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,
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Departments of Microbiology and Immunology, Influenza Research Center, Respiratory Pathogens Research Unit, and Departments of
Medicine and
Pediatrics, Baylor College of Medicine, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Following antigenic stimulation, Ag-specific IgA B cell precursors migrate from Peyer’s patches located in gut-associated lymphoid tissues and from bronchus-associated lymphoid tissue through draining lymph nodes to the thoracic duct and systemic circulation before homing back to the lamina propria through a process involving homing receptors 27, 28, 29, 30, 31, 32 . In these distant mucosal sites, B cells differentiate and become IgA-producing plasma cells. These previous studies have led to the concept of a common mucosal immune system, in which IgA precursors are generated at inductive tissues such as bronchus-associated lymphoid tissues and gut-associated lymphoid tissues and circulate to IgA effector sites, including lamina propria regions of the gut, the bronchi of the upper respiratory tract, the urogenital tract, and salivary glands 27, 28 . It is presumed that a consequence of this compartmentalization of the mucosal immune system and the specificity of lymphocyte homing is that systemic immunization, in general, is ineffective at inducing S-IgA Abs 28 . Hence, considerable effort is currently underway to determine ways for engineering vaccines to preferentially induce S-IgA in the mucosa 28 . One approach involves use of cholera toxin holoenzyme (CT) with or without the cholera toxin B subunit (CTB), which constitute the most extensively investigated reagents for their mucosal immunomodulatory and adjuvant properties and for induction of IgA 29, 30, 31, 32, 33, 34, 35 . Recently, studies have also evaluated the efficacy of Escherichia coli heat-labile enterotoxin, either alone or in combination with CTB/CT 36, 37 . Many of these studies have been conducted in mice for evaluation of protective mucosal immunity to influenza virus infection.
Induction of S-IgA has been correlated with protection against several upper respiratory tract pathogens, including influenza in humans 38, 39 and mice 13, 40, 41 . While some studies have suggested a relationship, the contribution of IgG and IgM to protection cannot be definitively excluded 41 . A direct role for IgA has been demonstrated in a number of studies. Renegar and Small have shown that anti-influenza A/PR/8 hemagglutinin (HA)-specific (anti-HA) monoclonal polymeric IgA (pIgA) injected i.v. was transported more efficiently into nasal secretions than monomeric IgA (mIgA) or IgG1 7, 8 . Mice injected with pIgA were significantly protected against influenza virus challenge compared with those injected with IgG1. It was further shown that treatment with anti-IgA Abs of immune mice previously infected with influenza virus, but not anti-IgG1 or anti-IgM Abs, abrogated the IgA-mediated protection. In related studies, Gerhard and co-workers have shown that i.p. injection of SCID mice with pIgA and IgM prevented infection with influenza virus but did not cure mice previously infected with virus 42 . In contrast, IgG1, IgG2a, IgG2b, and IgG3 injections in mice resulted in a cure of influenza virus infection, even when injection was performed 7 days after virus infection. These and other studies 40, 41 suggest that IgA (and IgM) function primarily to prevent virus infection, while IgG cures virus infection.
Transgenic IgA-/- knockout (KO) mice were previously generated by gene targeting in which deletion of the entire IgA switch region and the 5' half of the constant region occurred 43 . In the present study these selective IgA-deficient animals were used to determine the role played by IgA in protection against influenza virus infection and disease. In addition, the value of preferential induction of S-IgA Abs by influenza vaccination was determined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IgA transgenic KO mice were generated as previously described
43 . Briefly, a targeting vector that produced a deletion of the
entire IgA switch region as well as the first two C
exons and part
of the third C exon as previously described 45 was introduced by
electroporation 44 into an I2 embryonic stem (ES) cell clone that
was previously used by us to produce an I exon KO mouse 45, 46 .
Successfully targeted ES cell clones were introduced into blastocysts,
and chimeric mice were generated. Male chimeric mice with a high degree
of chimerism were mated to female C57BL/6 mice by standard methods.
Agouti offspring, which inherited either a wild-type or a mutated
allele from the targeted ES cells, were phenotyped for expression of
IgA in serum by ELISA 31, 47, 48 . F1 heterozygous mice
expressing the targeted ES cell allele were interbred to produce
homozygotes.
