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,
* Biology of Inflammation Center and Departments of
Medicine and
Immunology, Baylor College of Medicine, Houston, TX, 77030;
Department of Respiratory Medicine, Semmelweis University, Budapest, Hungary; and
¶ Departments of Biochemistry and Molecular and Cellular Biochemistry, and Neurobiotechnology Center, Ohio State University, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The distinction between allergen classes is further illustrated by comparing their immune properties. OVA given only through the airway induces a relative tolerogenic state termed IgE tolerance (16) in which murine B cells are induced to secrete only the Ig isotypes IgG1 and IgG2a (17) and Th effector responses are not observed. Allergic inflammation of the lung is not induced when OVA is given only through the airway (18), and lack of T effector responses persists even with subsequent priming with the same Ag and adjuvant (19). However, allergic reactions to other Ags are not affected in rodents tolerized to OVA (20). Thus, rather than an abnormal response with general effects on immunity, tolerance to inhaled Ag may be regarded as a highly selective, Ag-specific immune response that may have evolved as a means of protection against inappropriate immune activation in the lung.
In contrast to OVA, immunity to type II allergens derived from A. fumigatus is distinctly allergic, dominated by the presence of lung parenchymal and airway eosinophils and Th cells type 2 (Th2 cells),4 elevated serum titers of IgE, and the physiologic sequelae of this inflammation including airway hyperresponsiveness and airway mucus overproduction (13, 14, 21, 22, 23). T and/or B cell tolerance is not observed and robust inflammation is induced without the need for extrapulmonary Ag challenge or additional adjuvants. Despite these differences, the allergic lung disease induced by both type I and II allergens is highly stereotypical and pathologic airway obstruction is induced through a final common signaling pathway involving IL-13 (8, 23, 24, 25, 26, 27, 28).
Therefore, respiratory allergens differ immunologically only in terms of their intrinsic ability to bypass induction of airway tolerance. Because human allergic lung disease is likely induced by inhaled allergen, it is critical to understand the adjuvant properties of type II allergens which enable them to bypass normal tolerogenic mechanisms and establish allergic disease. Pathogenic roles have previously been suggested for proteases and amylases and other exogenous molecules common to human allergens (29, 30, 31, 32, 33). However, it has not been shown that exposure by inhalation to these microbial products is necessary to overcome airway tolerogenic mechanisms, enable Th2 priming, and establish allergic lung inflammation.
Using an experimental model of asthma, we have identified a variety of type II allergens and have determined that active protease represents a critical biochemical activity underlying intrinsic allergenicity. We identified three distinct type II allergens, all of which contained active protease and amylase activities. However, only active protease was required for Th2 commitment, Th2- and Ag-specific Ab isotype secretion and allergic lung inflammation. Protease-free OVA was incapable of inducing these features of asthma, but could be converted into a type II allergen simply by coadministering it intranasally with a single highly purified fungal protease. Thus, together with Ag, exogenous proteases are both necessary and sufficient to bypass tolerogenic responses to inhaled Ag and initiate Th2-dependent allergic lung inflammation. Therefore, as allergenic adjuvants, proteases are implicated as important virulence factors in diverse allergic reactions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice were used between 4 and 8 wk of age and bred at the American Association for the Accreditation of Laboratory Animal Care-accredited Baylor College of Medicine (Houston, TX) vivarium. Mice were maintained under specific pathogen-free conditions and used according to institutional guidelines.
Antigens
A. fumigatus Ag was prepared from live cultures (lot no. DC980809) as previously described (14). Whole ragweed pollen extract allergen (ragweed; lot no. AK000516) was prepared by pulverizing 1 g of ragweed pollen (Sigma-Aldrich, St. Louis, MO) in 8 ml of PBS, centrifuging at 10,000 rpm for 20 min and sterile filtering the supernatant. Aspergillus oryzae allergen was obtained commercially (Sigma-Aldrich) and reconstituted to 10 mg/ml using sterile PBS. Chicken egg OVA (grade V; Sigma-Aldrich) was reconstituted in sterile PBS and was either given alone or was added in identical amount (25 µg/dose) to protease-containing preparations immediately before administration. OVA fragments were prepared by incubating OVA (1 mg/ml) with A. oryzae allergen for 90 min at 37°C followed by centrifugation through a molecular-size exclusion column (Centricon 10). Fragment isolation and exclusion of protease were confirmed by SDS-PAGE followed by silver staining and determination of total protease activity (none detected in fragments). Mice were then administered 25 µg protein/dose intranasally. Total protein content of allergens was determined using a bicinchoninic acid-based protein assay according to the manufacturer’s instructions (Pierce, Rockford, IL).
