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Infection and Immunity, September 1998, p. 4425-4430, Vol. 66, No. 9
Divisions of
Geographic1 and
Pulmonary2 Medicine, Department of
Medicine, Case Western Reserve University, Cleveland, Ohio 44106
Received 25 March 1998/Returned for modification 14 May
1998/Accepted 4 June 1998
Infection with the parasitic helminth Brugia malayi can
result in development of a severe asthmatic response termed tropical pulmonary eosinophilia. This disease, thought to result from a host
inflammatory response to blood parasites which become trapped in the
lung microvasculature, is characterized by a profound eosinophilic infiltration into the lungs. Recruitment of eosinophils also correlates with the development of airway hyperresponsiveness (AHR) to
cholinergic agonists and severe asthmatic symptoms. Our studies
examined the role of interleukin-5 (IL-5) in helminth-induced pulmonary
eosinophilia and AHR. C57BL/6 mice immunized with killed B. malayi microfilariae and challenged intravenously with live
microfilariae exhibit many of the characteristics of human disease,
including peripheral and pulmonary eosinophilia. Cells recovered by
bronchoalveolar lavage of sensitized mice consisted of 3.8%
eosinophils on day 1 postchallenge and 84% on day 10. Extracellular major basic protein was present on the surface of
airway epithelial cells as early as day 1 and continued to be evident
after 8 days, indicating sustained activation and degranulation of
eosinophils in the lung. These histologic changes correlated with the
development of AHR to carbachol. In contrast to immunocompetent mice,
immunization and challenge with B. malayi in
IL-5 An estimated 130 million people are
infected with Wuchereria bancrofti and Brugia
malayi, the parasitic helminths that cause lymphatic filariasis
(26). Much of the pathology associated with the disease,
including elephantiasis, is attributed to the adult worms in the
lymphatics. First-stage larvae (microfilariae) circulate in the blood
and generally do not cause pathological sequelae; however, in certain
populations of individuals, the presence of microfilariae in the lungs
is associated with severe asthmatic symptoms and airway
hyperresponsiveness (AHR) (3, 6). This condition, termed
tropical pulmonary eosinophilia (TPE), is thought to be caused by
microfilariae trapped in the pulmonary vasculature and can be
distinguished from allergic asthma by the effectiveness of
anthelminthics in relieving clinical symptoms (27).
Previous studies from this laboratory demonstrated that immunization
with B. malayi microfilariae selectively induces a
Th2-associated response with production of interleukin-5
(IL-5) and eosinophilia (28-30). In the present study, we
demonstrate that intravenous (i.v.) injection of microfilariae into
sensitized mice stimulates several features similar to those of TPE
patients, including the development of profound pulmonary eosinophilia
and evidence of eosinophil degranulation. Importantly, the respiratory
smooth muscle of isolated tracheas from these animals is
hyperresponsive to the cholinergic agonist carbachol, indicating
pulmonary dysfunction. Furthermore, as IL-5 is an important regulator
of eosinophil growth, differentiation, and activation (4, 7, 20,
21), we used mice in which the IL-5 gene has been disrupted to
demonstrate that eosinophils are essential for the development of
filaria-induced AHR.
Parasites.
Microfilariae were obtained from male jirds
(Meriones unguiculatis) infected with B. malayi
(NIH contract 73262). Microfilariae were harvested by peritoneal lavage
with Dulbecco's modified Eagle's medium (BioWhittaker, Walkersville,
Md.), washed twice in Hanks balanced salt solution, and counted in a
Sedgewick-Rafter counting chamber. Parasites were used live for i.v.
challenge or stored at Immunization.
Female C57BL/6 mice (4 to 6 weeks old) were
obtained from Taconic Farms (Germantown, N.Y.). IL-5 gene knockout
(IL-5 BAL and differential leukocyte counts.
Bronchoalveolar
lavage (BAL) was performed by intratracheal instillation of 0.5 ml of
phosphate-buffered saline (Sigma, St. Louis, Mo.). Total leukocyte
counts in BAL fluids were determined with a hemocytometer.
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
An Essential Role for Interleukin-5 and Eosinophils
in Helminth-Induced Airway Hyperresponsiveness
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
/ mice did not induce peripheral or pulmonary
eosinophilia, and these mice failed to show AHR in response to
cholinergic agonists. Taken together, these data indicate that IL-5 and
eosinophils are required for the induction of AHR by filarial
helminths.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
70°C for subcutaneous (s.c.) immunization.