Immunization of wild-type and IgA-deficient mice with influenza virus vaccine
Homozygous IgA-/- mice derived by inbreeding of F1 heterozygotes, and wild-type nontargeted littermates (IgA+/+) were immunized by two intranasal (i.n.) or i.p. inoculations, 3 wk apart, using 2 µg of influenza A/Taiwan/1/86 subunit vaccine (SV; Connaught Laboratories, Swiftwater, PA) with 2 µg of CTB (Choleragenoid for Vibrio cholera; Sigma, St. Louis, MO) and 20 ng of CT as adjuvant (in 20 µl of PBS) following light anesthesia with methoxyflurane 49, 50 . Two weeks after the second inoculation three mice per group were bled for serum, then killed, and the nasopharynx was washed using 0.5 ml of medium. Serum and mucosal IgA, IgG, and IgM Abs were determined. Splenic CTL activity against influenza virus was also determined 51 . Three weeks after the second injection, the mice were challenged with 3 LD50 of A/Taiwan virus by small particle aerosol (SPA) 52 . On days 4 and 8 postvirus challenge three mice per group were killed for nasopharyngeal and pulmonary virus measurements. The remaining eight mice per group were observed for mortality for 21 days.
Passive immunization
Isotype-specific mAbs directed to influenza A/PR/8/34 (H1N1) virus HA in the form of ascites fluid from BALB/c mice or purified from SCID mouse ascites fluid were gifts from Dr. Walter Gerhard (Wister Institute, Philadelphia, PA). The mIgA (clone H37-50), pIgA (clone H37-66), IgM (clone H2-6C4-13), IgG1 (clone H37-65-5), and IgG2a (clone H37-77-3) mAbs and their HA specificities have been previously described 42 . IgA-/- mice (6–14 wk old) were administered a single i.p. injection of anti-HA mAb titrated to contain 4- log10 influenza virus neutralization titer units in PBS 42 . Four hours later three mice were killed to obtain serum, nasal wash, nasal turbinates, and lungs for Ab quantitation. The remaining mice were then challenged with 50 MID50 of A/PR/8 virus by SPA. Twenty-four and forty-eight hours later four mice per group were killed. Nasal wash and serum were tested for influenza-neutralizing Ab. Virus in the lung, nasal wash, and nasal turbinates was quantitated.
Quantitation of virus
Nasal passages were washed with MEM containing 1% FBS. To isolate nasal turbinates, the lower jaw was cut off, and the facial skin was stripped from the head. The nose part was cut from the rest of the head along the line of both eye balls. The tip of the nose area containing the foreteeth was cut off. After the cheek muscles were stripped off, the cheek bones and teeth were removed; the remaining nose part consisted of the nasal turbinate and other nasal tissues. Lungs were also obtained aseptically. Lungs and nasal turbinates were homogenized in vials containing 1-µm glass beads using a Minibeadbeater (Biospec Products, Bartlesville, OK) as previously described 53 . Virus was quantitated by growth in Madin-Darby canine kidney (MDCK) cell cultures 53 . Briefly, 0.7 log10 dilutions starting at 1/5 of lung specimens were made in serum-free MEM, and 0.2 ml of each dilution was inoculated in quadruplicate into 96-well tissue culture plates containing a monolayer of MDCK cells. Twenty-four hours later, 2 µg/ml of trypsin (Worthington Biochemical, Freehold, NJ) was added to each well. After incubation for 5 days at 37°C, 0.05 ml of 0.5% chicken erythrocytes was added to each well. Virus titers were expressed as the reciprocal of the last dilution exhibiting hemagglutination.
Neutralizing Ab tests
Influenza virus-specific neutralizing Ab was determined as previously described 53 . Briefly, MDCK cells were allowed to adhere in microtiter wells at 37°C for 4–6 h before aspiration of medium. Serial dilutions of sera or mAb in 0.05 ml of serum-free MEM were incubated with 100 50% tissue culture infectious doses of influenza virus at room temperature for 1 h. The serum-virus mixture was then transferred to the MDCK monolayer plates and incubated at 37°C. Trypsin was added at 2 µg/ml of trypsin after 24 h. The level of influenza virus-specific neutralizing Ab was determined by the inhibition of virus-induced hemagglutination of chicken RBC 5 days later.
