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*
Center for Immunology and Microbial Disease Research, Albany Medical College, Albany, NY 12208;
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106; and
Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595
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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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The precise role of IgA in anti-influenza immunity has recently been investigated using mice with a targeted disruption in IgA gene expression (IgA-/- mice) (2). IgA-/- and IgA+/+ mice immunized with an influenza subunit vaccine in the presence of cholera toxin B subunit (CTB)3 and whole cholera toxin (CT) were equally protected against subsequent influenza virus infection. Based on these observations, the authors suggested that IgA-mediated protection was not essential for immunity against influenza virus. However, the effects of vaccination in the absence of an added immunostimulatory agent were not investigated in this study. It is possible that the use of CTB and CT, which are potent mucosal adjuvants, masked the requirement for IgA in mediating protective anti-influenza immunity.
It is likely that there is another unrecognized function for IgA at
mucosal sites in addition to simple neutralization of pathogenic
organisms. Accumulating evidence suggests that cognate IgA-Fc
R
interactions are an important component of host defense. FcR have
been identified on phagocytic cells and are thought to enable
phagocytic cells to augment the protective effects of IgA (3, 4). In fact, IgA-mediated phagocytosis of Streptococcus
pneumoniae has been demonstrated with murine alveolar macrophages
(5).
Using IgA-/- mice, we have now demonstrated a novel role for IgA in mediating protection against influenza virus infection. Our results show that IgA-/- mice exhibit an intrinsic defect in Th cell priming and are highly susceptible to influenza virus infection upon immunization in the absence of an adjuvant. Inclusion of IL-12 during vaccination can overcome this deficiency by providing adequate Th cell priming.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 x 129 IgA-/- mice were generated as described previously (6) and genetically matched IgA+/+ mice were used as controls. Mice were bred and housed in the animal facility at Albany Medical College and provided food and water ad libitum. Animal care and experimental procedures were performed in compliance with the Institutional Animal Care and Use Committee guidelines.
Virus infection
Intranasal treatments were performed as described previously
(7, 8). Briefly, IgA-/- and
IgA+/+ mice were anesthetized i.p. with a
combination of ketamine HCl (Fort Dodge Laboratories, Fort Dodge, IO)
and xylazine (Bayer, Shawnee Mission, KA). Mice were immunized
intranasally (i.n.) on day 0 with 25 µl of sterile PBS containing 1
µg of subunit influenza vaccine which consisted of soluble
hemagglutinin subtype 1 (H1) and neuraminidase subtype 1 (N1) purified
from influenza virus A/PR8/34. This was followed on days 0, 1, 2, and 3
with i.n. inoculation of 1 µg of recombinant murine IL-12 (Genetics
Institute, Cambridge, MA) in PBS containing 1% normal mouse serum
(PBS-NMS) or in the case of control mice, with PBS-NMS only. Some mice
received only IL-12 in PBS-NMS or only PBS-NMS (no H1N1 subunit
vaccine). The dose of Ag chosen was based on previous experiments in
BALB/c mice (8) and no toxicity was observed with this
treatment regimen. Approximately 4–5 wk after primary immunization,
viral challenge was performed with 103 PFU of
infectious A/PR8/34 influenza virus administered i.n. to anesthetized
mice in 40 µl of sterile PBS. The mice were weighed daily and
monitored for morbidity and mortality. Survival data were analyzed
using a log rank test and compared by 
2
analysis.
Collection of bronchoalveolar lavage (BAL) fluid
BAL fluid was collected essentially as described elsewhere (7, 8). Briefly, mice were sacrificed and their tracheas were intubated using a 0.58-mm OD polyethylene catheter (Becton Dickinson, Sparks, MD). The lungs were then lavaged two to three times with PBS containing 5 mM EDTA. The recovered BAL fluid was centrifuged at 12,000 x g for 5 min at 4°C and the supernatant was stored at -70°C until use.