Proteases
The purified 33-kDa serine protease from A. fumigatus was prepared as described (34) and inhibited >95% by repeated addition (up to three times) of PMSF (1 mM; Roche, Basel, Switzerland) for 2 h at room temperature followed by overnight dialysis against PBS. Protease activity of A. oryzae allergen was inhibited >95% by repeated addition of phosphoramidon (500 µM; Roche) for 2 h at room temperature followed by overnight dialysis against PBS.
Active proteases were detected by gelatin gel zymography as described
(23). Total protease and amylase activities were
determined using quenched fluorescein-casein and fluorescein-starch
substrates, respectively (Molecular Probes, Eugene, OR). Enzymatic
release of the fluorescent signals was quantitated by a microplate
fluorometer (Bio-Tek Instruments, Watford Herts, U.K.) according to the
manufacturer’s instructions and data were expressed as fold increase
in signal above background following incubation at 37°C for 1 h
(Table I
). Specific activity of the
A. fumigatus serine protease was determined to be 400 U of
total protease activity per nanomole of protein (400 U/nmol).
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The Ag preparations used for these studies are listed in Table I
. Doses of Ag based on protease activity we empirically determined to
yield equivalent induction of the asthma phenotype following intranasal
challenge (Table I and Fig. 2). Doses of protease-inhibited allergens
were adjusted based on equivalent total protein content relative to
protease-uninhibited allergen. For intranasal Ag challenge, mice were
anesthetized with metofane vapor (Vedco, St. Joseph, MO) and
allowed to inhale 50 µl of allergen following application to the
nares with a pipette every 4 days for five total challenges. Data were
collected 24 h following the final Ag challenge and were expressed
as means ± SEM.
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Pt/V
(where Pt = change in tracheal pressure and
V = air flow) at 70% tidal volume, acetylcholine
chloride was administered i.v. over 1 s in escalating doses. The
provocative concentration of acetylcholine in microgam per gram of body
weight that caused a 200% increase in respiratory system resistance,
designated PC200, was calculated by linear
interpolation of appropriate dose-response curves. Significant
differences (defined as p < 0.05) were calculated on
the logarithm of PC200 by ANOVA using reference
to the specified control groups. Baseline pulmonary resistance did not
differ among the various groups of mice in these studies, ensuring
reliable comparison between the different experimental groups. BAL cells were collected by serially instilling and withdrawing 2- to 1-ml aliquots of PBS (pH 7.2) from the tracheal cannula. Aliquots of 105 cells were centrifuged onto glass slides, stained using modified Giemsa, and used to determine the absolute numbers of eosinophils.
Suspensions of whole lung cells were prepared by removing the lungs and dissecting away lymph node and thymic tissue. Lungs were finely minced and the fragments were pressed through a 40-µm nylon mesh filter. RBCs were lysed in hypotonic buffer and the remaining cells were washed twice, counted, and adjusted to 107 cells/ml in RPMI 1640 with 5% FBS and antibiotics.
For ELISPOT assays, duplicate cell samples were distributed to 96-well microtiter plates that had been precoated with mAb 11B11 anti-murine-IL-4 Ab, serial 2-fold dilutions of the cells were conducted, and the plates were incubated undisturbed for 18 h at 37°C. After washing away the cells, biotinylated secondary Ab against IL-4, BVD6-24G.2 (BD PharMingen, San Diego, CA), was added. Captured IL-4 was revealed using streptavidin-conjugated alkaline phosphatase (Jackson ImmunoResearch Laboratories, West Grove, PA) and developed using 5-bromo-4-chloro-indolyl-phosphate (Sigma-Aldrich) in 0.1 M 2-amino-2-methyl-1-propanol buffer (Sigma-Aldrich) suspended in 0.6% agarose. Individual blue spots were counted after solidification of the agar using inverted microscopy.