Ag-specific and isotype-specific ELISA assays
Secretions and serum were analyzed for Ag specificity and isotype (IgM, IgG, or IgA) using Ag-coated ELISA plates and isotype-specific anti-Ig Abs, similar to previously described methods 48, 54 . In brief, ELISA grade polystyrene microtiter plates were coated with Ag (2.5 µg/ml) or goat anti-mouse IgM, IgG, or IgA (5 µg/ml) in PBS and left overnight at 4°C. The plates were then washed three times with PBS and blocked with 1% BSA in PBS for 2 h at 37°C. Plates were again washed with PBS/0.25% Tween, and dilutions of serum or secretions to be tested were added to wells and incubated at 37°C for 2 h. Next, the plates were washed with PBS/Tween and incubated with appropriately diluted alkaline phosphatase-conjugated goat anti-mouse IgM, IgG, or IgA. Finally, the plates were washed, substrate (p-nitrophenylphosphate in diethanolamine) was added, and the plates were allowed to develop, then were read in an ELISA reader. Ab titers were determined by end-point titration (i.e., the final dilution at which the OD value remained 2 SDs above the mean value of control samples). The Ag-specific IgM, IgG, or IgA secretory Ab titers were expressed as a ratio of the titer of specific Ab to total IgM, IgG, or IgA, respectively, that was present in serum or secretions to correct for varying amounts of total Ig in secretions or sera of individual mice and for variations in the amount of secretions collected.
ELISA for IFN-
and IL-4
Supernatants from day 3 and day 6 CTL cultures were harvested
and tested for the presence of IFN- and IL-4 using a commercial
ELISA kit (BioSource, Camarillo, CA) or a modification of the sandwich
ELISA method 55 . Briefly, 96-well vinyl plastic plate (Nunc-Immuno
Plate MaxiSorp, Nunc, Naperville, IL) wells were coated with 100 µl
of solution (Pierce Coating Buffer, Pierce, Rockford, IL) containing
0.5–2 µg/ml of capture monoclonal rat anti-murine IFN- or
IL-4 Ab (PharMingen, San Diego, CA). The plates were incubated
overnight at 4°C and washed four times with Tris-NaCl buffer
containing 0.05% Tween-20 (Tris-NaCl-Tween) using an automatic
Titertek Microplate Washer (ICN Biomedicals, Costa Mesa, CA). After
blocking for 1 h with SuperBlock buffer in TBS (Pierce) and
washing four times, serial dilutions of recombinant murine IFN- and
IL-4 standards and undiluted test samples were added to the wells in
quadruplicate, and the plates were incubated at 37°C for 1 h.
After four washes, 100 µl of biotinylated rat anti-murine IFN-
or IL-4 Ab (0.0–2 µg/ml in SuperBlock) was added and incubated at
37°C for 1 h. The plates were washed, and 100 µl of
streptavidin alkaline phosphatase (Pierce) was added to each well;
wells were incubated at 37°C for 1 h and then washed four times.
Substrate (one or two tablets of 
-nitrophenol phosphate per 10 ml of
diethanolamine buffer, pH 9.8) was then added, and color was allowed to
develop for 10–120 min. Absorbance in each well was read at a
wavelength of 405 nm using a Molecular Devices automatic microplate
reader (Menlo Park, CA). The data were collected in a SOFTmax data
reduction software. Murine recombinant IFN- and IL-4 were used to
generate standard curves. The amount of cytokine in the test samples
was extrapolated from the standard curves and expressed as picograms
per milliliter of cytokine.
Generation of secondary CTL response and 51Cr release assay for CTL
Influenza A virus-specific CTL were generated by stimulating splenic lymphocytes with virus-infected autologous cells for 6 days. The effector cells so generated were assayed for cytotoxicity against virus-infected target cells in a 4-h chromium release assay as previously described 51, 53 .
