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Published ahead of print on August 11, 2004, doi:10.1164/rccm.200311-1610OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 952-959, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200311-1610OC

Original Article

The Role of Virus-specific Immunoglobulin E in Airway Hyperresponsiveness

Azzeddine Dakhama, Jung-Won Park, Christian Taube, Kosuke Chayama, Annette Balhorn, Anthony Joetham, Xu-Dong Wei, Rhi-Hua Fan, Christina Swasey, Nobuaki Miyahara, Taku Kodama, Alberto Alvarez, Katsuyuki Takeda and Erwin W. Gelfand

Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Azzeddine Dakhama, Ph.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: dakhamaa{at}njc.org


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.

Key Words: airway function • animal model • asthma • IgE • respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most common cause of acute bronchiolitis that occurs during early life and is associated with subsequent development of persistent wheezing and asthma (1–4). Although the nature of this relationship remains to be fully defined, clinical studies have shown that children with severe RSV bronchiolitis requiring hospitalization are at high risk for developing childhood asthma (5–8). Whether RSV infection of the lower respiratory tract by itself can lead to long-term immunologic and physiologic airway dysfunction (the causal hypothesis) or whether such alterations result from a preexisting condition, possibly determined by a predisposing genetic susceptibility that is evoked by RSV infection (the association hypothesis), remains a matter of intense investigation and debate (9–13). Nonetheless, identifying host response factors that may contribute to the pathogenesis of post-RSV wheezing and asthma is critical for establishing a functional association between RSV-induced bronchiolitis and the subsequent development of persistent wheezing and asthma. Among these factors, RSV-specific IgE (RSV-IgE) antibody responses are of particular interest given the involvement of specific IgE antibodies in the pathophysiology of asthma (14).

RSV-IgE antibodies were first reported in 1981 by Welliver and colleagues who detected increased levels in nasopharyngeal secretions collected from children with documented RSV infection (15). RSV-IgE antibody responses appeared mostly in children who developed wheezing and were associated with increased levels of histamine in nasopharyngeal secretions and correlated with the degree of hypoxemia. Although some studies failed to detect RSV-IgE antibodies in nasal washes or sera from children with wheezing (16, 17), several reports have confirmed the presence of RSV-IgE antibodies in nasopharyngeal washes and sera collected from children with more severe illness caused by RSV infection (18–21).

Based on these clinical observations, we hypothesized that RSV-IgE antibodies might play a role in the development of exaggerated airway responsiveness during subsequent RSV infection. To test this hypothesis, we first defined the kinetics of the development of RSV-IgE antibody responses in a mouse model of RSV-induced airway inflammation and airway hyperresponsiveness (AHR). We then examined the effects of these antibodies in vitro, on mast cell activation and serotonin release and in vivo on RSV-induced airway inflammation and hyperresponsiveness. Some of the results of these studies have been previously reported in the form of an abstract (22).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Additional detail on the methods is provided in an online supplement.

Animals
BALB/c mice (8–10 weeks old) were obtained from Jackson Laboratories (Bar Harbor, ME). Fc{epsilon}RI–/– mice, backcrossed on a BALB/c background, were generated as previously described (23). They were kindly provided by Dr. J. P. Kinet (Harvard Medical School, Boston, MA) and were bred under pathogen-free conditions in the animal facility at National Jewish Medical and Research Center (Denver, CO). The animal experiments were performed under a protocol approved by the Institutional Animal Care and Use Committee.

Virus and Animal Inoculation
Human RSV, strain A2 (catalog #VR-1302), was obtained from American Type Culture Collection (Manassas, VA). Stocks of virus were purified by ultracentrifugation on sucrose density gradients. Animals were inoculated under light anesthesia (Avertin 2.5%, 0.010 ml/g body weight) with 106 plaque-forming units of purified virus. Control animals received sham inoculum, consisting of virus-free preparation, or ultraviolet light (UV)–inactivated RSV (at a dose equivalent to 106 plaque-forming units).

