Transport Of Immunoglobulin A Research Articles

BTB and CNC homology 1 deficiency disrupts intestinal IgA secretion through regulation of polymeric immunoglobulin receptor expression.

Immunoglobulin A (IgA)-mediated mucosal immunity is important for the host because it contributes to reducing infection risk and to establishing host-microbe symbiosis. BTB and CNC homology 1 (Bach1) is a transcriptional repressor with physiological and pathophysiological functions that are of particular interest for their relation to gastrointestinal diseases. However, Bach1 effects on IgA-mediated mucosal immunity remain unknown. For this study using Bach1-deficient (Bach1-/-) mice, we investigated the function of Bach1 in IgA-mediated mucosal immunity. Intestinal mucosa, feces, and plasma IgA were examined using immunosorbent assay. After cell suspensions were prepared from Peyer's patches and colonic lamina propria, they were examined using flow cytometry. The expression level of polymeric immunoglobulin receptor (pIgR), which plays an important role in the transepithelial transport of IgA, was evaluated using Western blotting, quantitative real-time PCR, and immunohistochemistry. Although no changes in the proportions of IgA-producing cells were observed, the amounts of IgA in the intestinal mucosa were increased in Bach1-/- mice. Furthermore, plasma IgA was increased in Bach1-/- mice, but fecal IgA was decreased, indicating that Bach1-/- mice have abnormal secretion of IgA into the intestinal lumen. In fact, Bach1 deficiency reduced pIgR expression in colonic mucosa at both the protein and mRNA levels. In the human intestinal epithelial cell line LS174T, suppression of Bach1 reduced pIgR mRNA stability. In contrast, overexpression of Bach1 increased pIgR mRNA stability. These results demonstrate that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen via suppression of pIgR expression.

IL-25 Improves IgA Levels During Parenteral Nutrition Through the JAK-STAT Pathway

Parenteral nutrition (PN) impairs mucosal immunity and increases the risk of infection in part via lower IgA levels at mucosal surfaces. Transport of immunoglobulin A (IgA) across the mucosa to the gut lumen depends on the epithelial transport protein, polymeric immunoglobulin receptor (pIgR), which is reduced during PN. In vitro, studies demonstrate that IL-4 up-regulates pIgR production via Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Because IL-4 stimulates IgA and is reduced during PN, we hypothesized that the suppressed pIgR is a result of decreased JAK-1 and STAT-6 phosphorylation. Because IL-4 is mediated by IL-25, we also hypothesized that PN + IL-25 would restore luminal IgA by increasing phosphorylated JAK-1 and STAT-6, resulting in increased tissue pIgR and luminal IgA. Experiment 1: 2 days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 11) or PN (n = 9). Experiment 2: 2 days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 12), PN (n = 10), or PN + 0.7 μg of exogenous IL-25 (n = 11) per day. After 5 days, distal ileum tissue was collected, homogenized, and protein extracted for JAK-STAT expression levels using a phospho-specific antibody microarray. Tissue was homogenized to measure pIgR expression via Western blot or fixed in 4% paraformaldehyde to measure pIgR expression via immunohistochemistry. Small intestinal wash fluid was collected and IgA was quantified using enzyme-linked immunosorbent assay. Experiment 1: PN significantly reduced phosphorylated JAK-1 and STAT-6 compared with chow. PN also decreased the tissue levels of the Th2 cytokines, IL-4 and IL-13, as well as pIgR, and luminal IgA compared with chow. Experiment 2: Exogenous administration of PN + IL-25 increased the phosphorylated JAK-1 and STAT-6 compared with PN alone. IL-25 completely restored expression of IL-13 to chow levels. IL-4, pIgR, IgA, and phosphorylated JAK-1 were significantly increased with IL-25 treatment compared with PN but failed to reach levels measured in chow. STAT-6 was significantly increased with IL-25 treatment compared with chow and PN. PN significantly decreases the JAK-STAT pathway by reducing levels of phosphorylated STAT-6 and JAK-1. Consistent with our previous work, sIgA, pIgR, and IL-4 decreased with PN, whereas the addition of IL-25 to PN reversed these decreases and demonstrated the role of the JAK-STAT pathway in vivo during PN.