Serum was prepared from whole blood collected at the time of death for determination of total IgE and OVA- specific IgG1 and IgG2a. For total IgE, serum diluted 1/5 and 1/50 was added to plates precoated with anti-IgE Ab R35-72 (BD PharMingen) and developed with biotinylated Ab R35-118 (BD PharMingen) followed by streptavidin-conjugated alkaline phosphatase and nitrophenylphosphate (NPP; Sigma-Aldrich) substrate and the results compared with a standard curve prepared with monoclonal murine IgE (Sigma-Aldrich). To washed and blocked plates precoated with OVA (100 µg/ml in PBS), serum diluted 1/5, 1/50, 1/500, and 1/5000 was added, followed by biotinylated isotype-specific Abs (IgG1: LO-MG1 (Caltag Laboratories, Burlingame, CA); IgG2a: LO-MG2a (Caltag Laboratories)). Plates were washed, developed with streptavidin-conjugated alkaline phosphatase and NPP substrate, read in a standard spectrophotometer and relative concentrations were expressed as OD405.
Secreted airway mucin was quantitated using the mucin- binding lectin, jacalin (35), as described (23). A total of 40 µl of BAL diluted 1/100 and 1/1000 were added to individual wells of microtiter ELISA plates (Dynatech Laboratories, Chantilly, VA) and incubated 2 h at 37°C. Plates were washed and blocked with 3% I-block (Applied Biosystems, Foster City, CA) followed by addition of 0.002% biotinylated jacalin (Calbiochem, La Jolla, CA). After incubation for 1 h at 37°C, plates were washed and developed with streptavidin-conjugated alkaline phosphatase and NPP. Results were quantitated by comparison with a mucin (Sigma-Aldrich) standard curve.
Statistics
All data are representative of at least three independent
experiments with four to five mice in each in vivo experiment and are
expressed as means ± SEM. Significant differences
(p 
0.05) were determined using Student’s
t test (log PC200) or Mann-Whitney
U test (all other data).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Allergens prepared from A. fumigatus, A.
oryzae and the pollen of Ambrosia artemisiifolia
(ragweed) were compared with chicken OVA for their ability to induce
the asthma phenotype in mice when given intranasally. Allergens were
administered over a broad range of protease activities (1–500 protease
U/dose) and OVA was administered between 1 µg/dose and 1 mg/dose. The
data in Fig. 1 are selected to show only
maximal sublethal responses as greater amounts of allergen generally
resulted in unacceptable (>20%) mortality, although OVA alone induced
neither allergic disease nor mortality at any dose.
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). The fungal-derived allergens further induced comparable degrees of
peribronchovascular inflammation and airway goblet cell metaplasia
(Fig. 2, b and c).
Similar results were obtained with allergens administered
intradermally or i.p. followed by intranasal challenge (Refs.
13 and 14 and data not shown). These findings
document that three diverse Ag preparations are potent type II
allergens, all containing an activity or property which overcomes the
innate resistance of the airway to immune activation in response to Ag
challenge. Enzymatic activities of type II allergens and their requirement for allergic lung disease
The previous findings are remarkable given that they were obtained
using a mouse strain that is resistant to allergic lung disease
(18, 36) and other Th2-dependent phenomena
(37), and were induced by delivery of an allergen through
a mucosal route that normally elicits only tolerance (16, 38). Therefore, we sought to identify a factor common to these
allergens that is capable of overcoming induction of tolerance and
inducing strong lung allergic reactions in resistant mice. Further
analyses confirmed in all three allergens the presence of protease and
amylase activities (Fig. 3 and Table I)
which have both been linked to allergens and allergic phenomena
(39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51). Using a variety of inhibitor mixtures, we
determined the maximum degree of protease inhibition achievable for
subsequent in vivo studies. As shown, full inhibition of protease
activity was possible only with the A. oryzae allergen
(Table I).