Analysis of mRNA Expression
Lung tissue mRNA expression was analyzed by the reverse transcription-polymerase chain reaction method using specific oligonucleotide primers (Table 1). Lung infection was confirmed by reverse transcription-polymerase chain reaction detection of RSV nucleoprotein gene (24). Polymerase chain reaction products were resolved by electrophoresis on ethidium bromide-stained agarose gels. The relative mRNA abundance for each target was determined by densitometric measurement of target to ß-actin mRNA ratio using National Institutes of Health Scion Image software (version 1.62, developed at the U.S. National Institutes of Health and available on the Internet at http://rsb.info.nih.gov/nih-image/).


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  		TABLE 1. Oligonucleotide primers

 
Detection of RSV-specific Antibodies
RSV-specific antibodies were detected by a direct ELISA in sera collected on Days 7, 14, 21, and 28 after RSV inoculation.

Generation of RSV-IgE and IgG2a/2b Antibodies
To generate mouse sera with high titers of RSV-IgE or IgG2a/2b (RSV-IgG2), mice were repeatedly sensitized by injection of 10 µg of detergent-disrupted RSV antigens premixed with either alum adjuvant (AlumImuject; Pierce, Rockford, IL) or Freund's adjuvant (Sigma Chemicals Co., St. Louis, MO), respectively. For passive sensitization, RSV-IgE–enriched sera were depleted of total IgG (or IgE) antibodies by incubation with goat anti-mouse IgG (or IgE) immobilized on tissue culture plates. Complete depletion was confirmed by ELISA measurements. Normal mouse serum was similarly treated and used as control.

Mast Cell Degranulation
Bone marrow–derived mast cells (BMMCs) were generated by culture and used in a degranulation assay as previously described (25).

Airway Function, Bronchoalveolar Lavage, and Interferon-{gamma} Levels
Airway function was assessed in nonanesthetized unrestrained animals by measuring changes in Penh (enhanced pause) values, using whole body plethysmography (26) and in anesthetized mechanically ventilated animals by measuring changes in lung resistance (27) in response to increasing doses of inhaled methacholine (MCh), as previously described in detail. Bronchoalveolar lavage (BAL) fluids were recovered for measurements of interferon-{gamma} (IFN-{gamma}) levels by ELISA (BD PharMingen, San Diego, CA).

Statistical Analysis
Data are expressed as means ± SEM. Statistical significance at a p value of less than 0.05 was determined by analysis of variance using Statview 4.5 statistical analysis software package (Abacus Concepts Inc., Berkeley, CA). The Bonferroni procedure was used to correct for multiple comparisons of the means.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RSV Infection Results in the Development of an RSV-IgE Antibody Response
The results of reverse transcription-polymerase chain reaction analysis revealed that RSV infection induced both interleukin (IL)-4 and IL-13 mRNA expression in the lungs of these animals and upregulated the mRNA levels of CD40L, all considered to be critical signals required for IgE synthesis (Figures 1A and 1B). The data also show evidence for local IgE mRNA induction in the lungs of RSV-infected BALB/c mice (Figures 1C and 1D). In addition, both the high (Fc{epsilon}RI) and the low-affinity (CD23) receptors for IgE were upregulated at the mRNA level in RSV-infected mouse lungs.



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  		Figure 1. Respiratory syncytial virus (RSV)–mediated induction of mRNA expression for IgE and its receptors in the mouse lung. Representative agarose gels showing reverse transcription-polymerase chain reaction products (A and C) and relative mRNA abundance (B and D) for IgE, IgE receptors, interleukin (IL)-4, IL-13, and CD40L detected in the lungs of BALB/c mice inoculated with virus-free sham preparation (lanes 1 and 2), noninfectious, ultraviolet (UV)-inactivated RSV (lanes 3 and 4), or infectious RSV (lanes 5–7). RSV infection resulted in significant induction of mRNA for IgE, IgE receptors, and regulatory signals (IL-4, IL-13, CD40-L) in the lungs of mice. Data are representative of two independent experiments with a total of four sham-inoculated animals, four UV-inactivated RSV (uv-RSV)–inoculated animals, and six live RSV-infected animals. *Significant difference between the groups (p < 0.05).

