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The Journal of Immunology, 2004, 172: 1139-1145.
Copyright © 2004 by The American Association of Immunologists

IgE Enhances Parasite Clearance and Regulates Mast Cell Responses in Mice Infected with Trichinella spiralis 1

Michael F. Gurish*, Paul J. Bryce{ddagger}, Hong Tao*, Alison B. Kisselgof{ddagger}, Elizabeth M. Thornton§, Hugh R. Miller§, Daniel S. Friend{dagger} and Hans C. Oettgen2,{ddagger}

* Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115; {dagger} Department of Pathology, Brigham and Womens Hospital and Harvard Medical School, Boston, MA 02115; {ddagger} Division of Immunology, Children’s Hospital, Harvard Medical School, Boston, MA02115; and § Department of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Trichinella spiralis infection elicits a vigorous IgE response and pronounced intestinal and splenic mastocytosis in mice. Since IgE both activates mast cells (MC) and promotes their survival in culture, we examined its role in MC responses and parasite elimination in T. spiralis-infected mice. During primary infection, wild-type but not IgE-deficient (IgE-/-) BALB/c mice mounted a strong IgE response peaking 14 days into infection. The splenic mastocytosis observed in BALB/c mice following infection with T. spiralis was significantly diminished in IgE-/- mice while eosinophil responses were not diminished in either the blood or jejunum. Similar levels of peripheral blood eosinophilia and jejunal mastocytosis occurred in wild-type and IgE-deficient animals. Despite the normal MC response in the small intestine, serum levels of mouse MC protease-1 also were lower in parasite-infected IgE-/- animals and these animals were slower to eliminate the adult worms from the small intestine. The number of T. spiralis larvae present in the skeletal muscle of IgE-/- mice 28 days after primary infection was about twice that in BALB/c controls, and the fraction of larvae that was necrotic was reduced in the IgE-deficient animals. An intense deposition of IgE in and around the muscle larvae was observed in wild-type but not in IgE null mice. We conclude that IgE promotes parasite expulsion from the gut following T. spiralis infection and participates in the response to larval stages of the parasite. Furthermore, our observations support a role for IgE in the regulation of MC homeostasis in vivo.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Vigorous IgE Ab production is a characteristic response during infection with parasitic helminths, including Trichinella spiralis (1, 2). IgE Abs are produced primarily in mucosal-associated lymphoid tissue and, via their interaction with Fc{epsilon}RI on mucosal mast cells (MC),3 can trigger immediate hypersensitivity reactions. In parasite endemic regions of the world, high IgE levels are associated with resistance to reinfection (3, 4, 5). IgE production, however, is only one feature of a broader response in which type 2 Th (Th2) cells produce high levels of IL-4 and IL-5, which stimulate IgE Ab synthesis along with eosinophil (eos) production and activation (reviewed in Ref. 6). Thus, the associations of IgE with parasitic infection and immunity could be consistent either with a critical immune function of IgE per se or, alternatively, with the possibility that IgE production is simply a marker of a broader Th2 response in which other effectors (e.g., activated eos) are the key mediators of parasite elimination. In fact, much of the IgE that is produced in response to nematode infections is found not to be specific to the parasite, which has led some authors to speculate that the IgE may in fact aid the parasite by blocking IgE receptors with irrelevant IgE (directed against Ags other than those on the parasite) (reviewed in Ref. 7). The availability of mice with a targeted mutation of the C{epsilon} exons that encode the constant regions of the IgE {epsilon}-H chain has made it possible to examine this question directly (8). Using such mutants, we have recently observed that IgE augments immunity to Schistosoma mansoni during primary infection (9).

T. spiralis infects humans, rodents, and several other species (10, 11). Infection is accompanied by eosinophilia, the production of high levels of IgE, and a MC hyperplasia in the mucosa of the small intestine (12, 13, 14). Immediate cutaneous hypersensitivity to larval Ags is observed within the first 3 wk of infection, consistent with the production of parasite-specific IgE. Some patients also suffer from allergic symptoms including urticaria and angioedema.

Trichinosis can be investigated in rodents and the role of IgE has been studied using the passive transfer of immune IgE or by assessing the parasite susceptibility of relatively IgE-deficient mouse strains. Like humans suffering from trichinosis, T. spiralis-infected mice produce strong IgE responses (15, 16). The infusion of purified T. spiralis immune IgE into rats has been shown to confer rapid parasite expulsion to naive animals and the suppression of active IgE responses using anti-IgE in rats has been reported to markedly impair parasite clearance (17, 18, 19). In contrast, investigations using mice with defects in IgE production have given inconsistent results. One study showed that outbred mice selected for low Ab production had impaired immunity during primary infection while a separate investigation using relatively IgE-deficient SJA/9 inbred mice showed no defect (20, 21). These mouse studies, however, are limited in two ways. First, the IgE deficiency of the animals is not absolute and, second, the basis of IgE deficiency is not understood and could reflect a broader defect in Th2 response. For instance STAT6-deficient mice, which are IgE-deficient by virtue of impaired IL-4 signaling, have also been shown to have impaired immunity to T. spiralis (22).

IgE produced during infection with T. spiralis is primarily bound to mucosal MC in the gut (1). Studies using neutralizing Abs to the MC growth factor, c-kit ligand, or the MC-deficient mouse strains WBB6F1/J-KitW/KitW-v (W/Wv) and WCB6F1/J-KitlSl/KitlSl-d (Sl/Sld), which lack fully functional c-kit or its ligand stem cell factor (SCF), respectively, have shown a critical effector function for MC in immunity to T. spiralis (23, 24, 25). Neither MC-deficient mice nor animals treated with blocking Abs to SCF manifested the mastocytosis associated with T. spiralis infection or effective rejection of the worms. Recently, IgE has been shown to be a survival factor for MC in culture (26, 27). For us, this observation raised the possibility that IgE might function not only in the specific immune response to T. spiralis, but also by regulating MC homeostasis and maintaining this population of cells that are critical to parasite elimination.

