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Published ahead of print on November 1, 2007, doi:10.1165/rcmb.2007-0309OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 38, pp. 401-406, 2008
© 2008 American Thoracic Society
DOI: 10.1165/rcmb.2007-0309OC

Fc{gamma}RIII Is Protective against Pseudomonas aeruginosa Pneumonia

Lawrence M. Rhein1–3,, Michael Perkins1, Norma P. Gerard1,3 and Craig Gerard1,3

1 Pulmonary Division, Department of Pediatrics; 2 Division of Newborn Medicine, Children's Hospital; and 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Lawrence M. Rhein, M.D., Ina Sue Perlmutter Laboratory, Children's Hospital, 320 Longwood Ave., Boston, MA 02115. E-mail: Lawrence.rhein{at}childrens.harvard.edu


   Abstract
Top
 Abstract
CLINICAL RELEVANCE
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Defenses against bacterial infections involve activation of multiple systems of innate immunity, including complement, Toll-like receptors, and defensins. Reactions to chronic infections bring adaptive immune mechanisms into play as well, with the introduction of modulatory interactions between the two. In humans with chronic lung infections, the severity of inflammation and disease correlate with elevated levels of pathogen-specific immune complexes and complement activation. In mice with genetic deficiency in C5, or targeted deletion of the C5a receptor, Pseudomonas lung infections reveal a role for the C5a anaphylatoxin in disease severity. Deficient animals exhibit significantly reduced survival and clearance of infecting bacteria, simultaneous with greatly increased pulmonary influx of inflammatory cells. Among the actions of C5a on inflammatory cells mediated through the C5a receptor is a shift in the relative expression of Fc{gamma} receptors to increase Fc{gamma}RIII relative to Fc{gamma}RII. This shift may significantly impact defenses against chronic infection, reflecting the cellular activation profiles of these IgG receptors. We addressed the role of Fc{gamma}RIII in defense against Pseudomonas lung infection, and found that, like C5aR-deficient mice, animals with targeted deletion of Fc{gamma}RIII are more susceptible to mortality upon infection and exhibit reduced clearance of the pathogen. Pseudomonas infection was associated with an increase in the Fc{gamma}RIII/Fc{gamma}RII ratio in wild-type mice, and the data support its role as an additional mechanism of host defense against bacterial infection.

Key Words: Fc{gamma} • receptors • host defense • bacterial infection • Pseudomonas • pneumonia



   CLINICAL RELEVANCE
Top
 Abstract
 CLINICAL RELEVANCE
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The immunoglobulinG receptor, Fc{gamma}RIII, is protective in a murine model of Pseudomonas aeruginosa lung infection. Fc{gamma}RIII-deficient mice exhibit increased mortality after P. aeruginosa lung infection and are impaired in their ability to clear the organisms.

 
Chronic bacterial lung infections in humans are associated with the presence of pathogen-specific antibodies, and the severity of disease may correlate with levels of immunoglobulin (Ig)G containing immune complexes. In addition to promoting activation of complement to generate C5a anaphylatoxin and the membrane attack complex, these immune complexes engage Fc{gamma} receptors expressed on myeloid cells, promoting phagocytosis and bacterial killing.

Fc{gamma} receptors, selective for the Fc region of IgG, constitute a family of proteins with characteristic distribution on inflammatory cells and distinct activating or suppressing signaling properties (1). Like many other immune regulatory systems, the Fc{gamma} receptors support both stimulatory (Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV) and inhibitory functions (Fc{gamma}RII) and their relative expression determines the net cellular response (2). The activating receptor, Fc{gamma}RI, is important for promoting phagocytosis of bacterial pathogens, cytokine release, cellular cytotoxicity, and antigen presentation (3, 4). Mice deficient in Fc{gamma}RIIb reveal its suppressive functions, as they exhibit increases in humoral responses, IgG-induced anaphylaxis, increased pulmonary immune complex injury, and IgG-mediated clearance of pathogens and tumor cells (5–9). Contrasting this, Fc{gamma}RIII-deficient mice are protected from IgG-mediated injury, including autoimmune hemolytic anemia, thrombocytopenia, and immune complex injury (10, 11).