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). In contrast, no induction of these
allergic parameters was observed in mice challenge with vehicle
(saline) or OVA alone, whereas an intermediate dose of A.
oryzae allergen without OVAshowed no significant
alteration in allergenic activity. Thus, the quantity of active
protease, not OVA, determined the degree of expression of allergic
disease induced by the A. oryzae allergen.
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). Furthermore, such
treatment abrogated the robust peribronchovascular inflammation and
airway goblet cell metaplasia induced by the A. oryzae
allergen (Fig. 2, c and d). To confirm that
protease activity, and not exogenously derived digestion products, is
allergenic we compared reactivity of A. oryzae allergen
alone to a preparation containing only allergen-hydrolyzed OVA (OVA
peptides). As expected, A. oryzae allergen reconstituted
airway hyperresponsiveness and airway eosinophilia while the OVA
peptides showed no potential to induce the asthma phenotype or elicit
lung inflammation (Figs. 2f and 4). These studies
demonstrate that the protease present in the A. oryzae
allergen, not the amylase, was required for allergic disease. Requirement of protease for Th2 commitment and Ag-specific Ab secretion
In prior studies, we showed that the Ag-induced asthma phenotype
is dependent on the generation of Th2 cells and not other effector
cells such as CD8+ T cells (52),
NK-T cells (52), and B cells (14). Thus,
consistent with induction of the asthma phenotype that is itself a
robust indicator of Th2 effector development, we detected Th2 cells
following challenge with A. oryzae/OVA allergen. OVA added
to allergenic preparations permitted detection of Ag-specific IgG1,
which in the mouse is largely Th2- and IL-4-dependent
(53, 54, 55, 56) and IgG2a, an IFN-
-dependent isotype
(57). Similar to indices of allergic lung disease,
relative quantities of total IgE and OVA-specific IgG1 titrated
according to the strength of A. oryzae/OVA allergen
administered and were comparable at the highest dose to those achieved
with A. fumigatus/OVA allergen (Fig. 5). IgE and, in contrast to prior studies
(16, 17), IgG1, were largely absent from sera of mice
receiving protease-inactive A. oryzae/OVA allergen or OVA
alone, consistent with induction of Ag-specific tolerance. Furthermore,
IL-4-producing cells, consisting of predominantly Th2 cells and
eosinophils, were only detected in lungs of mice receiving active
protease (Fig. 6). In contrast, IgG2a was
expressed to the highest degree in mice receiving only OVA
(16). Together, these studies demonstrate that, in
addition to allergic lung disease, A. oryzae/OVA allergen
induced an Ag-specific Th2 response dependent only on the presence of
active protease.
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The preceding studies establish that the protease present in the
A. oryzae allergen is required for Th2 activation, total IgE
and Ag-specific IgG1 production and allergic lung disease, whereas OVA
alone is insufficient for these endpoints. However, it remains unclear
if these are properties unique to the A. oryzae protease or
if other proteases possess similar adjuvant properties. To demonstrate
that these findings are applicable to other proteases and distinct
allergens, we combined OVA with the secreted serine protease purified
from the extracellular fluid of A. fumigatus cultures
(34), the same serine protease contained in the A.
fumigatus allergen. When administered intranasally to mice
according to the same protocol as used with previous allergens,
A. fumigatus serine protease/OVA induced airway
hyperresponsiveness identical with that elicited by the more complex
A. fumigatus allergen and significant eosinophilia (Fig. 7). A 10-fold more active protease dose
of A. fumigatus serine protease further induced airway
eosinophilia comparable to levels observed in A. fumigatus
allergen-challenged mice (4.1 x 105 ±
1.6 x 105 vs 5.3 x
105 ± 3.6 x 105
total BAL eosinophils, respectively). We further documented recruitment
of IL-4-producing cells to the lungs of A. fumigatus serine
protease/OVA-challenged mice in numbers consistent with results
obtained with other allergens (Fig. 6). In contrast, no significant
induction of these allergic parameters was observed following challenge
with saline, OVA alone, protease alone, or OVA and protease inactivated
>95% by PMSF (a serine class protease inhibitor). These studies
demonstrate that an active protease distinct from that present in the
A. oryzae allergen is sufficient for induction of allergic
lung disease. Furthermore, our findings demonstrate that active
protease in combination with Ag is both necessary and sufficient to
overcome the innate resistance of the airway to Th2 activation and
allergic lung disease.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although absolute protease activity varied considerably in different preparations having equivalent allergenic activity, only protease activity correlated with disease induction; complete inactivation of protease in the A. oryzae allergen abrogated both inflammation and Th2 activation. Neither OVA (a type I allergen), a purified active protease (A. fumigatus serine protease), nor a protease-inactive allergen complex (A. oryzae allergen) was sufficient to induce the asthma phenotype if given intranasally. Remarkably however, a combination of only two molecules, a protease and type I allergen, was sufficient to induce allergic lung disease in a manner dependent only on the dose of active protease. Therefore, active protease, in combination with a type I allergen, is sufficient to bypass airway tolerance induction, stabilize Th2 effector commitment to the type I allergen, and sustain allergic lung inflammation.
