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The Journal of Immunology, 2001, 166: 3688-3692.
Copyright © 2001 by The American Association of Immunologists

A Mucosal IgA-Mediated Excretory Immune System In Vivo1

Janet K. Robinson*, Thomas G. Blanchard{dagger}, Alan D. Levine{ddagger}, Steven N. Emancipator* and Michael E. Lamm2,*

Departments of * Pathology, {dagger} Pediatrics, and {ddagger} Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The capacity of mucosal IgA Abs to serve as an excretory immune system in vivo was investigated. Mice expressing a transgenic TCR were immunized intragastrically with the cognate Ag to elicit a vigorous mucosal IgA Ab response. Soon after i.v. challenge, Ag was detected within the epithelial cells of the small intestinal crypts and to a lesser degree within the epithelial cells higher up the villi, paralleling the gradient in expression of the polymeric Ig receptor and the transport of its ligand, oligomeric IgA. Uptake of Ag into the epithelial cells occurred only from the basolateral aspect and only when Ag complexed to IgA Ab could be present in the lamina propria. The results support the concept that local IgA Abs can excrete Ags from the body by transporting them directly through mucosal epithelial cells, using the same mechanism that transports free IgA into the mucosal secretions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
How does the immune system deal with Ags that penetrate mucosal surfaces on an ongoing basis or that are released directly into the lamina propria from microbial pathogens during mucosal infections? Ags accessing the lamina propria would immediately encounter Abs, principally IgA that had been secreted by local plasma cells, which on a biosynthetic basis account for the majority of the body’s total pool of Igs (1, 2). One possibility for the IgA immune complexes forming in the lamina propria would be to reach the circulation, where they could interact with the mononuclear phagocyte system. An additional mechanism for clearing circulating IgA immune complexes, operative in rodents, is transport by the liver into the bile (3, 4, 5) because rodent hepatocytes express on their sinusoidal surface the polymeric Ig receptor (pIgR),3 the function of which is to transcytose oligomeric IgA across epithelial cells. However, this mechanism is not available in humans, whose hepatocytes do not express pIgR. Moreover, even in rodents, removal of immune complexes by the liver applies only to complexes that have reached the blood. Another, more direct means of removing mucosal Ags at the source, before they reach the circulation, and one that would function in humans as well as rodents would be to excrete them through the overlying epithelium into the lumen by the same route and mechanism used to transport free IgA into the mucosal secretions. In this process, oligomeric IgA binds via its Fc portion to pIgR, constitutively expressed on the basolateral surface of mucosal epithelial cells. Bound IgA is then endocytosed, transcytosed from basolateral to apical, and released into the lumen as secretory IgA (6). If this route also operates for IgA that is complexed to Ag, it could serve as a means for quickly removing Ags from mucous membranes, thereby minimizing the burden of immune complexes in the circulation. Another advantage of such a local excretory route is that IgA, the major mucosal Ig, is relatively noninflammatory (7), whereas Ag or immune complexes reaching the blood would more likely bind Abs of the phlogistic IgG class.

Earlier we demonstrated that soluble immune complexes containing oligomeric IgA Abs were readily transported intact into the apical medium across polarized epithelial cell monolayers that expressed the pIgR on their basolateral surface (8, 9). In other words, the Fc{alpha}-dependent mechanism used to transport IgA across epithelial cells functioned the same for IgA that was complexed to Ag by its Fab binding sites as it did for free IgA. Based on these experiments in vitro we suggested that an IgA-mediated excretory immune system could function in vivo. The present work was undertaken to explore whether such an excretory immune system indeed functions in vivo. The experimental design was to immunize mice intragastrically to stimulate an intestinal IgA Ab response, after which Ag was injected i.v. to generate soluble IgA-containing immune complexes in the intestinal lamina propria. Subsequent detection of Ag in small intestinal crypt cells was taken as evidence of mucosal excretion by specific IgA Ab.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

Transgenic BALB/c mice of both sexes expressing the {alpha}{beta} TCR from a T cell hybridoma, DO11.10, that recognizes a chicken OVA peptide (323–339) restricted by MHC class II I-Ad (10) were obtained from Dr. Kenneth Murphy (Washington University). They were maintained and bred in our animal facility with food and water ad libitum. TCR transgenic progeny were identified by PCR assays on DNA isolated from tail clips (11). Animal studies were approved by the Case Western Reserve University Institutional Animal Care and Use Committee and were performed in compliance with institutional guidelines.