Analysis of Ab and isotype expression by ELISA
For examination of Ab expression, mice were immunized i.n. on days 0, 14, and 28 with 25 µl of PBS containing 1 µg of H1N1 subunit influenza vaccine. This was accompanied on days 0, 1, 2, 3, and 28 by i.n. inoculation of 1 µg of IL-12 in PBS-NMS or of PBS-NMS only. Anti-H1N1 levels in serum and BAL fluid were determined by ELISA essentially as described previously (8). Microtiter plates (Nalge Nunc International, Rochester, NY) were coated overnight with 1 µg/ml H1N1 in PBS. The plates were washed with PBS containing 0.3% Brij-35 (Sigma, St. Louis, MO) and blocked for 1 h at room temperature with PBS containing 5% FCS (HyClone, Logan, UT) and 0.1% Brij-35. Serial dilutions of serum or undiluted BAL were added and the plates were incubated for 2 h at room temperature. The plates were washed and incubated with goat anti-mouse total Ig, IgG1, IgG2a, IgG2b, IgM, or IgA conjugated to alkaline phosphatase (Southern Biotechnology Associates, Birmingham, AL). After incubation for 1 h, the plates were washed and p-nitrophenyl phosphatase substrate was added to obtain color development. Plates were read at 405 nm with an ELISA microplate reader (Bio-Tek Instruments, Winooski, VT). In all cases, appropriate working dilutions and isotype specificities of the secondary Ab conjugates were determined using purified myeloma proteins of known isotypes (Sigma). Statistical significance was determined using the Mann-Whitney U test. Data were considered statistically significant if p values were < 0.05 using 50% end point titers for sera. Because of the low amounts of Ab in BAL fluids and the large dilution involved in the lavage procedure, titers could not be obtained for BAL and all samples were tested undiluted.
Lymphocyte proliferation assay
For in vitro lymphoproliferative responses, spleen cells (2 x 105 cells/well) were stimulated in 96-well microtiter plates with 10 µg/ml PHA with or without IL-12 (5 ng/ml or 50 ng/ml as specified in Results) in RPMI 1640 supplemented with 10% (v/v) FCS (HyClone), 1 mM sodium pyruvate (Life Technologies, Gaithersburg, MD), 4 mM L-glutamine (Life Technologies), and 10 µg/ml gentamicin (Sigma). The cultures were maintained at 37°C for 72 h, pulsed with [3H]TdR (1 µCi/well; ICN Radiochemicals, Irvine, CA) for 18 h and harvested onto glass fiber filters using a semiautomatic harvester (Tomtec Harvester 96; Tomtec, Hamden, CT). Incorporated [3H]TdR was measured using a beta scintillation counter (1450 Microbeta Trilux, EG&G Wallac, Turku, Finland). Statistical significance was determined by Student’s t test.
IFN-
expression
IFN- expression in PHA-stimulated cultures was measured by
RT-PCR as previously described (7, 9) and by ELISA using
microtiter plates (Costar, Cambridge, MA) that were coated overnight
with 100 µl of anti-IFN- mAb (2 µg/ml; clone R4-6A2).
Following washing, the wells were blocked with 10% FCS in PBS. Serial
dilutions of culture supernatants and recombinant murine IFN-
standards were added to the wells and the plates were incubated
overnight at 4°C. The plates were subsequently washed and incubated
for 1 h at room temperature with 100 µl of biotinylated
detection mAb (0.5 µg/ml anti-IFN-, clone XMG1.2). The plates
were again washed and incubated with streptavidin-peroxidase conjugate
(Sigma) for 2 h at room temperature. After incubation for 1
h, the plates were washed and 2,
2'-azino-di-(3-ethylbenzthiazoline-6-sulfonate) substrate (Kirkegaard &
Perry, Gaithersburg, MD) was added to obtain color development. Plates
were read at 630 nm with an ELISA microplate reader (Bio-Tek
Instruments).