Proteases have previously been linked to allergic asthma and many of the Ags most frequently implicated in disease are either proteases or strongly associated with protease activity. These include Der P I (29), the Ag most commonly linked to asthma worldwide (58), Fel d I (59), the most important allergen derived from the domestic cat and many pollens (48, 60, 61). Fungi are also implicated in allergic disease, and as shown in this study and elsewhere (62, 63), are potent sources of active protease. Intriguingly, occupational outbreaks of asthma are associated with the handling of bacterial-derived proteases used in the manufacture of detergent products, although it is not clear from these investigations which of several bacterial products were etiologic (64, 65).
A pathogenic role for exogenous protease, especially Der P I, has
previously been suggested through cleavage of a variety of endogenous
proteins, including the low-affinity IgER (CD23; Ref. 29)
and the IL-2R
chain (30), and by modifying the balance
between IFN- and IL-4 (66, 67). Furthermore, the
proteolytic activity of Der P I enhances titers of IgE specific for the
protease (68) and bystander Ags such as OVA
(69). However, the importance of exogenous proteases
regarding Th effector development and allergic lung disease have not
been investigated until now. Because proteases distinct from Der P I
are both necessary and sufficient for the complete spectrum of allergic
lung disease induced by the parent allergen, the data together suggest
that the lung responds to exposure to divergent proteases by activating
a stereotypical allergic effector response. The mechanism by which
proteases accomplish this is the subject of ongoing investigation, but
it is unlikely to involve Toll-like receptors, as mice deficient in all
Toll-like receptor signaling have diminished Th1, but not Th2,
responses (70). A more likely mechanism may involve C
proteins. We have recently shown that C protein 3, which undergoes
extensive proteolytic modification by a variety of exogenous proteases
(71, 72, 73, 74), is necessary for Th2 commitment and robust
allergic lung disease in response to a proteolytically active type II
allergen (75).
Exogenous proteases have also been shown to degrade proteins comprising the tight junctions of airway epithelium. Although this facilitates Ag presentation (31), IgG2a responses and IgE tolerance, both Ag-specific processes induced by intranasal OVA, proceed in the complete absence of airway protease challenge and, thus, proteolytic disruption of the epithelium. Thus, active protease is not required for airway Ag presentation, only allergic responses to Ag. Although protease and amylase activities were common to all of our allergens and numerous additional molecules (32, 33) potentially relevant to allergic disease are doubtless present in the A. oryzae allergen, only protease was required for disease. Thus, while many microbial factors may contribute to expression of some features of experimental allergic disease, our data strongly suggest that only protease is necessary for the asthma phenotype.