 
To document further the development of RSV-IgE antibody responses in BALB/c mice, we established a direct ELISA method designed to detect circulating, free (unbound) RSV-specific antibodies in the sera collected from animals at 7, 14, 21, and 28 days after RSV infection. The results further confirmed the development of an RSV-IgE antibody response peaking at 21 days after inoculation in the sera of infected animals (Figure 2A); at these time points, IgG responses were also detected (Figure 2B). Incubation of samples from the same animal sera with ELISA plates coated with total HEp-2 cell protein extracts did not result in a significant binding of IgE or IgG antibodies (Figures 2C and 2D).



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  		Figure 2. Kinetics of RSV-specific IgE (RSV-IgE) and IgG antibody responses in BALB/c mice. RSV-specific antibodies were measured in serum by direct ELISA. Paired samples from each individual mouse serum were incubated with ELISA plates coated with RSV antigens (A and B) to assess specific binding or with HEp-2 cell lysates (C and D) to assess nonspecific binding. Data are means ± SEM with n = 8 animals in each group. RSV infection resulted in the development of RSV-IgE (A) and IgG (B) antibody responses.

 
RSV-IgE Antibodies Trigger Mast Cell Degranulation in an IgE-dependent and Antigen-specific Manner
Mast cells are a potent source of mediators of bronchoconstriction (28). To establish a role for RSV-IgE antibodies in mast cell mediator release, we used an in vitro BMMC serotonin release assay (25).

To determine whether naturally occurring RSV-IgE antibodies can sensitize mast cells, BMMCs were sensitized with sera collected from RSV-infected mice and labeled with 3H-serotonin. Serotonin release was measured in the cultures 30 minutes after addition of culture medium alone (spontaneous release) or either live or UV-inactivated RSV, diluted with culture medium to obtain a multiplicity of infection of three as shown in preliminary experiments to be an optimal dose for inducing maximal serotonin release. The results clearly demonstrate that RSV-IgE, generated under natural infection, can sensitize mast cells to degranulate after stimulation with RSV (Figure 3A). The release of serotonin from IgE-sensitized BMMCs was identical whether the cells were stimulated with UV-inactivated or live RSV, indicating that infection of these cells was not required for the response induced by RSV antigens. Furthermore, RSV alone did not induce serotonin release from nonsensitized BMMCs (data not shown).



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  		Figure 3. Effect of RSV-IgE on mast cell degranulation. (A) Naturally occurring RSV-IgE can sensitize mast cells from wild-type (WT) but not Fc{epsilon}RI–/– mice to degranulate in the presence of RSV. Data are means ± SEM for n = 6 RSV-infected animal sera individually tested in triplicate cultures. (B) IgE-mediated mast cell degranulation is antigen specific. RSV-IgE mediates degranulation of mast cells only after stimulation with RSV but not with an irrelevant antigen such as ovalbumin (OVA). WT bone marrow–derived mast cells (BMMCs) were sensitized with hyperimmune RSV-IgE (IgG-depleted) serum or an OVA-specific monoclonal mouse IgE antibody. Data (mean ± SEM) are pooled from two independent experiments with quadruplicate cell cultures for each condition.

 
To demonstrate that naturally occurring RSV-IgE–mediated mast cell degranulation is IgE dependent, BMMCs were obtained from mice lacking the high-affinity receptor for IgE (Fc{epsilon}RI–/–) and were sensitized as described before. As shown in Figure 3A, RSV-infected animal sera failed to sensitize Fc{epsilon}RI–/– BMMCs to degranulate after RSV stimulation, indicating that the mast cell response to RSV is IgE dependent.

To assess the antigen specificity of the IgE-mediated mast cell response, BMMCs were sensitized with IgG-depleted hyperimmune RSV-IgE–enriched serum, obtained by active sensitization of mice with RSV using alum adjuvant, or with a mouse monoclonal antiovalbumin IgE antibody, previously developed and characterized in this laboratory (29). The cells were stimulated with UV-inactivated RSV or ovalbumin followed by assessment of degranulation by measuring serotonin release. As shown in Figure 3B, RSV induced serotonin release from BMMCs, but only if these cells were sensitized with RSV-IgE but not with ovalbumin-specific IgE. Depletion of IgE from RSV-IgE serum abolished IgE-mediated mast cell degranulation and incubation of BMMCs with hyperimmune RSV-IgG2a/2b–enriched serum failed to mediate mast cell degranulation in response to RSV stimulation (data not shown). Furthermore, unlike ovalbumin, RSV did not stimulate serotonin release from BMMCs that were sensitized with ovalbumin-specific IgE (Figure 3B).