Statistical analysis
Differences in cumulative mortality among different groups were
determined by the 
2 test using TRUE EPISTAT statistical
software (Epistat Services, Richardson, TX). Comparisons of geometric
mean titer (GMT) for virus and Ab titers, mean cytokine levels
(picograms per milliliter), and stimulation indexes between groups were
made with a two-tailed Student’s t test procedure in
ANOVA using the Statistical Analysis System (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether IgA-/- deficiency
rendered these mice intrinsically more susceptible to influenza virus
infection and disease, two experiments were performed. First, naive
IgA-/- and IgA+/+
littermates (16–20 wk old) were infected with a sublethal (0.1
LD50) dose of A/Taiwan/1/86 virus by SPA. Four and fifteen
days later, four mice per group were killed by CO2
inhalation. The lungs were harvested, and the levels of virus
replication were determined. Influenza A virus replicated to the same
peak levels on day 4 in both groups of mice and declined at identical
rates to similar titers 15 days later (Fig. 1
A). In the second experiment
mice were infected with a lethal (3.0 LD50) dose of virus
by SPA. Cumulative mortality was recorded for 14 days. Both groups of
mice were killed by the lethal influenza virus infection at the same
rate (Fig. 1B). These results suggest that
IgA-/- KO mice were not more susceptible to
influenza virus infection and mortality than normal
IgA+/+ littermates. They also cleared virus
infection normally.
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(Th1) and IL-4 (Th2) secretion by ELISA and mRNA expression for the
same cytokines showed similar patterns among
IgA-/- and IgA+/+ mice
(data not shown). Requirement for induction of IgA for protection of mucosal sites
To determine whether the induction of Ag-specific IgA at mucosal
sites is required for protection against influenza virus infection, two
experiments were performed. Firstly, IgA-/- and
IgA+/+ mice were immunized and boosted 3 wk later
by coadministration of 2 µg of influenza A/Taiwan/1/86 virus SV and
CTB/CT (20 ng/2 µg) i.n. or i.p., a regimen previously shown to
induce mucosal IgA 50 . Two weeks after the second inoculation, three
or four mice per group were bled for serum, then killed, and the
nasopharynx was washed. Serum and mucosal influenza A/Taiwan-specific
IgA, IgG, and IgM Abs were determined. Influenza SV plus CTB/CT induced
significant influenza HA-specific IgA in the nasal wash of
IgA+/+ (but not IgA-/-)
mice and IgG and IgM Abs in both IgA-/- and
IgA+/+ mice (Table I). As expected, i.n. immunization
stimulated a significantly higher level of IgA in the nasal wash
specimen than i.p. immunization among IgA+/+
mice. Interestingly, IgA-/- mice may have
compensated for IgA deficiency by producing a markedly higher level of
IgG than IgA+/+ mice (p =
0.09) in mucosal sites as well as in systemic sites after i.n.
immunization 24, 25 . The higher than expected IgG levels in
IgA+/+ mice following i.p. immunization are most
likely due to one mouse that exhibited an extremely high level of IgG
Ab compared with others in the same group.
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A). Influenza SV and CTB/CT
stimulated significant protection from influenza mortality among both
IgA-/- and IgA+/+ mice
compared with CTB/CT alone (Fig. 2, B and C).
Both IgA-/- and IgA+/+
mice immunized i.p. with influenza SV and CTB/CT also exhibited
significant reductions in lung virus replication on days 4 and 8. Both
immunized IgA-/- and
IgA+/+ mice were completely protected from death
(Fig. 2, B and C). Unimmunized control (CTB/CT)
IgA-/- mice exhibited a higher level of
mortality (88 vs 63%) and virus replication than
IgA+/+ control mice. However, the differences
were not significant.
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). Virus replication in the nasal
turbinates was unchanged in both IgA-/- and
IgA+/+ mice, while nasal wash virus was barely
detectable at 24 h. Forty-eight hours following virus challenge,
the level of virus in the lungs of both IgA-/-
and IgA+/+ mice was significantly reduced among
immunized mice compared with that in unimmunized controls
(p < 0.00001). Virus replication was also
significantly reduced in the nasal turbinates of immunized
IgA-/- (p < 0.01) and
IgA+/+ (p < 0.001) mice.
Interestingly, influenza vaccination reduced nasal wash virus to
undetectable levels in both IgA-/-
(p < 0.01) and IgA+/+
(p < 0.1) compared with that in unimmunized
mice. Immunization with influenza vaccine resulted in a higher level of
virus reduction among IgA+/+ mice compared with
IgA-/- mice. A tendency toward a higher level
of virus among unimmunized IgA+/+ mice compared
with IgA-/- mice may explain this
discrepancy.