Although our findings establish a potential link between allergenic proteases and human allergic disease, many atopic patients show serum reactivity to Ags with no known protease activity, raising questions as to the true relevance of protease to human illness (76). We demonstrated that fungal proteases are specifically capable of conferring allergenic potential to otherwise innocuous type I allergens applied to the respiratory tract. Thus, in response to inhaled allergens, Th2 activation and allergic lung disease require at least two exogenous signals: an Ag and allergenic adjuvant. Although the same molecule may represent these immune elements, we have shown that distinct molecules may just as likely express them. Interestingly, fungal proteases, some of which are excellent allergenic adjuvants as shown in this study, inexplicably make poor Ags for some heavily exposed patients, a property which likely explains why protease alone did not induce significant allergic lung disease in this study (43). Therefore, demonstration in allergic patients of serum reactivity to nonprotease allergens fails to account for potential concomitant exposure to an allergenic adjuvant, particularly when the latter is not serologically identifiable. Although these studies alone cannot exclude the existence of protease-inactive allergenic adjuvants, our data more importantly demonstrate the possibility that Th2 commitment and allergic phenomena arising from airway allergen exposure are ultimately driven by a protease-based mechanism.
Additional studies are required to define the protease virulence factors relevant to human allergic disease. Secreted endogenous proteases are abundant in normal human lung and airway secretions, but are tightly regulated through various means. Therefore, exogenous allergenic proteases that are uniquely capable of triggering inflammatory responses likely escape the regulatory processes which govern the activity of endogenous enzymes. Additional proinflammatory properties of exogenous proteases potentially include relative stability under a wide variety of environmental conditions and insensitivity to the effects of endogenous inhibitors. Another critically important issue is the relative abundance of free protease activity in combination with defined Ags in human environments, a subject about which little is known. Our study establishes that such analyses are now feasible and that in addition to serologically defined Ags, protease activity should be correlated in future studies with the incidence, prevalence and severity of a variety of human allergic conditions. Such studies promise to provide additional pathophysiologic and therapeutic insight into common allergic ailments such as asthma.
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Acknowledgments |
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Footnotes |
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2 F.K. and A.K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. David B. Corry, Baylor College of Medicine, 1 Baylor Plaza, Suite 520B, Houston, TX 77030. E-mail address: dcorry{at}bcm.tmc.edu
4 Abbreviations used in this paper: Th2 cell; Th cell type 2; BAL, bronchoalveolar lavage; NPP, nitrophenylphosphate.
Received for publication May 20, 2002. Accepted for publication September 5, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. Fattouh, M. A. Pouladi, D. Alvarez, J. R. Johnson, T. D. Walker, S. Goncharova, M. D. Inman, and M. Jordana House Dust Mite Facilitates Ovalbumin-specific Allergic Sensitization and Airway Inflammation Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 314 - 321. [Abstract] [Full Text] [PDF]
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J. A. Boyce and K. F. Austen No audible wheezing: nuggets and conundrums from mouse asthma models J. Exp. Med., June 20, 2005; 201(12): 1869 - 1873. [Abstract] [Full Text] [PDF]
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J. Xu, P. W. Park, F. Kheradmand, and D. B. Corry Endogenous Attenuation of Allergic Lung Inflammation by Syndecan-1 J. Immunol., May 1, 2005; 174(9): 5758 - 5765. [Abstract] [Full Text] [PDF]
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 M. C. Noverr, N. R. Falkowski, R. A. McDonald, A. N. McKenzie, and G. B. Huffnagle Development of Allergic Airway Disease in Mice following Antibiotic Therapy and Fungal Microbiota Increase: Role of Host Genetics, Antigen, and Interleukin-13 Infect. Immun., January 1, 2005; 73(1): 30 - 38. [Abstract] [Full Text] [PDF]
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M. C. Noverr, R. M. Noggle, G. B. Toews, and G. B. Huffnagle Role of Antibiotics and Fungal Microbiota in Driving Pulmonary Allergic Responses Infect. Immun., September 1, 2004; 72(9): 4996 - 5003. [Abstract] [Full Text] [PDF]
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H. J. de Heer, H. Hammad, T. Soullie, D. Hijdra, N. Vos, M. A.M. Willart, H. C. Hoogsteden, and B. N. Lambrecht Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen J. Exp. Med., July 6, 2004; 200(1): 89 - 98. [Abstract] [Full Text] [PDF]
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 A. KUMAR, S. LNU, R. MALYA, D. BARRON, J. MOORE, D. B. CORRY, and A. M. BORIEK Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma FASEB J, October 1, 2003; 17(13): 1800 - 1811. [Abstract] [Full Text] [PDF]
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