In vitro recall response to H1N1 subunit vaccine
Six- to 8-wk-old IgA-/- and IgA+/+ mice were immunized i.p. with 10 µg of H1N1 emulsified in CFA (Life Technologies). Two weeks after priming, spleens were removed and single-cell suspensions were prepared. T cells were enriched by depletion of B cells on anti-Ig-coated plates (10). Irradiated (3000 rad) spleen cells from unvaccinated IgA-/- and IgA+/+ mice were used as APCs. Enriched T cells (5 x 104 cells/well) and APCs (2.5 x 105 cells/well) were cultured along with H1N1 (1 or 10 µg/ml) with or without 5 ng/ml IL-12 in RPMI 1640 supplemented with 10% FCS. After 72 h, the cultures were assayed for proliferation by [3H]TdR incorporation. Only background levels of [3H]TdR incorporation were observed when the enriched T cells were incubated alone, with IL-12 only, or with H1N1 in the absence of added APCs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It was previously reported that IgA-/-
mice have the same susceptibility as IgA+/+ mice
to lethal doses of influenza virus after no pretreatment or after
vaccination in the presence of CT and CTB as adjuvants
(2). We similarly found that unvaccinated
IgA+/+ and IgA-/- mice
were equally susceptible to infection (Fig. 1
; PBS treatment group). However, i.n.
vaccination with soluble H1N1 in the absence of adjuvant revealed a
major difference between IgA-/- and
IgA+/+ animals. Challenge of these mice with
influenza virus 5 wk after immunization resulted in 75% survival of
IgA+/+ animals but only 13% survival among
IgA-/- animals (Fig. 1). Inclusion of IL-12 as
a mucosal adjuvant during vaccination (8) restored the
protective efficacy of the H1N1 vaccine such that 63% of
IgA-/- mice survived the challenge compared
with 75% of IgA+/+ mice. In mice that survive
virus challenge in this manner, there is typically no detectable virus
remaining in the lungs (8). Treatment with IL-12 only did
not lead to significant changes in overall survival rates, which is
consistent with our previous findings with BALB/c animals
(8). These results demonstrate that IgA deficiency results
in decreased effectiveness of vaccination and enhanced susceptibility
to respiratory infection. Nevertheless, this susceptibility can be
overcome by coadministration of appropriate immunostimulatory molecules
such as CT or IL-12 during vaccination.
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Protection against influenza challenge in vaccinated animals
treated with IL-12 is due to anti-influenza Ab (8). To
examine the mechanisms responsible for the observed differences in
protection between IgA-/- and
IgA+/+ mice, sera and BAL fluids were thus
analyzed for expression of anti-H1N1 Abs of defined isotypes.
IgA+/+ mice produced serum anti-H1N1 Abs of
all isotypes and the titers of these tended to be increased by IL-12
treatment, consistent with our previous findings (Fig. 2) (7, 8, 9, 11). A small
decrease in serum IgA expression was seen in
IgA+/+ mice due to IL-12 treatment, but this
decrease was not statistically significant. The same patterns were
observed in IgA-/- mice except that, as
expected, H1N1-specific IgA was not detected in the sera of
IgA-/- mice. Our results are essentially
identical to those obtained by Mbawuike et al. (2),
including a relatively large variation in responsiveness of individual
mice to H1N1 vaccination, which is likely attributable to the mouse
strain used.
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). In addition,
IgA-/- mice vaccinated in the presence of IL-12
had enhanced IgM Ab levels compared with IgA+/+
mice treated in the same fashion. Thus, IgA+/+
and IgA-/- mice did not differ dramatically in
levels of specific Abs (except for IgA) but IL-12 treatment clearly had
a stronger enhancing influence in IgA-/-
animals.