Mucosal Immune Function Comparison Between Amenorrheic and Eumenorrheic Distance Runners

This study examined the effects of amenorrhea on mucosal immune function and susceptibility to upper respiratory tract infection (URTI) in elite female distance runners. Based on their menstrual cycles during the prior year, 21 elite, collegiate, female distance runners were designated as eumenorrheic runners (ERs; n = 8; 19.9 ± 0.8 years) or amenorrheic runners (ARs; n n = 13; 20.0 ± 0.3 years). Resting saliva and blood samples were collected in the morning. The secretory immunoglobulin A (SIgA) concentration was measured using enzyme-linked immunosorbent assay. The SIgA secretion rate was calculated. Serum 17β-estradiol concentrations and serum progesterone concentrations were measured using radioimmunoassay. Subjects reported the appearance of URTI symptoms (sore throat, headache, runny nose, coughing, or fever), if any, during the prior month. The serum estradiol concentration and salivary SIgA secretion rate were significantly lower for ARs than for ERs (p < 0.05). Serum progesterone concentration was not significantly different between groups. Higher frequencies of headache, runny nose, coughing, and fever were observed in ARs than in ERs. Results show that athletic amenorrhea with low estrogen might accelerate downregulation of mucosal immune function in athletes and enhance susceptibility to infection.

Estrogen modulation of pneumonia? An immunoglobulin A effect

Laboratory and clinical studies demonstrated a salutary effect of estradiol (E2) on pneumonia and other infectious complications after trauma, while dihydrotestosterone (DHT) failed to show a similar effect. Secretory immunoglobulin A is the principle antibody in the respiratory and other mucosal secretions. Immunoglobulin A (IgA) production and transport into the mucosal secretion is regulated by Toll-like receptor 4 (TLR-4). In addition, E2 may influence immune regulatory cells via TLR-4. We hypothesized that the protective effect of E2 on the development of pneumonia may be related to modulation of IgA transport into respiratory secretions. Calu-3 respiratory epithelial cell monolayers were established in a two-chamber cell culture system. Calu-3 cells were then treated with either E2 or DHT for 3 days for maximal cell stimulation. Dimeric IgA was added to the basal chamber of Calu-3 cells, and IgA transcellular transport was indexed by recovery of secretory immunoglobulin A in the apical chamber media. In separate experiments, Klebsiella pneumonia (10(5) CFU/mL) was added to the apical chamber of treated Calu-3 cell monolayers, and bacterial passage across Calu-3 cells was determined by bacterial recovery from the basal chamber. Calu-3 cells not treated with E2 or DHT served as control. Calu-3 cells pretreated with E2 significantly increased IgA transport, and this effect was augmented in a dose-dependent fashion. Only cells pretreated with E2 significantly decreased bacterial passage, and this effect was exhibited in a dose- and time-dependent fashion. E2 led to a significant increase in TLR-4 expression. The protective effect of E2 against pneumonia may be related to augmented transport of IgA into the respiratory mucosal secretions.

Small intestine mucosal immune system response to injury and the impact of parenteral nutrition

Both humans and mice increase airway immunoglobulin A (IgA) after injury. This protective response is associated with TNF-α, IL-1β, and IL-6 airway increases and in mice is dependent upon these cytokines as well as enteral feeding. Parenteral nutrition (PN) with decreased enteral stimulation (DES) alters gut barrier function, decreases intestinal IgA, and decreases the principal IgA transport protein pIgR. We investigated the small intestine (SI) IgA response to injury and the role of TNF-α, IL-1β, IL-6, and PN/DES. Expt 1: Murine kinetics of SI washing fluid (SIWF) IgA; SI, SIWF and serum TNF-α, IL-1β, and IL-6, was determined by ELISA from 0 to 8 hours after a limited surgical stress injury (laparotomy and neck incisions). Expt 2: Mice received chow or PN/DES before injury and SIWF IgA and SI pIgR levels were determined at 0 and 8 hours. Expt 3: Mice received PBS, TNF-α antibody, or IL-1β antibody 30 minutes before injury to measure effects on the SIWF IgA response. Expt 4: Mice received injury or exogenous TNF-α, IL-1β, and IL-6 to measure effects on the SIWF IgA response. Expt 1: SIWF IgA levels increased significantly by 2 hours after injury without associated increases in TNF-α or IL-1β whereas IL-6 was only increased at 1 hour after injury. Expt 2: PN/DES significantly reduced baseline SIWF IgA and SI pIgR and eliminated their increase after injury seen in Chow mice. Expt 3: TNF-α and IL-1β blockade did not affect the SIWF IgA increase after injury. Expt 4: Exogenous TNF-α, IL-1β, and IL-6 increased SIWF IgA similarly to injury. The SI mucosal immune responds to injury or exogenous TNF-α, IL-1β, and IL-6 with an increase in lumen IgA, although it does not rely on local SI increases in TNF-α or IL-1β as it does in the lung. Similar to the lung, the IgA response is eliminated with PN/DES.