To examine the roles of IgE in immunity to T. spiralis, especially in regard to MC and eos responses provoked by this parasite, we infected IgE-/- BALB/c mice and compared them to normal BALB/c mice. Wild-type animals, but not the mutants, showed a vigorous IgE response peaking on day 14 of primary infection. A peripheral blood eosinophilia, jejunal mastocytosis, and eos influx occurred in both wild-type and IgE-deficient mice. However, MC numbers in the spleen of IgE-/- mice were markedly diminished and serum levels of the jejunal-specific secretory granule protease, mouse MC protease (mMCP)-1 were reduced. The intestinal worm burden of IgE-/- mice was elevated throughout the period of infection with the mutant animals harboring detectable numbers of intestinal worms for >1 wk longer than wild-type mice. The number of encysted larvae in the muscle of IgE-/- mice was also increased compared with BALB/c controls and there was less evidence of larval necrosis in the absence of IgE. The larvae in wild-type but not in IgE-deficient mice were found to be coated with IgE, suggesting that this isotype may participate in the reduction of larval burden. These findings provide evidence that IgE plays a role in parasite clearance and regulates the splenic MC responses during T. spiralis infection.


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

IgE-deficient mice were generated by gene targeting as previously described and have been backcrossed through 10 generations onto the BALB/cAnTac (Taconic Farms, Germantown, NY) background (8). BALB/cAnTac mice were used as controls. All mice were maintained in the animal facility at Children’s Hospital, Harvard Medical School. Mice used in these experiments were between 8 and 16 wk old. All animal protocols have been reviewed and approved by the Dana-Farber Cancer Institute and Children’s Hospital Animal Care and Use Committees in accordance with the Public Health Service Policy and provisions of the Animal Welfare Act.

T. spiralis infection and worm burden determination

Trichinella larvae were obtained from BALB/c mice infected > 1 mo before. The larvae were obtained by digesting the skeletal muscle in the presence of 1% pepsin (Sigma-Aldrich, St. Louis, MO) and 1% HCl in water as previously described (28). Larvae were washed in dH2O by low-speed centrifugation after being passed through a screen (60 gauge) to get rid of large pieces of undigested tissue and bone. The released larvae were counted microscopically. Mice were infected with ~450 larvae in 200 µl by direct gastric installation. Worm burden was determined at the times indicated by excising the small intestine, slicing it open longitudinally, and then into 4-mm-long sections. Each intestine was incubated in PBS for 3 h at 37°C with gentle agitation and the released worms were enumerated using an inverted microscope. Results were obtained using four to six animals per time point for days 4–14 and 28 and three mice for day 21.

IgE ELISA and immunocytochemistry

Serum IgE levels were determined using the standard protocol provided by BD PharMingen (San Diego, CA.). Briefly, 96-well plates were coated with purified anti-IgE at 1 µg/ml overnight at 4°C. The next day, plates were washed twice with PBS containing 0.05% Tween 20 (Sigma-Aldrich). Serum was added at dilutions ranging from 1/50 to 1/1000. Purified IgE was used as standard, ranging in concentration from 12.5 to 200 ng/ml. Standards and sera were diluted in PBS/1% BSA (Sigma-Aldrich) and left on plates overnight at 4°C. Plates were then washed four times and incubated for 45 min at room temperature with biotinylated anti-IgE at 1 µg/ml. After five washes, plates were given avidin conjugated to HRP (Zymed Laboratories, San Francisco, CA) and incubated for 30 min at room temperature. Plates were washed six times before adding substrate, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (Zymed Laboratories). ODs of wells were read 10–20 min after addition of substrate at 405 nm. Concentrations of IgE in sera were extrapolated from a graph of standard ODs vs concentrations.

Immunohistochemistry

Detection of IgE on muscle larvae was performed using tissue sections from the tongue of 28-day infected mice. These were prepared for immunostaining by successive washes through xylene, 100% ethanol, 90% ethanol, 80% ethanol, and PBS. Ag unmasking was achieved by microwaving the slides at full power for 15 min in 10 mM Tris/1 mM EDTA (pH 9.0). Endogenous biotin was blocked using an endogenous avidin/biotin blocking kit (Zymed Laboratories) as per the manufacturer’s instructions. The sections were then incubated at 37°C for 2 h in a humidified chamber with 5 µg/ml biotin-labeled anti-mouse IgE (BD PharMingen) diluted in 5% BSA/PBS. Following repeated washes in 5% BSA/PBS, the sections were incubated with 1.25 µg/ml streptavidin-HRP (Zymed Laboratories) at 37°C for 30 min. Finally, a diaminobenzidine-nickel cobalt substrate kit (Zymed Laboratories) was used as per the manufacturer’s instructions and the slides were dehydrated and mounted.

Cellular concentrations and densities

The enumeration of blood eos was done directly on whole blood. Blood was diluted 1/2 with PBS containing 100 U/ml heparin. This mixture was further diluted 1/10 in Discombe’s fluid (0.05% Eosin Y) and eos were counted directly in a hemocytometer (29).