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To directly determine the Ig classes or subclasses that could
mediate protection against local influenza virus challenge, naive
IgA-/- mice were administered i.p. mAbs
containing 4-log10 virus-neutralizing units of activity
against influenza A/PR/8/34 virus as previously described by Gerhard
and co-workers 42 . Four hours later, treated mice were challenged
with 50 MID50 of influenza A/PR/8/34 virus by small
particle aerosol. Figure 4 shows the
distribution of virus-neutralizing activity of transferred mAb in three
representative mice sacrificed 4 h after transfer. Serum from mice
administered influenza virus-specific pIgA, mIgA, IgM, or IgG1 mAb
exhibited significant neutralizing activity against influenza A/PR/8/34
virus. In addition, all four mAbs, except mIgA, had transuded or
transcytosed to the lungs and nasal turbinates, while only pIgA and IgM
exhibited some activity in the nasal passages. Significant serum
virus-neutralizing activity was also detected at 24 and 48 h
postchallenge for all mAbs except IgM, which declined significantly,
possibly due to its short half-life 42 . None was detected in the
nasal wash specimens.
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A). Administration of
IgA-/- mice with IgG2a mAb also resulted in
significant reduction of pulmonary virus (p <
0.05) 24 h following virus challenge (Fig. 5B). In
addition, pIgA, IgG1, and IgG2a prevented further replication of virus
(curing of virus infection), as indicated by further reduction of virus
titer determined 48 h after virus challenge. It is noteworthy that
only pIgA and IgG2a exhibited any efficacy in reducing virus titers in
the nasal turbinates and passages (nasal wash).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4 and
virus-specific CD8+ CTL activity, indicative of their
immunocompetence. The importance of IgA Ab in susceptibility to influenza virus infection and disease and in preventing influenza infection was determined using three approaches. The first approach tested the hypothesis that if IgA plays an important role in the infectivity of the upper respiratory tract with influenza virus, then naive IgA-/- mice will be more susceptible to influenza infection than control IgA+/+ littermates. The results show that the level of pulmonary virus replication and the rate of clearance were similar in naive IgA-/- mice and their heterozygous normal IgA+/+ littermates infected with a sublethal dose (0.1 LD50) of influenza A/Taiwan/1/86 (H1N1) virus by SPA. In addition, IgA deficiency did not render these mice more susceptible to severe influenza disease and mortality because the levels of cumulative mortality among IgA-/- KO and wild-type IgA+/+ mice infected with a lethal dose (3.0 LD50) of A/Taiwan/1/86 virus by SPA were similar. The results reported above also suggest that IgA does not play a role in attenuation of influenza disease. Recent LD50 titration in both groups of mice reveal similar susceptibility to influenza mortality (data not shown).
The second approach tested the hypothesis that if selective induction of Ag-specific IgA at mucosal sites is required for protection against influenza virus infection, then mucosal immunization with influenza vaccines will be more effective in IgA+/+ than IgA-/- mice. To determine whether the induction of virus-specific IgA Ab was essential for protection against influenza infection and disease, IgA-/- along with wild-type control nontargeted littermate IgA+/+ mice were immunized with influenza SV with a combination of CTB/CT, a regimen that stimulated significant mucosal and serum IgA, IgG, and IgM Abs in normal mice and IgG and IgM in IgA-/- mice. Following challenge with a lethal (3 LD50) dose of influenza virus by small particle aerosol, the levels of virus replication in the nasopharynx, nasal turbinate, and lung were similar. In addition, the protective efficacy of the influenza vaccine-CTB/CT regimen was similar among IgA-/- and IgA+/+ mice. These results suggest that IgA was not essential for preventing viral infection, a reduction in the severity of disease, or both. These results were further confirmed by challenging IgA-/- and IgA+/+ mice immunized with influenza SV as described above with 50 MID50 of influenza A/Taiwan by aerosol to test the effect of immunization on a less overwhelming virus load. Again, the levels of virus in the lung, nasal turbinate, and nasal cavity determined 24 and 48 h later showed that the influenza vaccine-CBT/CT regimen prevented virus infection to the same extent in IgA-/- and IgA+/+ mice. Furthermore, the results showed that while virus replication increased in control mice that received CTB/CT 48 h following challenge, influenza vaccine-CTB/CT regimen either prevented a further increase in virus titer or completely suppressed their replication in the nasal passages. No differences were demonstrated between IgA-/- and IgA+/+ mice.