Parenteral nutrition maintains pulmonary IgA antibody transport capacity, but not active transport, following injury

Background Parenteral nutrition (PN) increases post-trauma pneumonia versus enteral feeding. PN impairs murine immunoglobulin A (IgA) airway defenses and abrogates a normal IgA increase following injury. This work investigates the effect of type/route of nutrition on lung IgA and its transport protein, polymeric immunoglobulin receptor (pIgR), after injury. Methods Catheterized mice were randomized to Chow or PN for 5 days and sacrificed without injury (Chow: n = 12; PN n = 11), or 8 hours after laparotomy + neck incisions (Chow-injury: n = 11, PN-injury: n = 13). Bronchoalveolar lavage (BAL) and lung IgA levels were analyzed by enzyme-linked immunosorbent assay (ELISA) and lung pIgR by Western blot. Results BAL IgA levels increased in Chow-injury versus PN-injury ( P <.01) with no differences in pIgR. PN-injury tissue IgA levels decreased versus Chow ( P <.01), Chow-injury ( P <.01), and PN ( P <.05). Conclusions PN impairs the airway IgA response to injury but not due to impaired IgA transport capacity/pIgR level.

Intestinal Polymeric Immunoglobulin Receptor Is Affected by Type and Route of Nutrition

Secretory immunoglobulin A (SIgA) prevents adherence of pathogens at mucosal surfaces to prevent invasive infection. Polymeric immunoglobulin receptor (pIgR) is located on the basolateral surface of epithelial cells and binds dimeric immunoglobulin A (IgA) produced by plasma cells in the lamina propria. This IgA-pIgR complex is transported apically, where IgA is exocytosed as SIgA to the mucosal surface. Our prior work shows that mice fed intragastric (IG, an elemental diet model) and IV parenteral nutrition (PN) solution have reduced intestinal T and B cells, SIgA, and interleukin-4 (IL-4) compared with mice fed chow or a complex enteral diet (CED). Prior work also demonstrates a reduction in IgA transport to mucosal surfaces in IV PN-fed mice. Because IL-4 up-regulates pIgR production, this work studies the effects of these diets on intestinal pIgR. Male Institute of Cancer Research (ICR) mice were randomized to chow (n = 11) with IV catheter, CED (n = 10) or IG PN (n = 11) via gastrostomy and IV PN (n = 12) for 5 days. CED and PN were isocaloric and isonitrogenous. Small intestine was harvested for pIgR and IL-4 assays after mucosal washing for IgA. IgA and IL-4 levels were analyzed by enzyme-linked immunosorbent assay and pIgR by Western blot. Small intestinal pIgR expression, IgA levels, and IL-4 levels decreased significantly in IV PN and IG PN groups. Lack of enteral stimulation affects multiple mechanisms responsible for decreased intestinal SIgA levels, including reduced T and B cells in the lamina propria, reduced Th-2 IgA-stimulating cytokines, and impaired expression of the IgA transport protein, pIgR.

Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies.