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We also examined the proliferative responses of spleen cells from
naive IgA-/- and IgA+/+
mice to T cell mitogens. It was found that
IgA-/- mice had a significant decrease in the
in vitro proliferative response to PHA compared with
IgA+/+ mice (Fig. 4A). Addition of IL-12 to
IgA-/- spleen cell cultures reconstituted the
proliferative responses to wild-type levels. Since IL-12 is a potent
inducer of IFN-, IFN- expression was analyzed after in vitro
stimulation. RT-PCR analysis of PHA-stimulated
IgA+/+ and IgA-/- cells
revealed low levels of IFN- expression that was increased by
exposure to IL-12 (Fig. 4B). IFN- protein levels in the
supernatant fluids were comparable between IgA+/+
and IgA-/- PHA-stimulated cultures (Fig. 4C). Of note, this assay revealed that
IgA-/- spleen cells were much more responsive
to IL-12 than IgA+/+ cells, with a 2-fold
difference in IFN- production between IL-12-stimulated
IgA-/- and IgA+/+ spleen
cell cultures.
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To examine Ag-specific T cell responses to H1N1 in
IgA-/- and IgA+/+ mice,
in vitro recall proliferative assays were performed using enriched T
cells from immunized animals and irradiated APCs from naive animals.
H1N1-primed T cells from IgA+/+ animals were
incubated with APCs isolated from IgA-/- or
IgA+/+ mice. Interestingly, it was found that
IgA+/+ primed T cells cultured with
IgA-/- APCs had a significant reduction in
proliferation compared with T cells cultured with
IgA+/+ APCs (Fig. 5). Addition of IL-12 to the former
cultures reconstituted responsiveness to the levels seen in cultures of
T cells and IgA+/+ APCs. Converse experiments
revealed that in all cases, T cells from H1N1-primed
IgA-/- animals lacked memory responses to the
recall Ag regardless of whether they were incubated with
IgA+/+ or IgA-/- APCs. If
T cells from IgA-/- mice were inadequately
primed in vivo due to an APC defect, this is the result that would be
expected, i.e., a diminished secondary in vitro response even in the
presence of functional APCs. Similarly reduced memory responses in
IgA-/- mice were seen after vaccination with
other protein Ags such as OVA (data not shown). These results
demonstrate the existence of an intrinsic dysfunction in
IgA-/- APCs during mucosal priming with Ag. As
a result of this impairment, IgA-/- animals
have significantly lower memory T cell responses compared with
IgA+/+ animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Unimmunized IgA-/- and IgA+/+ animals had similar susceptibility to influenza virus infection. However, upon i.n. vaccination with soluble H1N1 subunit vaccine in the absence of adjuvant, IgA-/- animals were not protected against influenza virus infection. Inclusion of IL-12 during immunization restored protective immunity to the levels observed in IgA+/+ mice. Mbawuike et al. (2) recently reported that IgA is not necessary for prevention of influenza virus infection. In their study, IgA-/- mice vaccinated with a subunit vaccine in the presence of CTB and CT were found to be completely protected from subsequent influenza virus challenge. Like the present study, they used an H1N1 influenza virus; therefore, differences in antigenic recognition are unlikely to account for the differing results between the two studies. However, Mbawuike et al. (2) did not examine the protective efficacy of vaccination in the absence of CTB or CT. Both of these immunomodulators are potent mucosal adjuvants and therefore may have masked the need for IgA to achieve appropriate immune cell priming. In our studies, vaccination was performed in the absence of an adjuvant and, under these conditions, IgA-/- mice were found to be highly susceptible to influenza virus infection, demonstrating the need for IgA in protective antiviral immunity.