The final approach was to determine definitively whether passive immunization with influenza-specific pIgA was more effective than other isotypes for prevention of influenza infection in IgA-/- mice. Challenge of IgA-/- mice passively transferred with influenza A/PR/8/43 virus HA-specific mAb of pIgA, mIgA, IgG1, IgG2a, or IgM before challenge with A/PR/8/34 virus demonstrated that IgG1, IgG2a, and IgM as well as pIgA isotypes were all effective in preventing virus infection to varying degrees in the lung, nasal turbinate, and nasal passages. More importantly, IgG2a and to some extent IgG1 exhibited a similar virus-curing capacity as pIgA by preventing further virus replication, particularly in the lung.
The present results are in partial agreement with those of other studies 7, 8, 42 ; namely, 1) mAbs of the pIgA, mIgA, IgM, IgG1, and IgG2a isotypes were effective in preventing (or at least reducing) influenza virus infection; and 2) pIgA, but not mIgA, is most efficiently transcytosed to the mucosal surfaces, where they prevent or reduce virus infection. The present data suggest that in addition to IgG1 and IgG2a, pIgA was somewhat effective in "curing" virus infection. The present results are in agreement with two previous studies that demonstrated that passively transferred pIgA (but not mIgA) prevented mucosal influenza virus infections 7, 8, 42 ; these results also show, however, that IgG1 could protect against mucosal influenza infection in contrast to one of the studies 7, 8 . The difference in results may be due to the different modes of infection employed in the two studies. In those studies, mice were infected by small volume i.n. inoculation, which deposited virus initially in the nasal passages 7, 8 , while in the present study, as in that by Palladino et al. 42 , mice were infected by aerosolization, which deposited virus in both the lungs and nasal passages. Nonetheless, the passive transfer results, in which neutralizing Ab activity was detected in the lungs and nasal passages, suggest that IgG1 and IgG2a were equally as effective as pIgA in preventing virus infection and inhibiting replication in those compartments. Our results are further supported by a previous study showing that passive immunization with purified influenza HA-specific IgG was as effective as IgA in preventing homotypic influenza virus infection in normal mouse respiratory tract even though IgA was more effective against heterotypic challenge 40 .
This study has presented very compelling evidence that IgA may not be required for prevention of influenza virus infection and disease. This is supported by the fact that not all IgA-deficient subjects suffer from persistent respiratory infections 22, 23 . A recent study showed that J chain KO mice were readily protected from influenza virus infection, indicating that pIgA receptor-mediated transport is not required 56 as suggested by other studies. Similar results were obtained in showing that IgA was not required for protection against Helicobacter pylori infection in the gut 57 .
The present results have strong implications regarding strategies for stimulating selective induction of IgA in the mucosa. Since the i.p. immunization in the present studies was as or more effective than i.n. immunization in protecting the mucosa, and IgG2a protected equally well as IgA, one can argue that efforts should be directed at optimizing well-established systemic immunization strategies that induce both mucosal and systemic Abs, some of which can transudate and confer protection at the mucosal surfaces. Such an approach may include increasing the dose of Ags used for i.m. immunization. One recent study clearly showed that a ninefold increase in the dose of influenza virus vaccine was very effective in stimulating strong systemic as well as mucosal IgG and IgA Ab responses in young volunteers 58 . Influenza virus infection affects the upper respiratory (where IgA predominates) and lower respiratory (where IgG predominates) tracts, and MHC class I-restricted CD8+ cytotoxic T cells have been demonstrated to also mediate the clearance of viral infection. In principle, therefore, vaccination strategies that stimulate multiple Ab isotypes rather than being targeted exclusively to one isotype and that also induce CD8+ CTL responses represent the best approach for control of influenza virus infection and disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Innocent N. Mbawuike, Department of Microbiology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. E-mail address:
3 Current address: Immunology, Clinical Research, Centocor, 200 Great Valley Parkway, Malvern, PA 19355.
4 Abbreviations used in this paper: S-IgA, secretory IgA; CT, cholera toxin holoenzyme; CTB, cholera toxin B subunit; HA, hemagglutinin; pIgA, polymeric IgA; mIgA, monomeric IgA; KO, knockout; ES, embryonic stem; i.n., intranasal; SV, subunit vaccine; SPA, small particle aerosol; MID50, minimum 50% infectious dose; MDCK, Madin-Darby canine kidney; GMT, geometric mean titer.