Citrobacter rodentium, a murine model pathogen for human enteropathogenic Escherichia coli, predominantly colonizes the lumen and mucosal surface of the colon and cecum and causes crypt hyperplasia and mucosal inflammation. Mice infected with C. rodentium develop a secretory immunoglobulin A (IgA) response, but the role of B cells or secretory antibodies in host defense is unknown. To address this question, we conducted oral C. rodentium infections in mice lacking B cells, IgA, secreted IgM, polymeric Ig receptor (pIgR), or J chain. Normal mice showed peak bacterial numbers in colon and feces at 1 week and bacterial eradication after 3 to 4 weeks. B-cell-deficient mice were equally susceptible initially but could not control infection subsequently. Tissue responses showed marked differences, as infection of normal mice was accompanied by transient crypt hyperplasia and mucosal inflammation in the colon and cecum at 2 but not 6 weeks, whereas B-cell-deficient mice had few mucosal changes at 2 weeks but severe epithelial hyperplasia with ulcerations and mucosal inflammation at 6 weeks. The functions of B cells were not mediated by secretory antibodies, since mice lacking IgA or secreted IgM or proteins required for their transport into the lumen, pIgR or J chain, cleared C. rodentium normally. Nonetheless, systemic administration of immune sera reduced bacterial numbers significantly in normal and pIgR-deficient mice, and depletion of IgG abrogated this effect. These results indicate that host defense against C. rodentium depends on B cells and IgG antibodies but does not require production or transepithelial transport of IgA or secreted IgM.

Ethanol impairs intestinal barrier defense by modulation of immunoglobulin A transport

Background. Increased epithelial permeability may contribute to septic complications after alcohol intoxication. Prior ethanol (EtOH) exposure leads to structural and functional effects on cytoskeletal components important in maintaining barrier integrity. The cytoskeleton is also important in the transcellular transport of proteins including the polymeric immunoglobulin receptor (pIgR) mediated transport of immunoglobulin A (IgA) to the luminal surface of mucosal tissues. We (1) investigated the effects of acute EtOH exposure on cell monolayer barrier integrity and IgA transport and (2) assessed the importance of microtubule function on these functions in vitro. Methods. Confluent Madin-Darby canine kidney (MDCK) epithelial cells transfected with pIgR cDNA were exposed to 1% or 5% EtOH, and transcytosis of dimeric IgA was measured. Paclitaxel was used to pretreat a subset of MDCK cells. Results. EtOH exposure resulted in a concentration and time dependent decrease in IgA transcytosis. This was associated with physical derangements in the integrity of the cell monolayer. Pretreatment with paclitaxel completely abrogated these effects. Conclusions. EtOH causes both physical and immune derangement of epithelial cell barrier function. Decreased secretory IgA at mucosal surfaces may initiate septic complications after EtOH intoxication. (Surgery 2002;132:573-81.)

Actin Mediates Secretory Immunoglobulin a Transport: Effect of Ethanol

Secretory immunoglobulin A (IgA) is the principle antibody protecting against pathogens at mucosal sites. Ethanol (EtOH) exposure is related to adverse effects on the enterocyte cytoskeleton. The aim of this study was to assess the role of normal cytoskeletal function on IgA transcytosis and its modulation by EtOH by studying Madin-Darby canine kidney (MDCK) cells transfected with the polyimmunoglobulin receptor. MDCK cells were grown as confluent monolayers and treated with 5 per cent EtOH, cytochalasin D (Cyto-D, a cytoskeletal destabilizer), or pretreatment with prostaglandin E2 (a cytoskeletal stabilizer) followed by EtOH. Media alone served as control. IgA was then added to the basolateral side of the chambers, and apical samples were taken for enzyme-linked immunosorbent assay analysis at 0, 3, and 12 hours. Dimeric IgA transcytosis increased in all groups and was significantly depressed by 5 per cent EtOH and Cyto-D. Morphological slides revealed aggregation of actin after Cyto-D treatment. Prostaglandin E2 prevented the decrease in IgA transcytosis seen otherwise with 5 per cent EtOH treatment. We conclude that IgA transcytosis is dependent on actin microfilaments of the cytoskeleton. Decreased IgA transport may lead to mucosal immunodeficiency and infectious complications after EtOH exposure.

Impaired secretory immunity in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a congenital disorder characterized by blistering of the skin and oral mucosa. This study investigated the hypothesis that children with dystrophic epidermolysis bullosa have impaired oral secretory immunity. Immunoglobulin A (IgA), secretory IgA and IgG concentrations, and IgA and secretory IgA antibody levels to Candida albicans, Lactobacillus casei and Streptococcus mutans were measured in whole saliva from 22 children with dystrophic epidermolysis bullosa and 22 matched controls. Salivary total IgA and total IgG concentrations were significantly raised in dystrophic epidermolysis bullosa due to serum leakage from oral blistering, but the converse was seen with secretory IgA. This suggestion of a mucosal immune defect was supported by decreased secretory IgA antibody responses to all three microorganisms tested. This apparent defect in secretory immunity in dystrophic epidermolysis bullosa may be due to mucosal involvement and damage resulting in impaired antigen sampling in mucosal associated lymphoid tissue or to impaired transport of secretory IgA across the salivary gland mucosa.