ELISA for mMCP-1 serum concentrations

Serum mMCP-1 levels were determined as previously described (30). A sandwich ELISA was performed using affinity-purified rat monoclonal anti-mMCP-1 clone RF6.1 (31) for capture (5 µg/ml) and polyclonal sheep anti-mMCP-1 (32) for detection (2 µg/ml). A donkey anti-sheep IgG HRP conjugate (Sigma-Aldrich) was used at 1/8000 to develop the plates.

Histology

Animals were sacrificed at the indicated time points and tissue samples were obtained and immediately fixed in 4% paraformaldehyde as previously described (28). The tissues were embedded in JB4 glycolmethacrylate, sectioned at 2-µm thickness, and placed on glass slides. eos were enumerated after staining the tissues with Congo Red. MC were enumerated after staining the tissues for chloroacetate esterase. At least 20 high-power (x50 objective) fields (HPF) were counted for at least three mice each for each genotype at each of the seven time points.

Larval cysts and degenerate cysts containing necrotic larvae were assessed histologically in sections of the tongue after staining with DiffQuik (Dade-Behring, Newark, DE) as previously described (33). Briefly, necrotic cysts were identified by the loss of the cyst wall and infiltration of granulocytes into the cyst. Thirty low-power fields (LPF, x10 objective) were counted for each animal, and a mean number of cysts/LPF was calculated. Cysts with necrotic larvae were counted simultaneously and were expressed as the percentage of cysts with necrotic larvae in the tongue for each animal. Values are the mean ± SEM from five to six animals.

Statistical analysis

Data sets for wild-type and IgE-/- animals were analyzed for variance by two-way ANOVA using GraphPad Prism software (GraphPad, San Diego, CA). Some data sets, as indicated in the text, were also subjected to Student’s two-tailed t test (assuming equal variances) using Microsoft Excel (Redmond, WA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
T. spiralis elicits a vigorous IgE response and peripheral blood eosinophilia. Mice infected with T. spiralis displayed a dramatic rise in IgE levels, increasing to 53.3 ± 3.9 µg/ml on day 14 and, as expected, IgE-/- animals did not produce any IgE. Consistent with our previous observations (8), the IgE-/- mice had no defect in IgG responses. T. spiralis infection caused IgG1 levels to increase by >10-fold in both wild-type and IgE-/- animals (15.8-fold vs 21.0-fold for the BALB/c and IgE-/- mice, respectively).

Peripheral blood eosinophilia was also monitored following T. spiralis infection and showed a peak at day 21 (Fig. 1A). There was no impairment of eos production in the IgE-/- mice; in fact, their eos mobilization was actually significantly greater (p < 0.05). Blood eos counts in IgE-/- mice peaked at 617,000 ± 73,000 eos/ml, while the maximum for BALB/c controls was 383,000 ± 93,000 eos/ml. Tissue recruitment of eos to the jejunum of IgE-/- animals was intact and similar in both strains, with an initial peak at day 11 followed by a second wave of influx from days 21 to 28 (Fig. 1B).



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  		FIGURE 1. Blood and tissue eos responses following T. spiralis infection. A, Total blood eos counts were determined at the indicated time points in wild-type (•) and IgE-/- ({circ}) mice infected with T. spiralis (eos/ml ±SEM). B, Congo Red-stained 2-µm jejunal sections were prepared and eos/HPF (x50 objective) enumerated by light microscopy (mean eos/HPF ± SEM, n = 3/point). *, p < 0.05, NS, Not significant.

 
Alterations in tissue mastocytosis in T. spiralis-infected mice

We and others have observed that infection with T. spiralis stimulates a large increase in the number of MC and eos residing in the small intestine (16, 28). The normal expulsion of adult worms is dependent upon this mastocytosis (22, 23, 24, 25, 34, 35). Recently published data have suggested that IgE is a survival factor for cultured MC but the role of IgE in MC differentiation in vivo has not yet been clearly defined (26, 27). To investigate the relationship between IgE and tissue MC numbers during the course infection with T. spiralis, we examined the gut and spleen of infected mice

The most dramatic MC hyperplasia after T. spiralis infection occurs in the small intestine (Fig. 2). Increased MC numbers were evident in the jejunum as early as 7 days post-infection and peaked at 14 days with 20.5 ± 4.2 MC/HPF in wild-type mice and 20.6 ± 1.6 in IgE-/- mice.



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  		FIGURE 2. Gut and spleen MC numbers following T. spiralis infection. MC numbers/HPF (x50 objective) were determined by the chloroacetate esterase reaction in sections of jejunum (A) or spleen (B) at the indicated time points in wild-type (•) and IgE-/- ({circ}) mice infected with T. spiralis (MC/HPF ± SEM, n = 3/point). ***, p < 0.0001, NS, Not significant.

 
As previously reported (28), a marked increase in MC numbers was observed in the spleen as well, beginning 4 days after infection and persisting throughout the experiment. In contrast to the jejunal MC hyperplasia, the splenic mastocytosis was substantially reduced in IgE-/- mice (Fig. 2B). At the peak (day 11), IgE-/- mice had 0.9 ± 0.1 MC/HPF compared with 1.9 ± 0.2 in the control animals and the reduced MC numbers persisted in the IgE-/- animals throughout the 4-wk course of the study. These findings indicate that IgE supports the splenic MC hyperplasia observed after T. spiralis infection but is not critical for the jejunal MC response.