Others have also examined the role of IgA in protection against viral infection. Renegar and Small (12, 13) reported that IgA Abs in nasal secretions are the sole mediators of immunity to influenza virus infection in unimmunized mice. However, Gerhard and colleagues (14) found that IgG but not IgA or IgM Abs were able to cure influenza virus pneumonia. IgA was also reported not to be essential in protective immunity against other mucosal pathogens such as Helicobacter pylori and rotavirus (15, 16). However, using a ligated intestinal loop model to evaluate the ability of IgA to neutralize CT toxicity, Lycke et al. (17) found that IgA-/- mice display significant toxicity. Although these animals had elevated levels of anti-CT IgM Abs in the gut, this was not sufficient to provide functional protection.
The basis for increased susceptibility of IgA-/- mice to influenza virus was analyzed by in vitro lymphoproliferative responses. It was found that IgA-/- mice exhibited depressed proliferative responses upon stimulation with PHA, and these responses were reconstituted to normal levels with IL-12. Flow cytometric analysis revealed that IgA-/- mice had similar levels of CD3+ and B220+ lymphocytes in the splenic compartment compared with IgA+/+ animals (B. P. Arulanandam, V. C. Huber and D. W. Metzger, unpublished observations). This would suggest that the decreased proliferative responses observed in the IgA-/- mice were not due to skewed lymphocyte populations within the splenic compartment. However, further assessment of IgA-/- mice revealed a major impairment of APC function. This dysfunction could be overcome with IL-12, suggesting that the APCs in the IgA-/- animals were not sufficiently activated to allow adequate priming of memory T cells. Although IL-12 is known to also activate cytolytic T cells, such T cells are likely to be involved in recovery from infection whereas antiviral Ab is important for protection in immunized animals treated with IL-12 (8).
In humans, IgA deficiency is the most common immunodeficiency and
includes both healthy individuals and those with severe disease
(18, 19). In the latter group, individuals with IgA
deficiency have a greater predisposition to autoimmune and atopic
diseases (20, 21, 22). Interestingly, T cell immunity can also
be affected in IgA-deficient individuals. In fact, Ammann and
colleagues (23) found a marked reduction in the
proliferative responses of lymphocytes from IgA-deficient children to
PHA stimulation. IFN production in response to T cell mitogens was also
reported to be depressed in IgA-deficient individuals
(24). Our results would strongly suggest that the
impairment of T cell immunity observed in IgA-deficient individuals is
a result of underlying APC defects. Indeed, it was recently found that
the human FcR (CD89) is a functional receptor for effective Ag
presentation (L. Shen, unpublished observation).
It is of interest that splenic lymphocytes from
IgA-/- animals produced 2-fold more IFN-
than IgA+/+ cells in response to IL-12.
Furthermore, we have found increased production of NO from peritoneal
cells of IgA-/- animals stimulated with IL-12
compared with IgA+/+ mice (B. P. Arulanandam
and D. W. Metzger, unpublished observations). The increased
production of these molecules may be a compensatory mechanism for the
absence of IgA and related to the anti-inflammatory properties of
this Ab isotype (1, 25, 26). Experiments are currently in
progress to address the role of IgA in the regulation of inflammatory
responses.
In summary, our results indicate an important role of IgA in APC function and development of antiviral T cell memory. IgA-/- mice vaccinated i.n. with a soluble influenza subunit vaccine alone were highly susceptible to influenza virus infection and exhibited diminished protective immunity. These animals also displayed impaired Th cell priming due to a surprising defect in APC function that could be overcome by IL-12 treatment. Interestingly, it was recently shown by others (27) that B cells are critical for appropriate development of M cells and organogenesis of mucosal immune barriers.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dennis W. Metzger, Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY 12208.
3 Abbreviations used in this paper: CTB, cholera toxin B subunit; BAL, bronchoalveolar lavage; CT, cholera toxin; i.n., intranasal; H1, hemagglutinin subtype 1; N1, neuraminidase subtype 1; NMS, normal mouse serum.
Received for publication July 3, 2000. Accepted for publication October 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R (CD89)-mediated down-regulation of tumour necrosis factor- (TNF-) and IL-6 in human monocytes. Clin. Exp. Immunol 105:537.[Medline]
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