Vitamin A Is Required for Regulation of Polymeric Immunoglobulin Receptor (pIgR) Expression by Interleukin-4 and Interferon-γ in a Human Intestinal Epithelial Cell Line

The secretory immunoglobulin A (IgA) antibody response to infections of mucosal surfaces requires transport of IgA from the basal to apical surface of mucosal epithelial cells by a specific transport protein, the polymeric immunoglobulin receptor (pIgR). We have tested the hypothesis that the vitamin A metabolite all-trans retinoic acid (RA) is required for the regulation of pIgR expression by the cytokines interleukin-4 (IL-4) and interferon-γ (IFN-γ) in HT-29 cells, a well-differentiated human epithelial cell line derived from a colonic carcinoma. pIgR expression is upregulated by IFN-γ and IL-4 when HT-29 cells are grown in normal media, but this upregulation was significantly lower when cells were grown in vitamin A–depleted media. Treatment with RA at concentrations from 10−9 to 10−5 mol/L restored normal levels of pIgR expression. The percentages of cells expressing cell-surface pIgR after 24, 48 and 72 h of treatment with RA, IL-4 and IFN-γ were 66 ± 10, 90 ± 5 and 92 ± 1, respectively, significantly higher than the percentages seen without RA treatment, which were 32 ± 2.3, 72 ± 1.2 and 30 ± 7, respectively. In addition, the intensity of fluorescence of pIgR-positive cells was significantly higher in the RA-treated cultures than in the cultures without RA treatment. Similarly, pIgR mRNA levels (adjusted for β-actin mRNA levels) in RA-supplemented cultures were 404, 105 and 949% higher at 24, 48 and 72 h, respectively, than were pIgR mRNA levels in identical cultures grown in the absence of RA. These data indicate that RA strongly interacts with IL-4 and IFN-γ to regulate pIgR expression in HT-29 cells, suggesting that vitamin A may be required for proper in vivo regulation of IgA transport in response to mucosal infections.

Review article: Epithelial disposition of antigen.

Exogenous antigens can impinge upon the luminal surface of mucous membranes and to a limited degree, can even penetrate into the lamina propria. As a result of infection, microbial antigens can be present in mucosal epithelium or lamina propria. At all three levels (lumen, epithelium, lamina propria), locally produced antibodies, principally immunoglobulin A (IgA), can combine with antigens. As a result, antigens can be prevented from attaching to the epithelium, viruses can be neutralized inside epithelial cells and immune complexes in the lamina propria can be excreted into the lumen. As the Fc portion of IgA is specialized to facilitate epithelial transport of IgA rather than to activate inflammatory mediator systems (as is the case with other classes of immunoglobulin), the predominance of IgA among mucosal antibodies serves to limit the degree of local inflammation following antigen-antibody reactions.

Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus.

Diseases of the nasopharyngeal epithelium due to Epstein-Barr virus (EBV) infection typically occur in chronic virus carriers with preexisting virus-specific antibodies. In vitro studies have shown that EBV-specific immunoglobulin A (IgA) promotes infection of human epithelial cells, otherwise refractory to EBV, via the polymeric immunoglobulin receptor (pIgR). To determine if EBV similarly exploits IgA transport mechanisms in vivo, we examined the fate of IgA-EBV complexes in the blood of mice, where pIgR-mediated transcytosis of IgA immune complexes through hepatocytes eliminates exogenous antigens from the circulation. By PCR analysis we showed hepatobiliary transport of IgA-EBV in viremic mice, but without detectable hepatocellular infection by immunostaining. Because efficient transport of EBV immune complexes might avert an infectious outcome, we modulated the transcytotic pathway in polarized Madin-Darby canine kidney (MDCK) cells transfected with pIgR to determine the effect on viral antigen expression. Like hepatocytes in vivo, MDCK cells in polarized monolayers translocated IgA-EBV from the basal cell face into apical medium without evidence for infection. However, when exposed to IgA-EBV as unpolarized single-cell suspensions, MDCK cells expressed EBV immediate-early and early antigens. These results suggest that pIgR-mediated transcytosis of pIgA-EBV through epithelium facilitates endogenous spread of EBV in long-term virus carriers, with infection being confined to cells with altered polarity from prior cytopathology.