Diminished MC secretory granule protease release is associated with impaired worm clearance in T. spiralis-infected IgE-/- mice

We have previously observed that T. spiralis infection elicits not only increased MC numbers but also the release of mediators, including mMCP-1. Mice deficient in mMCP-1 were recently used to show that this protease plays a direct role in parasite immunity; mMCP-1-/- mice exhibit normal mastocytosis but delayed worm expulsion following primary T. spiralis infection (30). Since our current findings indicate a role for IgE in the splenic MC hyperplasia in this model and also since parasite-specific IgE, via Fc{epsilon}RI, could be critical for MC activation, we sought to establish whether normal levels of MC activation would be induced by T. spiralis infection in the absence of IgE. To investigate these questions, the release of mMCP-1 into plasma was monitored. Serum mMCP-1 levels did increase in infected IgE-/- mice but reached peak levels less than half of those observed in wild-type control animals (4.4 ± 0.4 vs 11.9 ± 0.7 µg/ml, mean ± SEM, n = 2 with four to six animals per time point, respectively; Fig. 3).



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  		FIGURE 3. mMCP-1 serum levels following T. spiralis infection. Wild-type (•) and IgE-/- ({circ}) mice were infected with T. spiralis. Serum samples were collected at the indicated time points and total mMCP-1 was determined by ELISA (mean ± SEM, micrograms per milliliter, n = 2). ***, p < 0.0001.

 
To determine whether these altered MC responses in IgE-/- mice are associated with an impaired ability to eliminate worms, we counted intestinal worms throughout the course of infection (Fig. 4). Wild-type and IgE-/- mice had similar worm burdens when first assessed at day 4 (281 ± 40 and 285 ± 17 worms, respectively). However, the groups diverged soon thereafter. From day 7 through the completion of the experiment at day 28, consistently greater worm numbers were recovered from the T. spiralis-infected IgE-/- mice. Although wild-type mice had already completely rid themselves of worms by day 21 (none of eight BALB/c mice evaluated in two separate experiments had any remaining worms), the IgE-deficient mice still had residual parasite counts through day 28 at the termination of the experiment (seven of nine IgE -/- mice had detectable worms on day 28). The mean intestinal worm number per IgE-/- mouse was 7.7 ± 1.5 on day 21 (mean ± SE of three mice, n = 1) and 2.2 ± 0.6 on day 28 (mean of nine mice, n = 2). The differences in worm burdens over time were significant (p = 0.01) as assessed by ANOVA. In addition, worm counts at individual time points, assessed by Student’s t test, differed significantly (p < 0.05) at all time points except days 4 and 11. These findings provide strong support for a protective role of IgE in mice in intestinal worm expulsion following primary infection with T. spiralis.



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  		FIGURE 4. Expulsion of T. spiralis from the jejunum. Wild-type (•) and IgE-/- ({circ}) mice received 450 worms on day 0. Five to six mice of each strain were analyzed for jejunal worm burden on the indicated days (mean worms recovered per mouse ± SEM). **, p = 0.01.

 
To examine the role of IgE Abs in the response to muscle larvae, we examined the numbers and morphology of T. spiralis cysts in the tongues of BALB/c and IgE-/- mice 28 days following infection (Fig. 5). Three weeks after infection, T. spiralis larvae are observed encysting the skeletal muscle. We have previously reported that assessment of larval cyst numbers in the tongue provides a good indication of encystment throughout the skeletal muscle and used tongue as the reference organ for monitoring larval encystment at the conclusion of this study (33). Because we have also previously observed that there is evidence of necrosis and cyst infiltration with granulocytes at this stage of infection, we examined the histological appearance of the T. spiralis cysts.



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  		FIGURE 5. Quantitation of cysts and necrotic larvae in IgE-/- and BALB/c control mice after T. spiralis infection. The number of cysts per LPF (A) and the percentage of degenerating cysts with necrotic larvae (B) were enumerated in the tongues of IgE-/- and wild-type BALB/c mice. Sections of tongue were stained with DiffQuik (reference bar in D is 20 µm). A representative intact larva is shown in C and a necrotic larva, with loss of cyst wall (white arrow) and infiltrating granulocytes, including eos (black arrows), is shown in D. The mean cyst number was obtained by counting at least 30 LPF from each animal. Values are the means ± SEM from five to six animals. Two-tailed t tests were used to assess statistical significance of differences between data sets: total cysts, p = 0.01; percent necrotic cysts, p = 0.05.

 
The number of cysts in the tongues of IgE-/- mice (3.6 ± 0.5/LPF) was more than twice that in control BALB/c mice (1.7 ± 0.1/LPF, p = 0.01, Fig. 5A). The percentage of cysts containing necrotic larvae in the IgE-/- mice was reduced (1.5 ± 0.4%) compared with that observed in BALB/c mice (4.0 ± 1.1%, p = 0.05, Fig. 5B). Because these results suggested that the IgE participates in larval toxicity, we sought the presence of IgE in and around the larvae. Sections of tongue from 28-day T. spiralis-infected mice were stained with anti-IgE Ab. Only the muscle larvae from wild-type mice stained intensely for IgE (Fig. 6), demonstrating significant binding of IgE to the worms at this stage in their life cycle. These findings indicate that IgE may facilitate not only expulsion of worms from the intestine but may also contribute to the immune response to T. spiralis larvae encysted in skeletal muscle.



