced tears, lactoferrin (seen as a double band), serum albumin, tear-specific prealbumin (TSPA), and lysozyme were clearly separated. Secretory IgA (sIgA) was seen as a smear on top of the gel. Immunostaining also showed a major Ig light chain containing protein. After reduction, the protein profiles showed marked changes. In reduced tears, immunoglobulin heavy and light chains (molecular weight [MW]: 64 and 28 kD, respectively) were detected on the SDS-PAGE profile after immunostaining, and represented disulfide cleavage fragments, which originated from sIgA. Reduction resulted in the liberation of the secretory component piece (MW: 85 kD), which was found to co-migrate with the tear lactoferrin bands. Both lactoferrin and serum albumin acted as larger proteins on SDS-PAGE after reduction. The authors found that the two methods of sample treatment, before electrophoresis, resulted in marked differences on the electropherograms.

Electrophoresis, Polyacrylamide Gel↗
PubMed2005

Secretory IgA possesses intrinsic modulatory properties stimulating mucosal and systemic immune responses.

Secretory IgA (SIgA) is essential in protecting mucosal surfaces by ensuring immune exclusion. In addition, SIgA binds selectively to M cells in Peyer's patches (PP), resulting in transport across the epithelium and targeting of dendritic cells (DC) in the dome region. The immunological consequences of such an interaction are unknown. In this study, we find that oral delivery of SIgA comprising human secretory component and mouse IgA induces human secretory component-specific Ab and cellular responses in mucosal and peripheral tissues in mice. This takes place in the absence of co-addition of cholera toxin, identifying so far unraveled properties in SIgA. Specific immune responses are accompanied by sustained IL-10 and TGF-beta expression in draining mesenteric lymph nodes and spleen. SIgA also triggers migration of DC to the T cell-rich regions of PP, and regulates expression of CD80 and CD86 on DC in PP, mesenteric lymph nodes, and spleen. These results provide evidence that mucosal SIgA re-entering the body exerts a function of Ag delivery that contributes to effector and/or regulatory pathways characteristic of the intestinal mucosal compartment.

Animals↗