Received for publication July 8, 1998. Accepted for publication December 3, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Y. Asahi, T. Yoshikawa, I. Watanabe, T. Iwasaki, H. Hasegawa, Y. Sato, S.-i. Shimada, M. Nanno, Y. Matsuoka, M. Ohwaki, et al. Protection Against Influenza Virus Infection in Polymeric Ig Receptor Knockout Mice Immunized Intranasally with Adjuvant-Combined Vaccines J. Immunol., March 15, 2002; 168(6): 2930 - 2938. [Abstract] [Full Text] [PDF]
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A. W. Zuercher, S. E. Coffin, M. C. Thurnheer, P. Fundova, and J. J. Cebra Nasal-Associated Lymphoid Tissue Is a Mucosal Inductive Site for Virus-Specific Humoral and Cellular Immune Responses J. Immunol., February 15, 2002; 168(4): 1796 - 1803. [Abstract] [Full Text] [PDF]
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K. J. Silvey, A. B. Hutchings, M. Vajdy, M. M. Petzke, and M. R. Neutra Role of Immunoglobulin A in Protection against Reovirus Entry into Murine Peyer's Patches J. Virol., November 15, 2001; 75(22): 10870 - 10879. [Abstract] [Full Text] [PDF]
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 C. Pilette, Y. Ouadrhiri, V. Godding, J-P. Vaerman, and Y. Sibille Lung mucosal immunity: immunoglobulin-A revisited Eur. Respir. J., September 1, 2001; 18(3): 571 - 588. [Abstract] [Full Text] [PDF]
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K. A. Benton, J. A. Misplon, C.-Y. Lo, R. R. Brutkiewicz, S. A. Prasad, and S. L. Epstein Heterosubtypic Immunity to Influenza A Virus in Mice Lacking IgA, All Ig, NKT Cells, or {{gamma}}{{delta}} T Cells J. Immunol., June 15, 2001; 166(12): 7437 - 7445. [Abstract] [Full Text] [PDF]
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N. A. Kuklin, L. Rott, N. Feng, M. E. Conner, N. Wagner, W. Muller, and H. B. Greenberg Protective Intestinal Anti-Rotavirus B Cell Immunity Is Dependent on {{alpha}}4{{beta}}7 Integrin Expression But Does Not Require IgA Antibody Production J. Immunol., February 1, 2001; 166(3): 1894 - 1902. [Abstract] [Full Text] [PDF]
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K. B. Renegar, C. D. Johnson, R. C. Dewitt, B. K. King, J. Li, K. Fukatsu, and K. A. Kudsk Impairment of Mucosal Immunity by Total Parenteral Nutrition: Requirement for IgA in Murine Nasotracheal Anti-Influenza Immunity J. Immunol., January 15, 2001; 166(2): 819 - 825. [Abstract] [Full Text] [PDF]
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B. P. Arulanandam, R. H. Raeder, J. G. Nedrud, D. J. Bucher, J. Le, and D. W. Metzger IgA Immunodeficiency Leads to Inadequate Th Cell Priming and Increased Susceptibility to Influenza Virus Infection J. Immunol., January 1, 2001; 166(1): 226 - 231. [Abstract] [Full Text] [PDF]
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T. K. Warren, K. A. Mitchell, and B. P. Lawrence Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Suppresses the Humoral and Cell-Mediated Immune Responses to Influenza A Virus without Affecting Cytolytic Activity in the Lung Toxicol. Sci., July 1, 2000; 56(1): 114 - 123. [Abstract] [Full Text] [PDF]
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C. M. O'Neal, G. R. Harriman, and M. E. Conner Protection of the Villus Epithelial Cells of the Small Intestine from Rotavirus Infection Does Not Require Immunoglobulin A J. Virol., May 1, 2000; 74(9): 4102 - 4109. [Abstract] [Full Text]
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S.-i. Shimada, M. Kawaguchi-Miyashita, A. Kushiro, T. Sato, M. Nanno, T. Sako, Y. Matsuoka, K. Sudo, Y.-i. Tagawa, Y. Iwakura, et al. Generation of Polymeric Immunoglobulin Receptor-Deficient Mouse with Marked Reduction of Secretory IgA J. Immunol., November 15, 1999; 163(10): 5367 - 5373. [Abstract] [Full Text] [PDF]
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