RSV-IgE Antibodies, not IgG2, Enhance RSV-induced AHR
To define the role of RSV-IgE in RSV-induced airway dysfunction, we passively sensitized BALB/c mice by intravenous administration of RSV-IgE or RSV-IgG2 sera 2 days after inoculation with live virus. In preliminary experiments, this time point showed maximal effects of passive sensitization on AHR. Control, sham-inoculated animals were administered normal BALB/c mouse serum. Airway responsiveness to inhaled MCh was measured by whole body plethysmography on Day 7 after infection. The results indicate that RSV-induced AHR was markedly enhanced by passive sensitization of mice with RSV-IgE antibodies (Figure 4A). If RSV-IgE was depleted from the serum, there was no enhancement of AHR. In contrast, mice administered RSV-IgG2 developed significantly lower AHR in response to RSV infection. As shown in Figure 4B, passive sensitization with RSV-IgE but not RSV-IgG2 resulted in markedly reduced numbers of lymphocytes recovered in the BAL fluids from RSV-infected animals.



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  		Figure 4. Effect of passive sensitization with RSV-IgE antibodies on RSV-induced airway hyperresponsiveness (AHR) (A and C) and airway inflammation (B and D). (A) Mice were inoculated on Day 0 with RSV and administered intravenously on Day 2 IgG-depleted RSV-IgE–enriched serum (IgE/RSV), IgE-depleted RSV-IgE–enriched serum (IgE depleted/RSV), RSV-specific IgG2 (IgG2/RSV), or normal serum (NS/RSV). Control mice (NS/Sham) were sham-inoculated and treated with normal serum. (B) Profile of inflammatory cells recovered in the bronchoalveolar lavage (BAL) fluids from the same groups of mice (as in A). (C) Mice were inoculated on experimental Day 0 with UV-inactivated RSV followed on Day 2 by an intravenous administration of either normal serum (NS/uv-RSV, Day 0) or RSV-IgE (IgE/uv-RSV, Day 0); other mice were inoculated on Day 3 with UV-inactivated RSV after administration on Day 2 of RSV-IgE (IgE/uv-RSV, Day 3). (D) Profile of inflammatory cells recovered in the BAL fluids from the same groups of mice (as in C). Data are means ± SEM with n = 8 animals in each group. *Significant differences between the groups, p < 0.05. Eos = eosinophil; Lym = lymphocyte; Mac = macrophage; Neu = neutrophil.

 
To determine whether infectious RSV was required for the IgE-mediated enhancement of AHR, BALB/c mice were inoculated with UV-inactivated RSV on Day 0 or Day 3 and were passively sensitized on Day 2 with RSV-IgE, followed by assessment of airway responsiveness to MCh on Day 7. Under each condition, no significant increase beyond normal airway responsiveness could be observed, demonstrating that active RSV lung infection was required for the enhanced response (Figure 4C). Similarly, no significant changes were seen between these groups in the profile of inflammatory cell populations recovered in the BAL fluids (Figure 4D). In addition, the normal airway responsiveness to MCh seen in sham-inoculated mice was not altered by passive sensitization of the mice with either RSV-IgE or RSV-IgG2 (data not shown), indicating that interaction of these antibodies with RSV in vivo during active lung infection is necessary to produce the exacerbated AHR.

To assess further the antigen specificity of IgE-mediated enhancement of RSV-induced AHR in vivo, mice were either actively sensitized twice to ovalbumin and infected with RSV 14 days after the second sensitization or passively sensitized 2 days after RSV infection by administration of ovalbumin-specific mouse monoclonal IgE antibody. In parallel, a group of sham-inoculated mice received RSV-IgE on Day 2 followed by intranasal administration of ovalbumin (50 µg in 25-µl saline) on Day 3 after inoculation. Control groups consisted of sham-inoculated and RSV-infected mice that received normal serum as described previously here. AHR and airway inflammation were assessed on Day 7 after inoculation by measuring changes in lung resistance to inhaled MCh. The data demonstrate that RSV-induced AHR is not enhanced after passive sensitization with IgE antibodies that are specific to an irrelevant antigen such as ovalbumin (Figure 5A). Similarly, an irrelevant antigen (ovalbumin) did not induce AHR in mice sensitized with RSV-IgE. As shown in Figure 5B, the profile of inflammatory cells recovered in the BAL fluids of RSV-infected animals was not altered by active sensitization to ovalbumin or by passive sensitization with ovalbumin-specific monoclonal IgE antibody. Similarly, the profile of the BAL cell population in the sham-inoculated animals was not altered after sensitization with RSV-IgE.