/) mice on a C57BL/6 background were generated by
Manfred Kopf (Basel Institute of Immunology) and kindly provided by
Edward Pearce (Cornell University). All mice used in these studies were housed in microisolators until sacrificed. Mice received three weekly
s.c. immunizations at the base of the tail with 100,000 killed (frozen)
microfilariae in 0.2 ml of saline, followed 10 days later by i.v.
injection with 200,000 live microfilariae.
Histopathology and immunohistochemistry. Lungs were fixed in 10% formalin and embedded in paraffin, and 5-µm sections were prepared for histology. Sections were stained with hematoxylin and eosin for the assessment of overall inflammatory response.
To detect eosinophils and major basic protein (MBP), paraffin sections were incubated with rabbit antisera to murine MBP at 1:1,000 dilution in 1% fetal calf serum in 0.05 M Tris-buffered saline at room temperature in a humidified chamber for 2 h (anti-MBP serum was prepared by Kirsten Larsen as described elsewhere [21] and kindly provided by Gerald Gleich, Mayo Clinic, Rochester, Minn.). Biotinylated goat anti-rabbit immunoglobulin (DAKO, Carpenteria, Calif.), diluted 1:200 in 1% fetal calf serum in 0.05 M Tris-buffered saline, was added for 30 min followed by a similar incubation with prediluted alkaline phosphatase-conjugated streptavidin (BioGenex, San Ramon, Calif.). Positive reactivity was visualized with substrate (VectorRed; Sigma) containing 12 mg of levamisole (Sigma) and counterstaining with modified Harris' hematoxylin (Richard-Allen, Kalamazoo, Mich.).Isometric measurement of tracheal smooth muscle response to cholinergic agonists. Tracheal reactivity was determined as described by Garssen et al. (13). Animals were sacrificed by intraperitoneal injection of 1.5 mg of pentobarbital sodium (Nembutal; Abbott Laboratories, North Chicago, Ill.). Tracheas were dissected and kept in modified Krebs-bicarbonate solution (118.1 mM NaCl, 25 mM NaHCO3, 4.7 mM KCl, 1.0 mM NaH2PO4, 0.5 mM MgCl2, 2.5 mM CaCl2, 11.1 mM dextrose [pH 7.4]) which was continuously gassed with a mixture containing 95% O2 and 5% CO2. Adventitia and fat tissue were removed from each trachea, and a 3.0-mm cylindrical section was cut from the midportion of the tissue. Tracheal cylinders were suspended between a metal rod and a force displacement transducer (World Precision Instruments, Inc., Sarasota, Fla.) connected to an amplifier. Tissues were equilibrated in an organ bath (Crown Glass Co. Inc., Somerville, N.Y.) filled with 20 ml of Krebs-bicarbonate solution and aerated for 40 to 45 min before stimulation. The temperature was maintained at 37°C by a constant-temperature circulating unit. Starting preload was 1 g followed by 0.1-g adjustments after each stimulation until the reproducible maximal response was obtained. Concentration response curves to carbachol were performed, and isometric force (grams) generated by smooth muscle was monitored and recorded on a rectilinear four-channel chart recorder (Gould, Cleveland, Ohio).
Statistics. Data are presented as mean ± standard error (SE). Smooth muscle contractile responses were averaged and analyzed by nonlinear regression, using PRISM (Graph Pad Software). Maximal force of smooth muscle contraction (Emax) and half-maximal dose of cholinergic agonist were calculated and compared by an unpaired t test.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Histopathology of filaria-induced pulmonary inflammation in C57BL/6
and IL-5/ mice.
The initiator of the inflammatory
response in the lung is thought to be dead and degenerating worms in
the lung microvasculature (27). Lung sections were
immunostained with antisera to eosinophil MBP. In both mouse strains,
microfilariae were detected in peripheral blood at day 1 (82.5 ± 22.6 versus 77.5 ± 15.6 parasites per 80 µl of blood;
P > 0.05). Microfilariae could be found in the
peripheral blood as late as 10 days postchallenge, although the numbers
detected were not significantly different between the two strains of
mice at any time. Microfilariae were also observed in lung vessels on
day 1 after i.v. challenge. Inflammatory cells were rarely detected on
the worm surface in IL-5/ mice. However, in C57BL/6
mice, the number of inflammatory cells on the worm surface was highly
variable; some microfilariae had few associated inflammatory cells
(Fig. 1A), whereas
others were coated with inflammatory cells, notably eosinophils (Fig.