Immunization

Chicken OVA (Sigma, St. Louis, MO) was coupled with biotin (Pierce Chemical, Rockford, IL) according to the supplier’s instructions at a weight ratio of 15% biotin. An average of seven biotins were coupled to each molecule of protein. Mice were immunized five to six times at weekly intervals with 10 mg biotinylated OVA or the control protein BSA (Sigma), by stomach tube in the presence of 10 µg of the mucosal adjuvant cholera toxin (12) in 0.5 ml of 0.2 M NaHCO3. IgA Ab titers in serum, measured by ELISA, reached a maximum at this time. In selected mice, it was confirmed that specific IgA Ab was also secreted into the intestinal lumen. For this, a segment of small intestine was rinsed with 5 ml of a mixture of protease inhibitors (Complete Protease Inhibitor Cocktail; Roche, Gipf-Oberfrick, Switzerland) in PBS (pH 7.2). Intestinal secretions collected with polywicks (Polyfiltronics Group, Rockland, MA) (13) were assayed for IgA Ab content by ELISA.

Measurement of Ab response

IgA Ab responses to biotinylated OVA were measured by ELISA. Nunc Immuno Plates (Naperville, IL) were coated by overnight incubation at 4°C with 10 µg/ml Ag in carbonate buffer (pH 9.5). Nonspecific binding sites were blocked with PBS containing either 1% BSA or 40% soy milk. Serial half-log10 dilutions of antisera (50 µl), made in either 1% BSA or 40% soy milk, were added and the plates were incubated at ambient temperature for 90 min. Plates were then washed with PBS and incubated with affinity purified, alkaline phosphatase conjugated goat anti-mouse IgA-specific Ab (Southern Biotechnology Associates, Birmingham, AL) at ambient temperature for 90 min. The plates were washed and developed with disodium p-nitrophenyl phosphate (Sigma) in glycine buffer (pH 9.6). After 60 min, ODs were read at 405 nm with a Molecular Devices Vmax plate reader (Menlo Park, CA). For each serum sample, the least-squares regression of the OD as a function of the log of the serum dilution was used to calculate the titer. The titer was defined as the log of the dilution that generated an OD equal to two SDs above the mean background OD developed with nonimmune syngeneic control serum.

Ag challenge and tissue preparation

Five to seven days after the final intragastric immunization, the mice were injected in the tail vein with 50 mg biotinylated OVA in PBS and sacrificed 30 min later. The small intestine was removed and the lumen was rinsed with 20 ml of cold PBS containing 0.9 mM Ca2+ and 0.49 mM Mg2+. The intestine was filled with OCT Compound (VWR, Bridgeport, NJ), coiled, snap frozen in 2-methyl butane, and stored at -70° before sectioning.

Microscopy

Cryostat sections (7–8 µm) of coiled small intestine were air-dried, fixed for 1 min in acetone, air-dried, and stored at -20°. For detection of biotinylated OVA Ag, sections were hydrated in PBS, exposed to avidin-biotinylated HRP complex (Vectastain Elite ABC; Vector Laboratories, Burlingame, CA) for 30 min, rinsed in PBS, exposed to diaminobenzidine, and rinsed in PBS. Sections were counterstained with hematoxylin, cleared, and sealed with a coverslip. For detection of mouse IgA, hydrated frozen sections were exposed to peroxidase-conjugated goat Ab (Southern Biotechnology Associates), rinsed, developed with diaminobenzidine, counterstained, cleared, and sealed with a coverslip. Slides were numbered randomly by one investigator and examined and scored in blinded manner by another on a scale of 0 (no staining) to 3 (prominent, dense small intestinal crypt cell staining easily observed at low power) by direct visual observation with a Leica DMLB microscope (Deerfield, IL). The semiquantitative peroxidase staining intensity scores for the amount of biotinylated OVA in the small intestinal crypt epithelium of the individual mice were subjected to one-way ANOVA, stratified by mouse group. Post hoc comparisons among the groups used Scheffe’s test and Fisher’s protected t test. In addition, the distribution of individual mice scored "positive" (intensity score >0) or "negative" (intensity score = 0) in each group was assessed by {chi}2 contingency analysis in a two (level) by three (group) design, with Fisher’s correction for small numbers applied. Photographs were made with a Diagnostic Instruments digital camera.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
D011.10 transgenic mice expressing a TCR for OVA were immunized intragastrically with biotinylated OVA to stimulate a mucosal IgA Ab response. This response, as monitored by serum IgA Ab, reached an ELISA titer of 1600. In contrast, control transgenic mice immunized instead with BSA did not manifest Ab to biotinylated OVA (t = 5.6; p < 0.001 vs mice immunized with biotinylated OVA). The transgenic mice were used because they make a more vigorous IgA Ab response than wild-type BALB/c mice after intragastric immunization with biotinylated OVA and, thus, are capable of excreting more Ag through intestinal epithelial cells. Immunized mice were then injected i.v. with a bolus of Ag to rapidly generate IgA immune complexes in the lamina propria of the intestinal mucosa. The complexes would then be available for endocytosis by the pIgR-expressing epithelial cells of the intestinal lining. In preliminary experiments, 30 min after challenge was found to be a suitable time to observe the effect. This short interval also enabled the experiments to focus on the immediate interaction of the immune complexes with preexisting epithelial cell surface pIgR, independent of cellular immune events that might evolve over time. Fig. 1Go illustrates the excretory route schematically.



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  		FIGURE 1. Schematic drawing of small intestinal mucosa. Shown is the relationship of the epithelial cells lining the crypts to the lamina propria (which contains numerous IgA-secreting plasma cells, not illustrated) and the crypt lumens, which are continuous at the crypt openings with the main intestinal lumen. IgA Abs that have been transcytosed across the crypt epithelial cells enter the crypt lumens, from which they reach the main intestinal lumen. In the current experiments, immune complexes containing biotinylated OVA and specific IgA Abs were present in the lamina propria and in the epithelial cells of the crypts, where maximal pIgR-mediated transcytosis occurs (see Fig. 3Go). Arrows show the direction of transport of IgA immune complexes from the lamina propria across the epithelium into the crypt lumens.

 
The biotinylated Ag was detected histochemically by its ability to bind to avidin that was in turn complexed to biotinylated peroxidase. As shown in Fig. 2Go (left-hand column vs other columns) and Fig. 3Go (A and B vs C and D) only mice that were immunized and subsequently challenged i.v. with the same Ag (biotinylated OVA) evidenced Ag in the crypt cells of the small intestinal epithelium. Both the amount of Ag in the crypt cells and the percentage of positive mice were statistically significantly different from two groups of control mice (Fig. 2Go). In one control, the mice were mucosally immunized in the same manner with an irrelevant Ag, BSA. In this case, the biotinylated OVA that was injected i.v. before sacrifice was not complexed by specific IgA Ab and, therefore, was not transported through the intestinal epithelial cells. In the second control, mice were immunized intragastrically with biotinylated OVA but received no i.v. challenge before sacrifice. Again, Ag could not be detected within the intestinal epithelium. As discussed below, the results presented in Figs. 2Go and 3Go indicate that Ag entered intestinal epithelial cells only from the basolateral surface and only when complexed to specific IgA Ab.



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  		FIGURE 2. Ag in intestinal crypt cells. D011.10 mice that had been immunized intragastrically with biotinylated OVA or BSA were challenged i.v. 30 min before sacrifice with biotinylated OVA or nothing. The ordinate shows the intensity of staining for biotinylated OVA within small intestinal crypt epithelial cells in arbitrary units. Solid horizontal lines indicate the mean intensity for the group and interrupted lines indicate the SE. Mice in the group at the left made IgA Abs that complexed with the challenge dose of biotinylated OVA Ag and excreted it through the mucosal epithelium. The mean intensity (±SE) in the first group (1.4 ± 0.3) is significantly higher (F = 7.3; t >3.5; p < 0.01) than in the second group (0.2 ± 0.2), and the fraction of positive mice (intensity score >0) in the first group (8/9) is significantly higher ({chi}2 = 3.6; p < 0.05) than in the second group (2/9).

 


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  		FIGURE 3. Microscopic demonstration of Ag in intestinal mucosa. Sections of small intestine were stained by peroxidase for biotinylated OVA (A–D) and IgA (E), and counterstained with hematoxylin. A, From a mouse orally immunized with biotinylated OVA and subsequently injected i.v. with biotinylated OVA, showing biotinylated OVA Ag prominently in crypt epithelial cells (arrows) and to a lesser degree in the villus epithelial cells and in the interstitial tissue of the lamina propria surrounding the crypts and in the cores of the villi. B, As in A but at greater magnification. The biotinylated OVA Ag at the upper arrow is in the epithelium of a crypt as it opens into the lumen between adjacent villi. C, From a control mouse orally immunized with irrelevant Ag (BSA) and subsequently injected i.v. with biotinylated OVA. In the absence of specific IgA Ab the epithelium of the crypts (C) lacks biotinylated OVA, although the lamina propria is prominently stained. D, As in C but at greater magnification. E, Section stained for IgA showing IgA in plasma cells in the lamina propria (small arrows), crypt epithelial cells (large arrow), and to a lesser degree in the lamina propria generally. Magnifications are x330 for A and C and x770 for B, D, and E. M indicates external muscle layer; L, intestinal lumen; V, villi; LP, lamina propria.

 
Because the epithelium lining mucous membranes is not a perfect barrier, Ags can penetrate mucosal surfaces to some degree as an ongoing process (14, 15, 16). Our earlier experiments in vitro (8, 9) provided initial support for the concept that IgA Abs secreted by the local plasma cell population could provide an internal immune barrier. In this schema, IgA Abs quickly bind Ags penetrating the epithelium or released into the lamina propria from pathogenic microbes. The resulting IgA immune complexes are then excreted via the pIgR across the epithelium into the lumen.

The current experiments were designed to create soluble immune complexes in mucosal lamina propria to test the hypothesis of a local excretory function for mucosal IgA Abs in vivo. To stimulate a potent mucosal Ab response, mice were immunized via the gastrointestinal tract. After the specific IgA Ab response, as reflected in the serum, reached a peak, the mice were challenged i.v. with a large dose of Ag to ensure that the entire extracellular fluid volume would be in Ag excess and to provide sufficient soluble IgA-containing immune complexes in the lamina propria for their excretion through mucosal epithelium to be detectable morphologically.

The requisite immune complexes in the intestinal lamina propria could have arisen by two mechanisms. One is diffusion of excess free Ag from the bloodstream into the lamina propria, where it combined with IgA Abs secreted by local plasma cells. The other possibility is formation of IgA immune complexes in the circulation and their subsequent diffusion into the lamina propria. Both mechanisms would have been facilitated by the large excess of injected Ag, designed to favor the formation of small immune complexes, with a limiting complex of one molecule of Ag and one molecule of Ab, with some Ag remaining free. Regardless, once in the lamina propria, the IgA immune complexes would be in a position to compete for available epithelial pIgR with background levels of free nonspecific oligomeric IgA and IgA immune complexes containing naturally prevalent Ags.

For several reasons we believe the biotinylated OVA that was detected in the small intestinal crypt cells was Ag being transported, i.e., excreted, by specific IgA Ab across the epithelium from basal to apical. First, biotinylated OVA was readily detected in the crypt cells of TCR transgenic mice that had been both mucosally immunized and subsequently challenged i.v. with biotinylated OVA. It was also detectable, but less prominently, in the crypt cells of wild-type BALB/c mice that had been treated similarly, but that, lacking the transgene, made a less vigorous IgA Ab response (results not shown). Specific Ag was not detected in the intestinal epithelium of mice that had been immunized mucosally with an irrelevant Ag (BSA) before i.v. injection of biotinylated OVA. Thus, in the absence of specific IgA Ab, biotinylated OVA in the lamina propria was not taken up by the intestinal epithelium. Second, mice that had been immunized intragastrically with biotinylated OVA but not subsequently challenged i.v. did not evidence biotinylated OVA in small intestinal crypt cells, showing that under the experimental conditions, luminal Ag from the mucosal immunization was not absorbed in detectable quantities into the crypt cells, either nonspecifically or bound to previously secreted IgA Ab. Third, the architecture of the small intestine provides an internal control, namely, a gradient of decreasing transit of IgA across the lining epithelium along the crypt-villus axis. This parallels the expression of epithelial pIgR, the transporter of IgA, which is also most prominent in the crypt cells, diminishing toward the tips of the villi (17, 18, 19). Consistent with this gradient in IgA Ab transport, biotinylated OVA Ag was detected much more prominently in crypt than in villus epithelial cells. This marked decrease in amount of Ag in the epithelium proceeding toward the tips of the villi, in turn, argues against epithelial uptake due to nonspecific events and staining artifacts.

Specific IgM Ab, also present after immunization (data not shown) and also capable of binding to epithelial pIgR, could contribute to uptake of Ag into intestinal epithelial cells. Quantitatively, however, mucosal IgA production greatly exceeds that of mucosal IgM; moreover, the transport of IgA appears to be favored under in vivo conditions (20).

Mucosal surfaces, especially in the gastrointestinal tract, are constantly exposed to foreign substances, and secreted IgA Ab in the lumen has long been known to provide an immunological barrier to limit the penetration of Ags into mucous membranes. From previous experiments in vitro (8, 9) and the present experiments in vivo, we propose that mucosal IgA Abs in the lamina propria additionally provide a backup, internal barrier beneath the epithelium that can trap Ags missed by the initial IgA barrier in the lumen. For example, Ags could by-pass luminal IgA Ab either during the early stages of a mucosal Ab response when there was insufficient Ab to prevent the absorption of all the Ag present or even in the face of an established response if there was sudden exposure to a particularly large quantity of luminal Ag. Moreover, Ags will also be released into the lamina propria from microbial pathogens during infections of the mucosae. Therefore, we believe that to some extent foreign Ags are a regular presence in mucosal lamina propria. Regardless of the origins of particular Ags at those sites, given the ongoing production of IgA by the numerous local plasma cells, IgA Abs are in a position to bind and efficiently transport Ags out of the body proper and into the lumen. Potentially IgA Abs could even excrete particles as large as intact viruses (21).

Removal of a variety of Ags from the lamina propria via the same mechanism that is used for transporting free IgA across mucosal epithelium would serve to limit the amounts of Ag reaching the circulation, where Ags would also be more likely to be bound by Abs of the more abundant and more phlogistic IgG class. In this way, the excretory function of IgA could help to prevent diseases that result from circulating immune complexes. A particularly relevant example is IgA nephropathy, the most common form of glomerulonephritis, which is thought to result from abnormal regulation of the immune response to mucosal infections (22).

In addition to extracellular locales, IgA Abs are also capable of binding to Ags inside epithelial cells during pIgR-mediated transport of free IgA. IgA Abs acting intracellularly have been shown to neutralize viruses (23, 24, 25, 26) and to block their apical to basal transcytosis (27). Thus, overall, IgA Abs appear to be capable of mediating an integrated, multilayered mucosal defense system (28). The first layer, in the lumen, is exclusion of Ag by secreted free IgA. The second layer, within the lining epithelial cells, allows for inhibition of intracellular pathogens like viruses. The third layer, as demonstrated in the current work, is the lamina propria from which IgA Abs can directly excrete Ags into the lumen.


   Acknowledgments
 
We thank Dr. Kenneth M. Murphy, Washington University for the transgenic mice.


   Footnotes
 
1 This research was supported by National Institutes of Health Grants AI-26449, AI-36359, and DK-46461, and a grant from the Crohn’s and Colitis Foundation of America. Back

2 Address correspondence and reprint requests to Dr. Michael E. Lamm, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106-4907. Back

3 Abbreviation used in this paper: pIgR, polymeric Ig receptor. Back

Received for publication October 18, 2000. Accepted for publication January 4, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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