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  		Figure 5. Antigen specificity of IgE-mediated enhancement of RSV-induced AHR. (A) Airway responsiveness to inhaled methacholine (MCh). Groups of mice were administered RSV-IgE and intranasally challenged with OVA (RSV-IgE/OVA, n = 6), administered monoclonal IgE antibody and infected with RSV (OVA-IgE/RSV, n = 6), actively sensitized to ovalbumin and infected with RSV (intraperitoneal-OVA/RSV, n = 6), or administered normal serum and infected with RSV (NS/RSV, n = 6) or sham inoculated (NS/Sham, n = 6). (B) Profile of inflammatory cells recovered in the BAL fluids from the same groups of mice.

 
The High-affinity IgE Receptor (Fc{epsilon}RI) Is Required for the Enhancement of RSV-induced AHR by RSV-IgE
The high-affinity IgE receptor, Fc{epsilon}RI, plays an essential role in mast cell activation and mediator release. To define the role of Fc{epsilon}RI in vivo, in the enhancement of RSV-induced AHR by RSV-IgE, we passively sensitized Fc{epsilon}RI–/– mice, on Day 2 after inoculation, by intravenous administration of either normal serum or RSV-IgE. Wild-type (WT) mice were similarly treated and served as controls for passive sensitization. Airway function was assessed on Day 7 after RSV inoculation in anesthetized, mechanically ventilated animals by measuring changes in lung resistance to increasing doses of inhaled MCh. Compared with WT mice (Figure 6A), Fc{epsilon}RI–/– mice developed a lower degree of AHR on Day 7 after RSV infection (Figure 6D). Nonetheless, the increases in AHR were significantly higher than in control animals, which received sham inoculation. However, after passive sensitization of Fc{epsilon}RI–/– mice with RSV-IgE, no further increases in lung resistance were observed after RSV infection (Figure 6D), demonstrating that the high-affinity IgE receptor is required for the enhanced response. In contrast, passive sensitization of WT mice with RSV-IgE significantly enhanced RSV-induced AHR (Figure 6A), further confirming the airway physiology data obtained by whole body plethysmography (shown in Figure 4A). Analysis of inflammatory cells recovered in the BAL fluids revealed significantly reduced numbers of lymphocytes after passive sensitization with RSV-IgE in WT (Figure 6B), but not in Fc{epsilon}RI–/– mice (Figure 6E).



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  		Figure 6. Requirement for the high-affinity IgE receptor (Fc{epsilon}RI). WT BALB/c mice (A–C) and Fc{epsilon}RI–/– mice (D–F) were inoculated on experimental Day 0 with RSV and administered on Day 2 RSV-IgE–enriched serum (IgE/RSV) or normal mouse serum (NS/RSV). Control mice were sham-inoculated and treated with normal mouse serum (NS/Sham). Airway function was assessed on Day 7 in anesthetized, mechanically ventilated animals by measuring changes in lung resistance to inhaled MCh (A and D), followed by total and differential BAL cell counts for the same groups animals (B and E). Lung viral titers were determined on separate animal groups on Days 4 and 7 after infection by culture plaque assays (C and F). Data (mean ± SEM) are presented for n = 8 animals in each group. *Significant difference between the groups, p < 0.05.

 
To determine the effects of RSV-IgE antibodies on viral clearance, lung viral titers were measured on Days 4 and 7 after infection for both strains of mice. The results showed no significant differences between the two strains of mice in the amounts of replicating virus recovered from the lungs (Figures 6C and 6D). Furthermore, in both strains of mice, the lung viral titers were not affected by passive sensitization with RSV-IgE.