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  		FIGURE 6. Anti-IgE immunostaining of skeletal muscle larvae in IgE -/- and BALB/c control mice. Sections of tongue from 28-day post-T. spiralis-infected BALB/c (A) or IgE-/- (B) mice were stained with a rat anti-mouse IgE Ab. No staining was observed in control sections of BALB/c mice not incubated with the primary Ab.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
T. spiralis infection in humans and rodents has long been known to elicit a vigorous IgE response. In mice, infection is correlated with a dramatic MC hyperplasia in the intestine and spleen. Using mice with a targeted disruption of the IgE H chain gene and congenic wild-type BALB/c controls, we have now been able to directly assess the role of IgE both in elimination of the worms and in the regulation of MC responses in vivo. In our experiments, infection with T. spiralis elicited the expected sharp increase in IgE levels in wild-type but not IgE-/- mice. Peripheral blood eosinophilia and migration of eos into the gut also was seen in both mutant and control animals. Both groups of animals displayed similar kinetics and levels of jejunal mastocytosis. Strikingly however, the MC number in the spleen was markedly diminished in IgE-/- mice. The IgE-null mice also had significantly lower levels of circulating mMCP-1 and persistently greater worm burdens throughout the course of infection and retained detectable worms in their intestines for a week longer than did wild-type controls. The number of larvae in the skeletal muscle was significantly less in wild-type BALB/c mice than in IgE-/- mice and this was associated with binding of IgE to the muscle larvae and evidence of increased cyst necrosis. These findings provide strong support for a role for IgE in immunity to primary infection with T. spiralis and indicate that IgE Abs play a prominent role in jejunal MC activation and regulation of splenic MC numbers in vivo.

Previous investigations on the role of IgE in the clearance of T. spiralis have given varied results. Naive rats have been reported to exhibit enhanced parasite clearance after passive immunization with T. spiralis-immune IgE (17, 18). Active suppression of IgE responses during primary infection using anti-IgE Abs has been shown to markedly impair parasite elimination (19). Using outbred mice selected for impaired IgE production, Perrudet-Badoux et al. (20) observed impaired resistance in the low-responder mice. However, these genetically heterogeneous mice likely differed from controls at many loci. Since the basis of their depressed IgE response was not characterized, the possibility that low IgE per se increased their susceptibility to T. spiralis could not be distinguished from the alternative that more global immunological defects affecting T cell responses, Ab isotype switching, MC activation, and/or other immunological functions accounted for their altered response to the parasite. To focus the analysis on IgE in the current study, we used IgE-deficient BALB/c mice generated by gene targeting. These mice are genetically very similar to the control animals, likely differing only at a very few tightly linked loci around the C{epsilon} gene. Thus, our findings provide direct evidence for the importance of the IgE isotype in T. spiralis clearance. We have previously observed that these mice also have impaired responses to S. mansoni (9) and now demonstrate that their response to T. spiralis is impaired as well (Fig. 4). BALB/c mice typically reject the parasite burden we use after 14–17 days. Yet the IgE-null mice still had detectable worms 28 days postinfection. Thus, a significant protective benefit is afforded by the IgE response even in a primary infection.

Our examination of cyst numbers in the tongues of BALB/c and IgE-/- mice revealed that significantly fewer cysts were present in the muscle of wild-type mice and that the extent of necrosis was increased in the presence of IgE (Fig. 5). Furthermore, tissue staining for IgE revealed the presence of IgE in and around the encysted larvae (Fig. 6). Previously published reports on the kinetics of cyst rejection have shown that cyst destruction can occur during this acute phase in miniature swine (36). Studies in rats have suggested that IgE Abs are important in the early response to cysts, mediating both the recruitment of eos to encysted larvae in muscle and reducing the numbers of muscle cysts (19). In recent studies of T. spiralis-infected mice, we have observed that the chemokine receptor CCR3 is important for eos recruitment and acute larval cytotoxicity (33). Thus, our observations indicate that the role of IgE in immunity to T. spiralis is not restricted to facilitating the expulsion of adult worms from the intestine but also includes killing of larval stages of the parasite.

The effective recruitment of granulocytes to muscle cysts in wild-type but not IgE-/- mice and the increased rate of cyst necrosis in wild-type animals implicates IgE Abs in supporting an effective cytotoxic response. Neither Fc{epsilon}RI nor CD23 (high- and low-affinity IgE receptors, respectively) are believed to be expressed by eos or other cytotoxic effector cells in mice. However, activation of tissue MC by parasite-specific IgE Abs is likely to elicit the release of an array of cytokines, chemokines, and lipid mediators capable of recruiting an acute inflammatory response. It is less likely, but also possible, that IgE Abs directly target larvae for destruction by effector cells, including eos and NK cells. It has been reported that Fc{gamma}RIII can bind IgE (37, 38), This receptor is expressed by eos and thus provides a potential mechanism whereby eos-mediated larval killing is enhanced in the presence of IgE (39). Capron et al. (40) reported that IgE Abs can opsonize parasites for killing by eos in rodents.

Our observations contrast with those of Watanabe et al. (21) who found that SJA/9 mice, which have a markedly depressed IgE response to nematode parasites, had no defect in the clearance of T. spiralis compared with wild-type controls. Two possible explanations for this discrepancy exist. First, these mice do not have an inherent defect in IgE biosynthesis per se but rather have abnormal IL-4 production (41). They do produce small amounts of IgE and it is possible that this modest response (in contrast to the total lack of IgE in the IgE-/- mice) was sufficient to support elimination of T. spiralis. Second, the SJA genetic background is different from BALB/c and it is possible that alternative effector mechanisms, not operative in BALB/c mice, compensate for the low IgE response in the SJA/9 strain.

The absence of an IgE response did not impair the ability of IgE-/- mice to mobilize eos to the gut in response to T. spiralis infection in our study. In fact, the mutant animals had the same degree of eos influx into infected jejunum as wild-type mice and peripheral blood eos counts were actually significantly elevated (Fig. 1). One possible explanation for the more robust response observed in IgE-/- mice is that their heavier parasite burden through the course of infection provided a stronger stimulus for eosinophilopoiesis and recruitment. Alternatively, IgE might affect eos development, migration, or life span (as indicated for splenic MC, see below).

T. spiralis infection leads to marked increases in MC numbers in the gut and spleen and a number of studies have established that MC are critical in the process of parasite expulsion (23, 24, 25). Wild-type and IgE-/- mice both showed jejunal mastocytosis following T. spiralis infection in our study, indicating that this Ab does not play a role in the recruitment and expansion of mucosal MC in the gut following nematode infection (Fig. 2). However, the splenic mastocytosis was markedly attenuated in IgE-/- animals. We previously reported that many of the splenic MC in T. spiralis-infected mice are undergoing apoptosis (42). We have hypothesized that the spleen represents a site of MC clearance during the resolution of parasitic infections of the gut as many of the splenic MC appeared to have migrated back to the spleen from the small intestine during the resolution of the mastocytosis. In this context, our finding that T. spiralis-infected IgE-/- mice have fewer MC in the spleen than the infected wild-type controls suggests that signals that support MC survival, or prevent their apoptosis, may be lacking in these mutant mice. A number of factors including SCF, IL-3, IL-4, IFN-{gamma}, and TNF-{alpha} have been reported to play a role in the mastocytosis (24, 43, 44, 45, 46). In addition, two groups have identified monomeric IgE itself as an anti-apoptotic factor for cultured MC (26, 27). In these studies, IgE altered MC survival in the absence of specific Ag. Cultured MC deprived of growth factors normally undergo apoptosis (47, 48); however, in the presence of monomeric IgE, but without Ag, the cells were protected from death. The mechanism of this effect remains unsettled. Although Kalesnikoff et al. (27) reported that monomeric IgE induced the production of cytokines with autocrine activity, Asai et al. (26) did not detect any induction of cytokine synthesis by monomeric IgE and hypothesize that IgE directly triggers an antiapoptotic signal via Fc{epsilon}RI.

In parallel to the diminished MC number in their spleens, we also observed depressed serum mMCP-1 levels in T. spiralis-infected IgE-/- mice (Fig. 3). As one of the most potent stimuli for MC to exocytose granule-associated proteases is activation by Fc{epsilon}RI-bound IgE cross-linked by polyvalent (parasitic) Ags, the diminished mMCP-1 levels likely reflect diminished MC activation via this Ag-specific pathway. Low mMCP-1 levels in IgE-/- mice might contribute to persistence of T. spiralis since the secretory granule {beta}-chymase is specifically expressed in mucosal MC (31), mMCP-1 levels peak at the time of worm expulsion (49), and mMCP-1-/- animals have a significant delay in worm expulsion during T. spiralis infection (30). Like IgE-/- animals, mMCP-1-deficient mice (which are also on a BALB/c background) have gut worm burdens similar to those of controls early in the course of infection but begin to show higher worm counts at the later time points.

Thus, our study provides support for the long-held but disputed notion that parasitic infections have provided the evolutionary pressure that has selected for the persistence of the IgE-Fc{epsilon}RI system. Despite the consistent correlation between high IgE levels and parasitic infection, there has been some disagreement regarding the direct role of this Ab isotype in immunity. Our data show that in the case of T. spiralis, IgE clearly does enhance parasite clearance at two different stages in its life cycle. Our finding that MC homeostasis and mMCP-1 release are altered in IgE-/- mice provides some clues as to possible mechanisms for its effects on the jejunal worm burden and along with past studies suggest a possible mechanism for the larval cytotoxicity. Furthermore, the decreased numbers of splenic MC in IgE-null mice following T. spiralis infection is the first evidence to our knowledge that in vivo IgE may be enhancing MC survival. Further studies will be necessary to clarify the connections among IgE, MC turnover, and T. spiralis clearance.


   Footnotes
 
1 This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants AI054471-01, AR/AI 47417-01, AI 07306 HL 36110-16, and AI 31599-11, Wellcome Trust Grant 060312, and Biotechnology and Biological Sciences Research Council Grant 15/S10130. Back

2 Address correspondence and reprint requests to Dr. Hans C. Oettgen, Division of Immunology, Children’s Hospital, Boston, 320 Longwood Avenue, Boston, MA 02115. E-mail address: hans.oettgen{at}tch.harvard.edu Back

3 Abbreviations used in this paper: MC, mast cell; SCF, stem cell factor; mMCP-1, mouse MC protease-1; HPF, high-power field; LPF, low-power field; eos, eosinophil. Back

Received for publication February 19, 2002. Accepted for publication November 4, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Alizadeh, H., J. F. Urban, Jr, I. M. Katona, F. D. Finkelman. 1986. Cells containing IgE in the intestinal mucosa of mice infected with the nematode parasite Trichinella spiralis are predominantly of a mast cell lineage. J. Immunol. 137:2555.[Abstract]
  2. Capron, A., J. P. Dessaint, M. Capron, J. H. Ouma, A. E. Butterworth. 1987. Immunity to schistosomes: progress toward vaccine. Science 238:1065.[Abstract/Free Full Text]
  3. Dunne, D. W., A. E. Butterworth, A. J. C. Fulford, H. C. Kariuki, J. G. Langley, J. H. Ouma, A. Capron, R. J. Pierce, R. F. Sturrock. 1992. Immunity after treatment of human schistosomiasis: association between IgE antibodies to adult worm antigens and resistance to reinfection. Eur. J. Immunol. 22:1483.[Medline]
  4. Hagan, P., U. J. Blumenthal, D. Dunn, A. J. G. Simpson, H. A. Wilkins. 1991. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 349:243.[Medline]
  5. Rihet, P., C. E. Demeure, A. Bourgois, A. Prata, A. J. Dessein. 1991. Evidence for an association between human resistance to Schistosoma mansoni and high anti-larval IgE levels. Eur. J. Immunol. 21:2679.[Medline]
  6. Oettgen, H. C., R. S. Geha. 2001. IgE regulation and roles in asthma pathogenesis. J. Allergy Clin. Immunol. 107:429.[Medline]
  7. Pritchard, D. I., C. Hewitt, R. Moqbel. 1997. The relationship between immunological responsiveness controlled by T- helper 2 lymphocytes and infections with parasitic helminths. Parasitology 115:S33.
  8. Oettgen, H. C., T. R. Martin, A. Wynshaw-Boris, C. Deng, J. M. Drazen, P. Leder. 1994. Active anaphylaxis in IgE-deficient mice. Nature 370:367.[Medline]
  9. King, C. L., J. Xianli, I. Malhotra, S. Liu, A. A. Mahmoud, H. C. Oettgen. 1997. Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with Schistosoma mansoni. J. Immunol. 158:294.[Abstract]
  10. Despommier, D.. 1977. Immunity to Trichinella spiralis. Am. J. Trop. Med. Hyg. 26:68.
  11. Most, H.. 1978. Trichinosis–preventable yet still with us. N. Engl. J. Med. 298:1178.[Medline]
  12. Matossian, R. M., I. Salti, E. Stephan. 1977. Variation in serum immunoglobulin levels in acute trichinosis. J. Helminthol. 51:1.[Medline]
  13. Morakote, N., K. Sukhavat, C. Khamboonruang, V. Siriprasert, S. Suphawitayanukul, W. Thamasonthi. 1992. Persistence of IgG, IgM, and IgE antibodies in human trichinosis. Trop. Med. Parasitol. 43:167.[Medline]
  14. Rosenberg, E. B., S. H. Polmar, G. E. Whalen. 1971. Increased circulating IgE in trichinosis. Ann. Intern. Med. 75:575.
  15. Gabriel, B. W., D. E. Justus. 1979. Quantitation of immediate and delayed hypersensitivity responses in Trichinella-infected mice: correlation with worm expulsion. Int. Arch Allergy Appl. Immunol. 60:275.[Medline]
  16. Urban, J. F., Jr, Katona I. M., Dean D. A., F. D. Finkleman. 1984. The cellular IgE response of rodents to infection with Nippostrongylus brasiliensis, Trichinella spiralis and Schistosoma mansoni. Vet. Parasitol. 14:193.[Medline]
  17. Ahmad, A., C. H. Wang, R. G. Bell. 1991. A role for IgE in intestinal immunity: expression of rapid expulsion of Trichinella spiralis in rats transfused with IgE and thoracic duct lymphocytes. J. Immunol. 146:3563.[Abstract]
  18. Bell, R. G., J. A. Appleton, D. A. Negrao-Correa, L. S. Adams. 1992. Rapid expulsion of Trichinella spiralis in adult rats mediated by monoclonal antibodies of distinct IgG isotypes. Immunology 75:520.[Medline]
  19. Dessein, A. J., W. L. Parker, S. L. James, J. R. David. 1981. IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection. J. Exp. Med. 153:423.[Abstract/Free Full Text]
  20. Perrudet-Badoux, A., R. A. Binaghi, Y. Boussac-Aron. 1978. Trichinella spiralis infection in mice: mechanism of the resistance in animals genetically selected for high and low antibody production. Immunology 35:519.[Medline]
  21. Watanabe, N., K. Katakura, A. Kobayashi, K. Okumura, Z. Ovary. 1988. Protective immunity and eosinophilia in IgE-deficient SJA/9 mice infected with Nippostrongylus brasiliensis and Trichinella spiralis. Proc. Natl. Acad. Sci. USA 85:4460.[Abstract/Free Full Text]
  22. Urban, J. F., Jr, Schopf L., Morris S. C., Orekhova T., Madden K. B., Betts C. J., Gamble H. R., Byrd C., Donaldson D., Else K., F. D. Finkelman. 2000. Stat6 signaling promotes protective immunity against Trichinella spiralis through a mast cell- and T cell-dependent mechanism. J. Immunol. 164:2046.[Abstract/Free Full Text]
  23. Donaldson, L. E., E. Schmitt, J. F. Huntley, G. F. Newlands, R. K. Grencis. 1996. A critical role for stem cell factor and c-kit in host protective immunity to an intestinal helminth. Int. Immunol. 8:559.[Abstract/Free Full Text]
  24. Grencis, R. K., K. J. Else, J. F. Huntley, S. I. Nishikawa. 1993. The in vivo role of stem cell factor (c-kit ligand) on mastocytosis and host protective immunity to the intestinal nematode Trichinella spiralis in mice. Parasite Immunol. 15:55.[Medline]
  25. Ha, T. Y., N. D. Reed, P. K. Crowle. 1983. Delayed expulsion of adult Trichinella spiralis by mast cell-deficient W/Wv mice. Infect. Immun. 41:445.[Abstract/Free Full Text]