Cytokine Regulation of the Mucosal Immune System: In Vivo Stimulation by Interferon-γof Secretory Component and Immunoglobulin A in Uterine Secretions and Proliferation of Lymphocytes from Spleen*

The secretory immune system in the female reproductive tract is known to be regulated by sex hormones and antigen. The purpose of the present study was to examine the control by interferon-gamma (IFN gamma) of the secretory component (SC), the polymeric immunoglobulin A (IgA) receptor, and IgA in uterine secretions and to determine whether IFN gamma influences the proliferation of spleen cells in response to mitogens. When measured by RIA, SC levels in uterine secretions were elevated when increasing doses of IFN gamma (1000-5000 U/uterus) were placed in the uterine lumen of ovariectomized rats. In contrast, IFN alpha-beta (5000 U/uterus) placed in the uterine lumen had no effect on uterine SC levels. To determine whether IgA movement increases in response to IFN gamma, animals were treated with estradiol to increase uterine tissue IgA levels without stimulating the accumulation of IgA or SC in uterine secretions. Under these conditions, intrauterine IFN gamma increased SC and IgA levels in uterine secretions, suggesting that in vivo IFN gamma stimulation of uterine SC increases the transport of IgA from tissue to lumen. Analysis of uterine tissues indicated that intrauterine IFN gamma had no apparent effect on epithelial cell morphology. In contrast, intraepithelial lymphocytes and polymorphonuclear leucocytes, which were sparse in control tissues, increased markedly with IFN gamma treatment. This increase was antagonized when estradiol was administered along with IFN gamma. In other studies, IFN gamma placed in the uterine lumen significantly increased spleen cell proliferation in response to Concanavalin-A, phytohaemagglutinin, and lipopolysaccharide mitogens relative to those in spleen cells from control animals. These studies demonstrate that in vivo treatment with IFN gamma stimulates the mucosal immune system in the female reproductive tract by increasing SC and IgA levels in the uterine lumen and promoting the infiltration of intraepithelial lymphocytes and polymorphonuclear leucocytes into uterine tissue. Further, it suggests that antigen, in stimulating a local uterine response, may act through cytokines, particularly IFN gamma, to regulate the transport of IgA into uterine secretions as well as modulate lymphocyte proliferation at sites distal to the uterus.

Transforming growth factor-β enhances secretory component and major histocompatibility complex class I antigen expression on rat IEC-6 intestinal epithelial cells

Transforming growth factor-β (TGF-β) has been implicated as having a role in inflammatory responses by inducing cellular infiltration and the release of inflammatory cytokines. In this study, the IEC-6 rat intestinal epithelial cell line was used as a model to assess the effect of TGF-β 1 on the expression of various plasma membrane determinants. TGF-β 1 induced a dose-dependent increase in the percentage of cells expressing surface secretory component (SC) and class I major histocompatibility (MHC) antigens. However, the expression of class II MHC was unaffected. In contrast, epidermal growth factor had no effect on any of the surface proteins studied. The TGF-β 1-enhanced expression of SC was accompanied by an enhanced binding of polymeric, but not monomeric, immunoglobulin A (IgA). Preincubation of the TGF-β 1-treated cells with an anti-human β-galactosyltransferase (β-GT) antiserum did not block the binding of the anti-SC antibody, indicating that the TGF-β-induced increase in SC staining was due to SC expression and not the polymeric immunoglobulin-binding enzyme, β-GT. These results indicate that TGF-β 1 may be important in immune functions involving intestinal epithelial cells by enhancing the expression of surface class I MHC antigens and SC, a protein responsible for the transport of polymeric IgA into the intestinal lumen.