Passive Sensitization with RSV-IgE Antibodies Decreases RSV-induced IFN-{gamma} Levels
IFN-{gamma} may play a significant role in the pathogenesis of RSV bronchiolitis (30). To define the effects of RSV-IgE antibodies on the IFN-{gamma} response to RSV lung infection, we measured the levels of this cytokine in the BAL fluids recovered from both WT and Fc{epsilon}RI–/– mice after RSV infection and passive sensitization with RSV-IgE antibodies. RSV infection led to a marked increase in IFN-{gamma} levels in both strains of mice, with WT mice showing significantly higher levels than Fc{epsilon}RI–/– mice (Figure 7). However, passive sensitization with RSV-IgE resulted in significantly lower IFN-{gamma} production in the lungs of WT mice (Figure 7A) but not in the Fc{epsilon}RI–/– mice (Figure 7B).



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  		Figure 7. Effect of RSV-IgE on IFN-{gamma} production in vivo. The treatment groups are the same as in Figure 6. Interferon-{gamma} (IFN-{gamma}) levels were measured by ELISA in the BAL fluids recovered on Day 7 after infection from the lungs of BALB/c mice (A) and Fc{epsilon}RI–/– mice (B). *Significant difference between the groups, p < 0.05; n.s. = not significant.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The nature of the clinical association that exists between RSV bronchiolitis and subsequent development of wheezing and asthma in young children remains controversial. However, genetic susceptibility and host response factors are likely to play important roles in the pathogenesis of postbronchiolitis wheezing and asthma. In this study, we investigated the role of RSV-IgE antibodies in the pathophysiology of RSV-mediated airway dysfunction. Consistent with clinical reports from human studies, the results of this animal study confirmed that the development of RSV-IgE antibodies is a component of the host response to RSV infection. The peak levels of circulating, free (unbound) RSV-IgE antibodies were detected in serum at 3 weeks after infection. Similar findings have been reported earlier by other studies conducted in different animal species including calves (31) and guinea pigs (32).

The development of virus-specific IgE antibodies is not unique to RSV infection. Numerous human studies have also shown that specific IgE antibodies can be produced in response to infection by other pathogens, including a variety of viruses (33–39) and atypical bacteria (40, 41). However, the role of pathogen-specific IgE antibodies has not been determined in these studies, although when studied, in most cases, the responses were associated with a poorer prognosis.

The induction of an IgE antibody response is T-helper cell dependent and requires a primary signal delivered by a Th2 cytokine IL-4 (or IL-13) and a secondary signal delivered by the interaction between CD40, expressed on B cells, and its natural ligand (CD40L) expressed on activated T cells (42, 43). Once initiated, IL-4-driven IgE synthesis can either be enhanced by Th2 cytokines (IL-5, IL-6, and IL-9) or inhibited by Th1 cytokines (IFN-{gamma}) or antiinflammatory cytokines such as IL-10 and transforming growth factor-ß (44). Thus, Th2 cells, and possibly basophils and mast cells, which may constitute a considerable source of IL-4 and IL-13 (45), are crucial for the control of IgE production. Accordingly, the initial induction of RSV-IgE antibody production is likely to be dependent on a Th2 response that develops during RSV infection, albeit discrete, and is most likely compartmentalized to the lung tissue.

Because some studies have failed to detect Th2 cytokines in clinical samples obtained from children with RSV infection, the issue as to whether natural RSV infection can elicit a Th2 response remains a matter of debate. Nonetheless, the ability of RSV to induce Th2 cytokine production is well documented (46–48), and there are consistent data from clinical studies that described an otherwise low level but significant Th2 response that is associated with RSV bronchiolitis (49–54). Some animal studies suggest that the extent of these responses could be limited because of the predominant IFN-{gamma} production induced during acute RSV infection (55). In this study, the results of reverse transcription-polymerase chain reaction analysis of mRNA expression revealed that both critical signals required for IgE synthesis, including CD40L and the Th2 cytokines IL-4 and IL-13, were upregulated in the lungs of mice during RSV infection. Furthermore, the expression levels for both the low-affinity (CD23) and the high-affinity (Fc{epsilon}RI) IgE receptors were also increased in the lungs of RSV-infected mice.

Based on the similarities between postbronchiolitic wheezing and asthma and the well known involvement of IgE in the pathogenesis of asthma (14), we hypothesized that RSV-IgE antibodies could play a significant role in the pathophysiology of RSV-mediated airway dysfunction. Our in vitro studies demonstrated that cross-linking of RSV-IgE antibodies on the surface of sensitized mast cells triggers a degranulation response and the release of serotonin. We therefore postulated that if present in vivo, RSV-IgE antibodies might trigger similar responses that could result in the development or enhancement of a bronchoconstrictive airway response after RSV infection. As expected, mice that were passively sensitized with RSV-IgE antibodies developed further increases in airway responsiveness to inhaled MCh after RSV infection as compared with RSV-infected mice that were treated with normal serum or RSV-IgE-depleted serum. Surprisingly, noninfectious (UV-inactivated) virus failed to induce AHR after passive sensitization of mice with RSV-IgE antibodies (Figure 4). This is in contrast to our in vitro data where both infectious and noninfectious RSV induced equal amounts of serotonin release from sensitized mast cells. However, the differences observed in vivo may be related to the requirement of infectious virus to upregulate IgE receptor expression in the lungs. On the other hand, passive sensitization of Fc{epsilon}RI–/– mice with RSV-IgE antibodies failed to enhance RSV-mediated AHR, further identifying a critical role for the high-affinity IgE receptor in the in vivo–mediated effects on AHR.

In mice, acute RSV lung infection typically results in the development of a predominantly mononuclear cell inflammation that can be sampled in the BAL fluid. In this study, the number of lymphocytes recovered in the BAL fluid was significantly lower in RSV-infected BALB/c mice administered RSV-IgE antibodies. This decrease in the cellular response was associated with lower levels of IFN-{gamma} in the recovered BAL fluids. However, the decreases were not reflected in altered lung viral titers, which were not affected by passive sensitization with RSV-IgE antibodies. In contrast, in RSV-infected Fc{epsilon}RI–/– mice, neither the numbers of recovered lymphocytes nor the levels of IFN-{gamma} were decreased in the BAL after passive sensitization with RSV-IgE antibodies.

Deficient IFN-{gamma} production has been associated with RSV infection and correlated with severity of disease in human studies (18, 56–61). In animal studies, deficient IFN-{gamma} production by RSV-specific CD8+ T cells has been related to the inability of these cells to mount appropriate effector and memory cytolytic responses (30), although viral clearance can be achieved in the absence of CD8+ T cells (62). A more recent study emphasized the importance of IFN signaling pathways in the development of Th1-protective immunity against RSV infection (63). The authors described a strong Th2-biased, RSV-induced lung histopathology in mice lacking either the intracellular STAT1 signaling molecule or both of IFN-{gamma} and IFN-{alpha}/ß receptors. Because there are multiple cellular sources of IFN-{gamma} production in the lungs, including natural killer cells (64), and both {alpha}ß and {gamma}{delta} TCR+ T cells (56) and a variety of cells other than mast cells and basophils, including monocytes (65), eosinophils (66), dendritic cells (67, 68), and airway epithelial cells (69) can also express the high-affinity receptor for IgE, further studies are required to elucidate fully the mechanisms whereby RSV-IgE antibodies mediate lower IFN-{gamma} production in the lungs and enhanced airway dysfunction after acute RSV infection.

In summary, the results of this study document the development of RSV-IgE responses in RSV-infected BALB/c mice and establish a role for these antibodies and the high-affinity IgE receptor in the development of exaggerated AHR after active RSV lung infection. Because recurrent RSV infection is common in children (70), the described interactions might contribute to the development of airway dysfunction in children who have developed RSV-IgE antibodies.


   Acknowledgments
 
The authors thank Diana Nabighian for secretarial assistance and the Biological Resource Facility staff at National Jewish Medical and Research Center for assistance with animal handling and care.


   FOOTNOTES
 
Supported by National Institutes of Health grants HL-61005, HL-36577, and AI-42246 and Environmental Protection Agency grant R825702.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.-W.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; X.-D.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.-H.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.W.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form November 25, 2003; accepted in final form August 6, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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