1B).
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/ mice; however, immunostaining with antisera to
eosinophil MBP demonstrated that eosinophils were a prominent component
of the perivascular infiltrate of C57BL/6 mice (Fig. 1C) but were not detected in IL-5/ mice (Fig. 1D). Consistent with this
observation, eosinophils were also prominent in the peribronchial area
(Fig. 1E), whereas the cellular infiltrate in IL-5/
mice consisted mostly of macrophages and lymphocytes (Fig. 1F), with
few eosinophils.
In addition to recruitment of intact eosinophils into the lung
parenchyma of immunocompetent mice, there was also significant extracellular MBP detected in the lungs. Figure 1E also shows extensive
deposition of MBP in the airways, which at higher magnification (Fig.
1G) was found to coat the apical surface of the respiratory epithelial
cells. Although these figures are from day 8 after challenge, MBP was
detected in the airways as early as day 1 postchallenge (not shown). In
contrast to C57BL/6 mice, no MBP was detected in the airways
of IL-5/ mice at any time (Fig. 1F and H).
Together, these data indicate that the presence of filariae in the
lungs of immunocompetent animals stimulates eosinophil recruitment and
degranulation, whereas in the absence of IL-5, filariae induce a
mononuclear cell infiltrate.
Effect of IL-5 deficiency on cells recovered from BAL fluid.
One of the hallmarks of TPE is the presence of eosinophils in BAL fluid
(27, 31). To determine the extent of inflammatory cell
recruitment to the lung, lavages were performed at various time points
after parasite challenge (Fig. 2A). In
C57BL/6 mice, the percentage of eosinophils in the BAL fluid increased
from 1.2 × 103/ml (3.8%) on day 1 postchallenge to
2.2 × 104/ml (40%) on day 4. By day 10, the total
number of cells in the BAL fluid had increased more than 13-fold, with
5.3 × 105/ml (84%) of these cells being eosinophils
(Fig. 2B). The BAL fluid of IL-5/ mice sacrificed
day 8 postchallenge contained 105 (± 1.5 × 104) cells/ml, which was not significantly different
from the value for C57BL/6 mice. However, in contrast to C57BL/6
mice, the cellular infiltrate was primarily mononuclear (97.2%),
composed of lymphocytes (58.2%) and macrophages (39%) (Fig.
2C).
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Role of IL-5 in filaria-induced AHR.
To determine if
vasculitis, eosinophil recruitment to the lung, and degranulation were
associated with physiologic changes in lung function, we evaluated AHR
in sensitized C57BL/6 and IL-5/ mice. Measurement of
contractile responses of airway smooth muscle to cholinergic agonists
is a standard method to examine AHR (2, 13, 35).
|
/ mice had a dose-response curve similar to
that for naive C57BL/6 mice (Fig. 3B). However, in contrast
to sensitized, immunocompetent mice, tracheas from sensitized
IL-5/ mice did not exhibit hyperresponsiveness to
carbachol (Emax, 1.25 ± 0.16 g versus
1.23 ± 0.22 g; P = 0.96) (Fig. 3).
Therefore, these data indicate a requirement for IL-5 and eosinophils
in filaria-induced AHR.
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In this study, we used IL-5 gene knockout mice to investigate the
role of eosinophils in the inflammatory response and subsequent pathophysiology induced by i.v. injection of B. malayi into
sensitized mice. A previous study found that BALB/c mice develop
pulmonary eosinophilia and elevated serum immunoglobulin E after
immunization and i.v. challenge with B. malayi antigens
(8). The data presented here extend these observations by
demonstrating that microfilariae injected i.v. into sensitized mice
also induce vasculitis, eosinophil degranulation, and release of MBP
and stimulate AHR. While IL-5/ mice also develop
vasculitis in response to parasite challenge, the cellular infiltrate
is primarily mononuclear. Importantly, IL-5/ mice do
not develop AHR, providing evidence for an essential role for
eosinophils in filaria-induced pulmonary dysfunction.