Regulation of Fc{gamma} receptor expression is accomplished at least in part by the complement anaphylatoxin, C5a, and interaction with its primary receptor, the C5aR. This interaction triggers Gi protein–dependent signal transduction, and, in addition to its other cellular activation functions, sets the balance of inhibitory and stimulatory Fc{gamma}Rs toward Fc{gamma}RIII (12). Our studies have demonstrated that activation of the C5aR is critical for mucosal defense against Pseudomonas aeruginosa lung infections (13). In its absence, or in animals lacking C5 (14), infected mice are more susceptible to mortality in spite of a massive influx of neutrophils. Mechanistically, this may at least in part reflect a defective modulation of Fc{gamma}R expression. In addition, the recently characterized secondary C5a receptor, C5L2, which does not transduce signals through activation of G proteins used by the C5aR, appears to negatively modulate C5aR functions (15). A role for this receptor in Fc{gamma}R expression has not been demonstrated. In wild-type mice, bacterial infection leads to significant increases in expression of the C5aR, without concomitant up-regulation of C5L2 (16). The relationship of the change in C5aR expression to the Fc{gamma}RII/III balance is not established, nor is a distinct role for Fc{gamma}RIII in defense against bacterial pathogens. The present study was undertaken to investigate the role of Fc{gamma}RIII in the complex mechanisms of host defense against bacterial lung infections. We demonstrate a critical role for this component, potentially resulting from deficiency in the C5a-C5aR-Fc{gamma}R axis.


   MATERIALS AND METHODS
Top
 Abstract
 CLINICAL RELEVANCE
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Animals
All studies were performed according to institutional and National Institutes of Health guidelines for animal use and care. Experiments were performed using Fc{gamma}RIII–/– mice on the C57BL/6 background (Jackson Labs, Bar Harbor, ME). Wild-type C57BL/6 mice were used as controls. Animals were housed under barrier conditions; age (6–10 wk old)- and sex-matched mice were used for all studies described.

Induction of Pneumonia
P. aeruginosa, strain PAO1, was kindly provided by Dr. Gerald Pier (Harvard Medical School). Bacteria in log phase growth were suspended in PBS containing 1% fetal calf serum (FCS) at OD650 = 0.5, and 2 x 106 colony-forming units (CFU) PsA was administered intranasally in 20 µl to anesthetized mice (ketamine, 90 mg/kg, and xylazine, 10 mg/kg, intramuscularly) for determination of survival. For all other experiments an inoculum of 5 x 106 CFU per animal was used, and mice were killed at 12 and 24 hours thereafter.

Quantitation of P. aeruginosa–Specific IgG
Enzyme-linked immunosorbent assay (ELISA) plates were coated with PsA at OD650 of 0.5 in 40 mM sodium phosphate, pH 7.0 by incubating overnight at 4°C. Plates were washed with PBS containing 0.05% Tween-20, and blocked with 1% bovine serum albumin (BSA) in PBS. Mouse serum, diluted 1:10 in PBS containing 1% BSA and 0.05% Tween-20, was serially diluted through four sequential 1:2 dilutions and plated in duplicate. After 90 minutes at 37°C, plates were washed and incubated for 90 minutes at 37°C with Fc-specific goat anti-mouse IgG conjugated with alkaline phosphatase (diluted 1:1,000). Reactivity was detected by measuring the OD405 developed with p-nitrophenyl phosphate, and the relative titer of anti-PsA IgG assessed from the dilution resulting in no further change in color development.

Analysis of Bacterial Clearance and Histopathology
At 12 or 24 hours after PsA infection, animals were killed and the lungs and spleens were harvested. Organs were homogenized in 1 ml of 1% proteose peptone at 0°C, and an aliquot suspended in 1 ml Dulbecco's modified Eagle's medium/F12 containing 10% FCS and 0.5% Triton X-100. Serial 10-fold dilutions were plated on MacConkey agar for overnight growth. For histologic examination, lungs were fixed in Bouin's solution. Paraffin sections were stained with hematoxylin and eosin and evaluated by light microscopy.

Measurement of Vascular Permeability
Vascular permeability 24 hours after infection was determined using Evans blue dye. Four hours before killing, mice were injected intraperitoneally with 200 µl 1% Evans blue dye in PBS. Bronchoalveolar lavage (BAL) and serum were collected and permeability changes evaluated by comparison of the ratio of OD600 in BAL to serum.

Analysis of BAL
Lungs were lavaged with PBS at 4°C, three times 0.8 ml, and total cell count was assessed (Beckman Coulter, Fullerton, CA). