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*
Department of Medical Microbiology and Immunology, University of Göteborg, Göteborg, Sweden; and
Immunology Group, Department of Cellular and Molecular Immunology, Lund University, Lund, Sweden
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This transport is mediated by up-take of dimeric IgA and polymeric IgM containing a J chain, which binds to the polymeric Ig receptor (pIgR) expressed on the basolateral side of the epithelial cell (1, 2). Thus, the plasma cell produces the J chain, which is a 15-kDa glycoprotein that covalently associates by disulfide linkages with polymeric IgA and IgM, but not to IgG, before secretion (1, 2, 5). After binding of the J chain Ig polymer to the pIgR, the complex is transported through the epithelial cell to the luminal side, where the receptor is proteolytically cleaved off (2, 5). This results in the formation of secretory IgA (sIgA), shown to be particularly resistant to proteolytic degradation (1, 2). Whether polymeric IgM at mucosal surfaces also has increased stability compared with serum IgM is less well known (1, 4).
To investigate in vivo the role of the pIgR pathway for the transport of IgA into the lumen, Hendrickson et al. recently developed a J chain-deficient mouse (6, 7). In their first report, the concentration of IgA in feces was dramatically lowered compared with wild-type (WT) mice (6). However, in a follow-up study, using a different detection system, IgA Abs, albeit monomeric forms, were present in normal concentrations at the mucosal surfaces in the intestine, mammary gland, and lung in J chain-deficient mice, suggesting that the J chain was not absolutely required for IgA transport into the lumen (7). This unexpected finding contrasted with the requirement for J chain in the hepatic transport of IgA found in these same mice (6). Although most previous studies have demonstrated a clear association between the presence of J chain and transport of IgA into the lumen (1, 2, 4, 5, 8), there are a few studies that support the view that IgA may reach the lumen through a J chain-independent pIgR-mediated transport (2, 9, 10). The mechanism or the functional relevance of such a system has not been investigated.
Cholera toxin (CT) induces severe diarrhoeal disease (11).
Following active oral immunization in humans and experimental animals,
a high degree of antitoxic protection is induced (11, 12).
Protection is thought to depend on the presence of intestinal sIgA Abs
(13, 14, 15), although some investigators have argued for
other factors, such as IFN-
, neuropeptides, or anti-secretory
factors (ASF), to be responsible for the development of antitoxic
protection (16, 17, 18).
We recently developed a mouse with an inactivated J chain and have reported on the systemic effects on IgM secretion of this gene deletion (19). In the present study, we addressed whether the J chain plays an essential role in the secretion and transport of intestinal antitoxin IgA and if this process is associated with an increased resistance to CT challenge of small intestinal ligated loops in orally immunized mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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WT (J chain+/+) mice or mice with homozygous (J chain-/-) or heterozygous (J chain+/-) deletions of the J chain (19) were bred at the Department of Cellular and Molecular Biology at Lund University (Lund, Sweden) and housed under pathogen-free conditions at the Department of Medical Microbiology and Immunology at the University of Göteborg (Göteborg, Sweden) before experimentation.
Immunization
Age- and sex-matched mice were given three oral immunizations 10 days apart with 10 µg of CT (List Biological Laboratories, Campbell, CA) in 6% (w/v) NaHCO3 in PBS through a baby feeding tube under light ether anesthesia (13, 20). Control mice received PBS alone. Analysis of small intestinal antitoxic protection and systemic and local antitoxin Ab production were performed 4 or 7 days after the final immunization as indicated.
Intestinal lavage samples
Intestinal secretions for Ab determinations were collected by a method adopted from Elson et al. (21). Briefly, the small intestines were removed, rinsed in PBS to discard feces, and carefully injected with 3 ml of a protease inhibitor solution consisting of 0.1 mg/ml soybean trypsin inhibitor (Sigma, St. Louis, MO), 50 mM EDTA (Merck, Darmstadt, Germany), and 1 mM PMSF (Boehringer Mannheim, Mannheim, Germany) in PBS. After incubation for 10 min at room temperature, the intestinal content was transferred to a test tube, vigorously vortexed, sonicated, and centrifuged for 10 min at 1800 rpm at 4°C. The supernatant was transferred to a microfuge tube, and PMSF (Boerhinger Mannheim) was added to a final concentration of 1 mM. After mixing the solution, it was again centrifuged at 13,000 x g for 15 min at 4°C. The resulting supernatant was mixed with PMSF and sodium azide to a final concentration of 1 mM and 0.001%, respectively, and incubated at 4°C for 30 min. Thereafter, 50 µl FCS was added per ml solution, which was then centrifuged for an additional 15 min at 13,000 x g at 4°C. The supernatants were stored at -70°C until analyzed.
Preparation of Peyer’s patch (PP) and LP lymphocytes
PP were excised from the serosal side of the intestine and passed through a nylon net as described (22). Intestinal LP lymphocytes were prepared as previously described (22). Briefly, after thorough washing in Ca2+- and Mg2+-free HBSS (CMF-HBSS) (Life Technologies, Paisley, U.K.), the tissue pieces were incubated in CMF-HBSS containing 5 mM EDTA (Merck) to remove epithelial cells and intraepithelial lymphocytes. The intestinal pieces were then incubated in RPMI 1640 (Life Technologies) containing collagenase type C-2139 (300 U/ml; Sigma) to enzymatically extract the LP lymphocytes. The single-cell suspensions of PP and LP lymphocytes were then washed three times in CMF-HBSS (Life Technologies) and diluted to a final concentration of 2 x 106 cells/ml in Iscove’s medium (Life Technologies) containing 5% FCS (Life Technologies).
Serum and lavage Ab determinations by ELISA
Flat-bottom 96-well microtiter plates (Nunc, Roskilde, Denmark) were coated with 0.5 nmol/ml GM1 ganglioside (Sigma) in PBS at 4°C overnight followed by 0.5 µg/ml CT (List Biological Laboratories) in PBS at 4°C overnight as described (23). Total IgA, IgM, or IgG determinations in serum or lavage were performed using highly isotype-specific unlabeled goat anti-mouse IgA, IgM, or IgG Abs (Southern Biotechnology Associates, Birmingham, AL) at 5 µg/ml in PBS at 4°C overnight. After washing in PBS and blocking with 0.1% BSA/PBS for 30 min at 37°C, serial 3-fold dilutions of sera at 1/200 or intestinal lavage at 1/20 was performed in corresponding subwells in 0.1%BSA/PBS, and the plates were incubated at 4°C overnight. For antitoxin-specific IgA, IgM, or IgG determinations, serum was diluted 1/100 and lavage was diluted 1/2 and subjected to 3-fold serial dilutions in corresponding subwells. After washing in PBS/0.05% Tween 20, alkaline phosphatase (AP) -conjugated or HRP-conjugated goat anti-mouse IgA, IgM, or IgG Abs (Southern Biotechnology Associates) at 1/500 dilution in 0.1%BSA/PBS were added to total isotype- and CT-specific wells, respectively, and the plates were incubated 2 h at room temperature. Ag-specific HRP-labeled Abs bound to the plate were visualized using ortho-paraphenylenediamine (1 mg/ml)-0.04% H2O2 substrate in citrate buffer, and the reaction was read at 450 nm using a Titertek Multiscan spectrophotometer (Flow Laboratories, Irving, U.K.). AP-labeled Abs were visualized using phosphatase-substrate tablets nitrophenyl-substrate (Sigma) at 1 mg/ml in ethanolamine buffer, pH 9.6, added to the wells, and the reaction was read at 405 nm in the Titertek Multiscan spectrophotometer (Flow Laboratories). Antitoxin titers were defined as the interpolated OD reading giving rise to an absorbance of 0.4 above background, which consistently gave OD readings on the linear part of the curve. Titers were given in log10 means ± SD of five mice per group. Total IgA, IgM, or IgG in µg/ml was calculated from standard curves generated by serial dilutions of purified hybridoma IgA, IgM, or IgG (PharMingen, San Diego, CA) of known concentrations. The isotype-specific antisera were highly specific and did not cross-react with purified proteins of other isotypes.
ELISPOT assay
Individual cells secreting Igs, spot-forming cells (SFC), were determined by the ELISPOT technique essentially as described (24). Briefly, polystyrene petri dishes (Nunclon; Nunc) were coated with 3 nmol/ml of GM1 ganglioside (Sigma) in PBS at 4°C overnight, followed by an additional incubation at 4°C with 3 µg/ml CT (List Biological Laboratories) in PBS overnight. For isotype-specific SFC, 96-well flat-bottom microtiter plates (Nunc) were coated with 5 µg/ml goat anti-mouse IgA, IgG, or IgM Abs (Southern Biotechnology Associates) in PBS at 4°C overnight. After washing with PBS, the petri dishes or the microtiter plates were blocked by 0.1% BSA in PBS for 30 min at 37°C. Lymphocytes at 4 x 105 in 400 µl medium were added to each petri dish or 105 lymphocytes in 150 µl medium were added to the top row in 96-well plates and then serially diluted 1:3 in corresponding subwells and sedimented by centrifugation for 3 min at 400 rpm. All dilutions were performed using Iscove’s medium (Seromed, Berlin, Germany) supplemented with 10% FCS (Seromed), 5 x 10-5 M 2-ME (Sigma), 1 mM L-glutamine, and 50 µg/ml gentamicin. Cells were incubated for 4 h in 37°C in 8% CO2. After incubation, each petri dish or well was washed out by repeated rinsing in PBS containing 0.05% Tween 20. Single LP anti-CT SFC were visualized by adding goat anti-mouse IgA primary Ab at 1/300 dilution (Cappel, Durham, NC) followed by HRP-conjugated rabbit anti-goat Ig-secondary Abs (Dako, Carpinteria, CA) at 1/200. For the isotype-specific SFCs, AP-conjugated Abs (Southern Biotechnology Associates) at 1/500 dilution were used. For the petri dishes, (HRP substrate) paraphenylenediamine substrate (Sigma) in 1% agar-in-PBS solution was used, and for the 96-well plates (AP substrate) we used 5-bromo-4-chloro-3-indolylphosphate (Sigma) in agarose-in-water as described (24). The SFCs were counted under low magnification. Isolated PP or LP lymphocytes were pooled from two mice, and each pair was analyzed in duplicate petri dishes or triplicate wells plus one uncoated well as a control for unspecific binding. Values were expressed as mean SFC/107 lymphocytes ± SD of at least three pairs per group.
Ligated loop test
For evaluation of protection against CT-induced diarrhea/fluid loss, the method described by Lange and Holmgren was used (25). The abdomen was opened under light ether anesthesia, and a 6- to 8-cm loop was ligated in the middle part of the small intestine. CT (List Biological Laboratories), 2,5 µg in 0.2 ml of PBS, was injected into the loop, and the abdomen was closed. After 4 h, the mice were sacrificed, whereafter the loop with its fluid content was weighed and its length was determined. Unimmunized mice of all strains were equally sensitive to CT injected in ligated small intestinal loops. Values for fluid accumulation in the ligated loops, reflecting the degree of immune protection, were expressed as the weight-per-length ratio in mg/cm ± SD of five to seven mice per group.
Immunohistochemistry
Frozen sections (5 µm) from unimmunized or CT-immunized mice were prepared on microslides using a cryostat (model 1720; Leitz, Wetzlar, Germany) and frozen at -70°C. The slides were fixed in 50% acetone for 30 s followed by 100% acetone for 5 min at 4°C. After washings in PBS, the slides were treated with 5% horse serum in PBS for 15 min in a humid chamber. For detection of germinal center (GC) reactions and IgA+ and IgM+ cells in the gut-associated lymphoid tissue, fixed sections were double labeled with FITC-conjugated peanut (Arachis hypogaea) hemagglutinin (PNA; Sigma) and Texas Red-conjugated anti-mouse IgA or IgM (Southern Biotechnology Associates), both at 1/100 dilution (26). For detection of IgA plasma cells in LP, the sections were labeled with FITC-conjugated anti-IgA (Southern Biotechnology Associates). The slides were mounted with fluorescence mounting media (Dako), and sections were evaluated and photographed using DAS Mikroskop, (Leica Microscope System, Welzar, Germany).
Statistical analysis
We used Student’s t test for independent samples for analysis of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Conflicting information regarding the relative distribution of
total IgA and IgM in serum and gut mucosal secretions in J
chain-deficient mice have recently been published (6, 7, 19). However, previous studies assessed mucosal IgA levels in
fecal extracts or by applying wicks tampons directly to the mucosal
surface of the small intestine (6, 7, 27), but a more
reliable method is to collect intestinal lavage fluid from the entire
small intestine using a buffer containing strong protease inhibitors
(13, 14, 20, 21). Thus, we collected serum and gut lavage
from WT mice or mice with a homozygous or heterozygous deletion of the
J chain gene (19). We found that both J
chain-/- and J chain+/-
mice had significantly reduced levels of total IgA and IgM in gut
lavage compared with WT mice (Fig. 1
). In
contrast, and in agreement with previous reports (6, 7),
serum IgA levels were increased (Fig. 1) while serum IgM levels were
dramatically reduced in J chain-/- and J
chain+/- mice compared with WT mice
(19). The mean IgM values of three experiments were
34 ± 16, 113 ± 74, and 236 ± 98 µg/ml,
respectively. Intestinal total IgG levels were similar in J
chain-/-, J chain+/-,
and WT mice and roughly 300-fold lower than serum IgG levels in these
mice (not shown). At the single-cell level, IgM-producing cells (SFC)
were significantly fewer in both the PP and the LP of J
chain-/- than in WT mice (Table I). In contrast, the level of total IgA
SFC were similar in PP and LP of J chain-/- and
WT mice, indicating that the ability to develop IgA responses was
unperturbed in J chain-deficient mice. This conclusion was supported
further by immunohistochemical analysis of IgA B cell differentiation
and maturation at inductive sites, i.e., PP, as well as at the
LP-effector site in the intestinal mucosa (Fig. 2). We found no reduction in the number
of IgA+ cells in the LP and PP and no alteration
in the ability to develop GC in the PP of J chain-deficient mice (Fig. 2). Thus, the induction, differentiation, and maturation of IgA B cells
into plasma cells occurred normally in the absence of J chain, but
there was a significant reduction in luminal concentrations of IgA
and IgM.
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Next we addressed whether oral immunization of J chain-deficient
mice resulted in the development of specific systemic and mucosal
antitoxin Ab responses. Following three oral immunizations, we detected
10-fold increased IgA antitoxin titers in the serum of J
chain-/- mice, while IgM antitoxin Ab levels
were significantly reduced compared with WT mice (Fig. 3). Mice with a homozygous deficiency
exhibited higher IgA and lower IgM responses, compared with
heterozygous and WT mice, suggesting a gene-dosage effect. The serum
anti-CT IgG responses were equivalent in all mouse strains (Fig. 4). By contrast, the presence of
antitoxin IgA in gut lavage was reduced in a gene-dependent fashion
with only poor IgA antitoxin levels in J
chain-/-, intermediate in J
chain+/-, and strong anti-CT IgA levels in
WT mice (Fig. 4). Very low, but similar, titers of IgG and no IgM
anti-CT Abs were detected in gut lavage in J
chain-/-, J chain+/-, or
WT mice (not shown). Further, detection of anti-CT SFC responses in
the LP of immunized mice demonstrated that the development of specific
Ab-producing cells in the LP of J chain-deficient mice was unaltered
compared with that in WT mice (Table II).
Therefore, the J chain deficiency was not associated with a defect in
the induction of antitoxic IgA immunity, but was clearly hampering the
secretion of specific IgA into the intestinal lumen.
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Given that host resistance against CT-induced diarrhea requires
the neutralization of toxin with specific sIgA at the mucosal surface
(13, 14, 15, 20, 28), we investigated the consequence of an
impaired pIgR-mediated transport for the ability to develop gut
antitoxic protection following oral immunization with CT (13, 28). We found that, whereas WT mice demonstrated strong
protection against CT challenge, the J chain-deficient mice were poorly
protected (Fig. 5). Compared with
unimmunized control animals, WT mice exhibited 80% protection while J
chain-/- mice were only protected to 20%,
indicating that the lack of IgA transport in J chain-deficient mice
dramatically reduced the ability to neutralize luminal CT. Heterozygous
J chain+/- mice showed intermediate protection,
consistent with a gene-dosage effect in the ability to develop
intestinal antitoxic protection. These statistically significant
results (p < 0.05) argue for a strong
dependence on J chain-pIgR transport of sIgA across the intestinal
epithelium for local protective immunity against CT.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Furthermore, the presence of gut lavage IgG Abs, the isotype that does not bind J chain and, therefore, cannot associate with the pIgR, did not differ between the three strains, arguing that passive diffusion is unlikely to account for the translocation of protective Igs into the lumen. If this had been the case, then the 10-fold increased serum IgA antitoxin levels detected in J chain-/- mice following immunization should also have augmented the representation of gut lavage IgA and protection in mice lacking the J chain relative to those that have intact J chain production. Whether IgM antitoxin Abs have a protective function against CT cannot be answered by the present study, because, consistent with our previous findings, J chain-deficient mice appeared to have a perturbed IgM secretion (19). However, in a parallel study using IgA-deficient mice (29), we observed a similarly low level of protection, around 20%, despite a 10-fold compensatory increase in gut lavage anti-CT IgM levels compared with WT mice (N.Y.L., unpublished observation). Thus, the latter observation would argue against a functional protective role of gut polymeric IgM antitoxin Abs in host resistance against CT.
The findings reported here are at variance with a previous study by Hendrickson et al. using a different strain of J chain-deficient mice (6, 7). Although we targeted exon 1, whereas Hendrickson et al., targeted exon 2, of the J chain gene, we have no reason to believe that the targeting strategy can explain the conflicting observations, because both approaches led to a failure to detect J chain gene transcripts (6, 19). Rather, we think that differences in the methods for detection of mucosal Abs and perhaps to some extent environmental factors or the recently discussed polymorphism in I129 mice (30) could have influenced the results. Although the neutralizing ability of monomeric IgA and resistance to proteolytic degradation is poor compared with that of sIgA (1, 2, 4), we do not think that the J chain-deficient mice that we have studied secreted monomeric or dimeric IgA (lacking J chain) into the lumen, as was suggested by the findings of Hendrickson et al. (7).
First, we detected very little IgA in the gut lavage, despite the fact that our ELISA was sufficiently sensitive to detect high levels of the predominantly monomeric IgA (6, 19) in serum of the J chain-/- mice. It should be noted that J chain-deficient mice also have substantial levels of dimeric IgA (6, 7, 19), supporting our observation that dimerization of IgA in the absence of J chain is not sufficient for luminal transport. Secondly, our lavage method of collecting intestinal IgA is more representative and sensitive than the wicks tampon method used previously. Although both methods exclude feces, the wicks detect Abs in only a limited region, while the lavage method collects IgA from the entire length of the small intestine (20, 21, 27). Moreover, it is difficult to rule out the possibility that the tampons establish a fluid diffusion gradient that may affect the barrier functions of the intestinal mucosa, thereby allowing the diffusion of IgA from the LP and serum into the tampons. Therefore, we believe that the lavage method is more accurate and provides highly reproducible measurements of luminal IgA. Although Hendrikson et al. used the lavage method for detection of IgA in bronchoalveolar fluid of J chain-/- mice (7), we think that the increased levels of IgA that they reported reflect the transudation of tissue and serum IgA into the alveolar lumen, similar to that seen in the genital tract (1, 4). Third, CT causes fluid loss after binding to the GM1 receptor on the epithelial cell (11, 12). If normal levels of surface dimeric anti-CT IgA had been present in immunized J chain-/- mice (7), we would have expected these Abs to confer a higher degree of protection, because the ability to neutralize toxin should not be a function of the presence of J chain or secretory component (1, 4, 13, 14, 15, 28).
Our study clearly demonstrates a strong association between the
presence of specific IgA Abs in the gut lumen and protection against
CT-induced fluid loss. This finding agrees well with previous studies
using other models to show a direct relationship between gut mucosal
transport of IgA and protection, as, e.g., the back-pack IgA-hybridoma
model developed by Neutra and co-workers (15, 28) However,
evidence has been presented to suggest that antitoxic protection may
not be mediated solely by antitoxin Abs and may involve additional
factors such as IFN-, or other cytokines, neuropeptides, or ASF,
which were recently cloned and purified (16, 17, 18). However,
the present results are difficult to reconcile with any major antitoxic
protective function of these alternative factors in vivo, a conclusion
supported further by our demonstration that antitoxic protection
develops normally in IFN- receptor-deficient mice (31)
and that also IgA-deficient and B cell-deficient mice fail to develop
significant antitoxic protection (N.Y.L., unpublished observation). Of
course, our results with the J chain-deficient mice do not exclude a
protective function of ASF or other factors against CT-induced
diarrhea, although we do not know why the absence of the J chain in our
model would have affected the level or function of, e.g., ASF
(16). We did observe 20% protection in immunized J
chain-/- mice. Whether this level of protection
was conferred by the presence of low levels of luminal anti-CT IgA,
lacking J chain, or these alternative factors is not known. However,
orally immunized B cell-deficient mice exhibit no protection at all
against CT challenge (N.Y.L., unpublished observation). Also, we find
it highly unlikely that there would be any connection between the
neuropeptides or ASF and the J chain, or for that matter a dependence
on epithelial transcytosis of local dimeric IgA Abs and these
alternative protective factors. Further analyses are required to
delineate the role of these factors in intestinal antitoxic
protection.
Consistent with our previous report on the J chain-deficient mouse, we observed low levels of IgM Abs (19). Not only did we find decreased levels of IgM in gut lavage, we also had low serum IgM concentrations and 5-fold reduced total IgM SFC in the gut LP as compared with WT mice. Therefore, the low gut IgM levels in the J chain-/- mice seem to be an effect of poor plasma cell differentiation, rather than an effect of impaired pIgR transport. Thus, this maturational defect appears to affect IgM B cells selectively, as both IgG and IgA production, including gut anti-CT IgA SFC, were normal. This is an intriguing finding, demonstrating that the production of J chain is not required for terminal maturation of IgA plasma cells in the gut. Because almost all IgA- or IgG-producing cells in human gut LP express J chain and only few cells of these isotypes produce J chains in peripheral lymph nodes, Brandtzaeg and coworkers have speculated that coexpression of J chain would constitute a maturational requirement for mucosal B cell development (1). However, the data from J chain-deficient mice does not appear to support such a notion (7, 19). At present, we do not have an explanation for why coexpression of J chain is selectively more important for IgM plasma cell differentiation. Potentially, the J chain is critical in the assembly and secretion of polymeric IgM (32). Alternatively, it plays no role in terminal plasma cell maturation; rather, it may be that, in the absence of J chain, the secreted form of IgM is highly unstable and is rapidly degraded in serum and tissue. However, the work of many investigators has indicated that the J chain is not critical for production of polymeric IgM, including hexameric IgM, which is the most complement-activating form of IgM (1, 33). In our previous study, we found lower concentrations of both hexameric and monomeric forms of IgM in serum of J chain-/- mice, and serum from these mice was a significantly poorer activator of complement compared with serum from WT mice, indicating that there are also qualitative differences (19). Further studies will be undertaken in this model to address the role of the J chain for the maturation of IgM plasma cells.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nils Lycke, Department of Medical Microbiology and Immunology, University of Göteborg, S-413 46 Göteborg, Sweden. E-mail address:
3 Abbreviations used in this paper: LP, lamina propria; ASF, anti-secretory factor; CT, cholera toxin; PP, Peyer’s patches; sIgA, secretory IgA; SFC, spot-forming cells; GC, germinal centers; PNA, peanut hemagglutinin; WT, wild type; pIgR, polymeric Ig receptor; CMF, Ca2+- and Mg2+-free; AP, alkaline phosphatase.
Received for publication February 17, 1999. Accepted for publication April 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-Interferon-mediated down-regulation of electrolyte secretion by intestinal epithelial cells: a local immune mechanism?. Scand. J. Immunol. 30:499.[Medline]
deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance. Immunology. 92:60.[Medline]
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