  26. Asai, K., J. Kitaura, Y. Kawakami, N. Yamagata, M. Tsai, D. P. Carbone, F. T. Liu, S. J. Galli, T. Kawakami. 2001. Regulation of mast cell survival by IgE. Immunity 14:791.[Medline]
  27. Kalesnikoff, J., M. Huber, V. Lam, J. E. Damen, J. Zhang, R. P. Siraganian, G. Krystal. 2001. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14:801.[Medline]
  28. Friend, D. S., N. Ghildyal, K. F. Austen, M. F. Gurish, R. Matsumoto, R. L. Stevens. 1996. Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype. J. Cell Biol. 135:279.[Abstract/Free Full Text]
  29. Colley, D. G.. 1972. Schistosoma mansoni: eosinophilia and the development of lymphocyte blastogenesis in response to soluble egg antigen in inbred mice. Exp. Parasitol. 32:520.[Medline]
  30. Knight, P. A., S. H. Wright, C. E. Lawrence, Y. Y. Paterson, H. R. Miller. 2000. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J. Exp. Med. 192:1849.[Abstract/Free Full Text]
  31. Scudamore, C. L., L. McMillan, E. M. Thornton, S. H. Wright, G. F. Newlands, H. R. Miller. 1997. Mast cell heterogeneity in the gastrointestinal tract: variable expression of mouse mast cell protease-1 (mMCP-1) in intraepithelial mucosal mast cells in nematode-infected and normal BALB/c mice. Am. J. Pathol. 150:1661.[Abstract]
  32. Wastling, J. M., P. Knight, J. Ure, S. Wright, E. M. Thornton, C. L. Scudamore, J. Mason, A. Smith, H. R. Miller. 1998. Histochemical and ultrastructural modification of mucosal mast cell granules in parasitized mice lacking the {beta}-chymase, mouse mast cell protease-1. Am. J. Pathol. 153:491.[Abstract/Free Full Text]
  33. Gurish, M. F., A. Humbles, H. Tao, S. Finkelstein, J. A. Boyce, C. Gerard, D. S. Friend, K. F. Austen. 2002. CCR3 is required for tissue eosinophilia and larval cytotoxicity after infection with Trichinella spiralis. J. Immunol. 168:5730.[Abstract/Free Full Text]
  34. Ruitenberg, E. J., A. Elgersma. 1976. Absence of intestinal mast cell response in congenitally athymic mice during Trichinella spiralis infection. Nature 264:258.[Medline]
  35. Itayama, H., Y. Oku, M. Kamiya. 1987. Longevity and fecundity of Trichinella spiralis in mast cell-deficient Sl/Sld mice. Jpn. J. Vet. Res. 35:195.[Medline]
  36. Madden, K. B., R. F. Moeller, Jr, L. W. Douglass, T. Goldman, J. K. Lunney. 1993. Trichinella spiralis: genetic basis and kinetics of the anti-encysted muscle larval response in miniature swine. Exp. Parasitol. 77:23.[Medline]
  37. Takizawa, F., M. Adamczewski, J. P. Kinet. 1992. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc{gamma}RII and Fc{gamma}RIII. J. Exp. Med. 176:469.[Abstract/Free Full Text]
  38. Bocek, P., >Jr, Draberova L., Draber P., I. Pecht. 1995. Characterization of Fc{gamma} receptors on rat mucosal mast cells using a mutant Fc{epsilon}RI-deficient rat basophilic leukemia line. Eur. J. Immunol. 25:2948.[Medline]
  39. Kita, H., G. J. Gleich. 1997. Eosinophils and IgE receptors: a continuing controversy. Blood 89:3497.[Free Full Text]
  40. Capron, M., H. Bazin, M. Joseph, A. Capron. 1981. Evidence for IgE-dependent cytotoxicity by rat eosinophils. J. Immunol. 126:1764.[Abstract]
  41. Savelkoul, H. F., B. W. Seymour, L. Sullivan, R. L. Coffman. 1991. IL-4 can correct defective IgE production in SJA/9 mice. J. Immunol. 146:1801.[Abstract]
  42. Friend, D. S., M. F. Gurish, K. F. Austen, J. Hunt, R. L. Stevens. 2000. Senescent jejunal mast cells and eosinophils in the mouse preferentially translocate to the spleen and draining lymph node, respectively, during the recovery phase of helminth infection. J. Immunol. 165:344.[Abstract/Free Full Text]
  43. Crowle, P. K., N. D. Reed. 1981. Rejection of the intestinal parasite Nippostrongylus brasiliensis by mast cell-deficient W/Wv anemic mice. Infect. Immun. 33:54.[Abstract/Free Full Text]
  44. Lawrence, C. E., J. C. Paterson, L. M. Higgins, T. T. MacDonald, M. W. Kennedy, P. Garside. 1998. IL-4-regulated enteropathy in an intestinal nematode infection. Eur. J. Immunol. 28:2672.[Medline]
  45. Madden, K. B., J. F. Urban, Jr, H. J. Ziltener, J. W. Schrader, F. D. Finkelman, I. M. Katona. 1991. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J. Immunol. 147:1387.[Abstract]
  46. Svetic, A., K. B. Madden, X. D. Zhou, P. Lu, I. M. Katona, F. D. Finkelman, J. F. Urban, Jr, W. C. Gause. 1993. A primary intestinal helminthic infection rapidly induces a gut-associated elevation of Th2-associated cytokines and IL-3. J. Immunol. 150:3434.[Abstract]
  47. Iemura, A., M. Tsai, A. Ando, B. K. Wershil, S. J. Galli. 1994. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am. J. Pathol. 144:321.[Abstract]
  48. Mekori, Y. A., D. D. Metcalfe. 1994. Transforming growth factor-{beta} prevents stem cell factor-mediated rescue of mast cells from apoptosis after IL-3 deprivation. J. Immunol. 153:2194.[Abstract]
  49. Huntley, J. F., C. Gooden, G. F. Newlands, A. Mackellar, D. A. Lammas, D. Wakelin, M. Tuohy, R. G. Woodbury, H. R. Miller. 1990. Distribution of intestinal mast cell proteinase in blood and tissues of normal and Trichinella-infected mice. Parasite Immunol. 12:85.[Medline]



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