Effects of Percutaneous Transhepatic Biliary Drainage on Blood-Bile Permeability and Selective IgA Transport in Patients with Biliary Obstructions

Biliary obstruction induces a increase in the permeability between blood and bile, and a decrease in the rate of immunoglobulin A (IgA) transport into bile. We investigated the effects of percutaneous transhepatic biliary drainage (PTBD) on these derangements. PTBD reduced the extent of elevation of the bile-to-serum ratio of Immunoglobulin G (IgG; IgG-BS ratio) in patients with obstructive jaundice. Because IgG is known to be passively transported from serum to bile, the results indicate that PTBD restores the blood-bile barrier function. The IgA-BS ratio/IgG-BS ratio index (IgA/IgG index) and the IgM/IgG index, which indicated the function of selective transport of IgA and IgM into bile, initially decreased and then returned to the normal range 17 days after PTBD in patients who experienced a rapid resolution of hyperbilirubinemia. However these indices remained low in patients who did not experience this resolution. The serum secretory IgA levels in patients who did not experienced rapid resolution of hyperbilirubinemia markedly increased before PTBD. The serum secretory IgA levels in the patients who did and those who did not experience rapid resolution of hyperbilirubinemia, after initially increasing, decreased after PTBD. However the level returned to the control range only in patients who experienced a rapid resolution. These results indicate that the secretory IgA level is a sensitive indicator of hepatobiliary function, and measurement of the level of secretory IgA could predict the effect of PTBD.

Massive plasma cell infiltration of the digestive tract

Abstract A 29-yr-old Tunisian man had a clinical immunoproliferative small intestinal disease, different from α-chain disease. Serum contained 52.5 mg/ml of polymeric immunoglobulin A (IgA). Immunohistochemistry revealed a massive diffuse polyclonal IgA (99%)-plasma cell infiltration in the small bowel mucosa, with a smaller increase of IgA-producing cells in gastric and colonic mucosae. Secretory IgA levels were normal in jejunal and bronchoalveolar secretions. However, both fluids contained polymeric IgA devoid of secretory component, and free secretory component was absent. This suggests that secretory component was the limiting factor in transport of IgA in the secretions. A relative deficiency in secretory component, as compared with the huge supply of polymeric IgA, may have limited the secretory component-mediated active transport of IgA into secretions. This resulted in the appearance of high levels of polymeric IgA, unlinked to secretory component, both in serum and in the jejunal and bronchoalveolar fluids.

Massive plasma cell infiltration of the digestive tract: Secretory component as the rate-limiting factor of immunoglobulin secretion in external fluids

A 29-yr-old Tunisian man had a clinical immunoproliferative small intestinal disease, different from α-chain disease. Serum contained 52.5 mg/ml of polymeric immunoglobulin A (IgA). Immunohistochemistry revealed a massive diffuse polyclonal IgA (99%)-plasma cell infiltration in the small bowel mucosa, with a smaller increase of IgA-producing cells in gastric and colonic mucosae. Secretory IgA levels were normal in jejunal and bronchoalveolar secretions. However, both fluids contained polymeric IgA devoid of secretory component, and free secretory component was absent. This suggests that secretory component was the limiting factor in transport of IgA in the secretions. A relative deficiency in secretory component, as compared with the huge supply of polymeric IgA, may have limited the secretory component-mediated active transport of IgA into secretions. This resulted in the appearance of high levels of polymeric IgA, unlinked to secretory component, both in serum and in the jejunal and bronchoalveolar fluids.

Alterations in protein transport events in rat liver after estrogen treatment.

The effects of 17 alpha-ethynylestradiol (EE) treatment on the hepatic processing of rat polymeric immunoglobulin A (IgA) and human asialoorosomucoid (ASOr) were studied. After 5 days of treatment with EE (5 mg/kg) or solvent alone, male rats were anesthetized and injected with tracer doses of the test proteins. Bile flow rates had been reduced by greater than 60% in the EE-treated animals. A previously reported radiolabeling strategy was used to monitor both the transport of intact protein to bile and the degradation of protein in lysosomes. Transport of intact IgA to bile was reduced by 43%, with transport peaking 27 min later in EE-treated animals compared with controls. There was a corresponding impairment of uptake of labeled IgA from blood. EE induced no kinetic change in the uptake or processing of ASOr. However, there was an increase in the proportion of ASOr reaching bile intact from 3% to 15-23% of the injected dose. The data indicate that EE disables the transport pathway for IgA and causes a partial change in the routing of ASOr after endocytosis in favor of direct transport to the bile canaliculus. These findings may have implications for the importance of membrane composition in protein transport events.