Several murine models of asthma have demonstrated that AHR develops after aerosol challenge with environmental allergens (5, 10, 14, 35). Filaria-induced AHR differs from these models in that (i) it relies on a hematogenous route of challenge; (ii) vasculitis is a prominent pathological feature in the lungs; and (iii) AHR is observed at 8 days postchallenge, indicating a sustained inflammatory response. Despite these differences, our data are in agreement with studies by Foster et al. in demonstrating a role for eosinophils and IL-5 in AHR (10, 18).
Our findings indicate that development of AHR requires both a sensitization phase and a localized inflammatory response. IL-5, which is essential for eosinophil production, is induced after prolonged exposure to parasite antigens (chronic exposure in humans [24, 25, 34] or repeated immunization in mice [4, 10, 33]). Dead and degenerating parasites in the lungs then stimulate a localized inflammatory response that leads to recruitment of eosinophils to the site. Lung biopsies from patients with TPE show microfilariae surrounded by eosinophilic material (6, 19, 39). The stimulus for migration of eosinophils into the airways is unclear but may involve production of IL-1 or tumor necrosis factor alpha from vascular endothelial cells at the site of parasite death which then stimulate respiratory epithelial cells to release eosinophil chemoattractants such as eotaxin (16, 23, 32).
Temporal analysis of eosinophil recruitment into the airways demonstrated that eosinophils continue to accumulate over time, with eosinophils in BAL fluid increasing to greater than 80% of the total inflammatory infiltrate on day 10 after challenge. Our data indicate that eosinophils not only are recruited to the lungs but also degranulate, releasing MBP in the airways. The observed eosinophil degranulation is consistent with the highly activated state of eosinophils recovered by BAL from patients with TPE (31). Our working hypothesis is that eosinophil degranulation and release of MBP are responsible for the pathophysiology observed in TPE. Consistent with this notion, MBP deposition on bronchial epithelial cells correlated with enhanced tracheal contractile responses. This was evident both at day 1 and day 8, indicative of a sustained response.
Although MBP is one of several cationic granule proteins with known cytotoxic activity, including eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase (1, 15), numerous studies have demonstrated a relationship between MBP and allergic airway disease. For example, MBP concentration has been correlated with severity of bronchial hyperresponsiveness in patients with allergic asthma (12, 37, 38). In addition, intratracheal instillation of MBP induced AHR in rats and monkeys (17, 36), and antibody neutralization of MBP suppressed allergen-induced AHR in guinea pigs (9, 22). Furthermore, in vitro studies have shown that MBP has a dose-dependent cytotoxic effect on tracheal epithelial cells (11). Future studies will determine the role of MBP in relation to other granule proteins in development of filaria-induced AHR and will examine the molecular mechanisms involved in the development of AHR.
In summary, this study demonstrates that i.v. injection of
B. malayi microfilariae into sensitized,
immunocompetent mice induces immunological and physiological changes
which have similarities to those described for TPE (27, 31),
notably pulmonary eosinophilia and the development of AHR. Furthermore,
the presence of MBP in airways provides a possible causal link between
eosinophil granule proteins and AHR. Importantly, the absence of AHR in
IL-5/ mice demonstrates that eosinophils are
responsible for the pathophysiology associated with this disease.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge receipt of IL-5/ mice
from Manfred Kopf and Edward Pearce and receipt of anti-MBP sera from
Kirsten Larsen and Gerald Gleich. We also appreciate the technical
assistance of Bernadette Erokwu and Eugenia Diaconu, and we thank James
Kazura, Christopher King, Frederick Heinzel, and Richard Silver for
critical review of the manuscript. We also thank Carol Farver and
Rosana Cohen for helpful discussions.
This work was supported by Burroughs Wellcome New Investigator Award 0720 (E.P.) and National Institutes of Health grant HL50527 (M.A.H.).
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Geographic Medicine, Case Western Reserve University School of Medicine, W137, 2109 Adelbert Road, Cleveland, OH 44106-4983. Phone: (216) 368-1856. Fax: (216) 368-4825. E-mail: exp2{at}po.cwru.edu.
Editor: J. M. Mansfield
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Discussion
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Infection and Immunity, September 1998, p. 4425-4430, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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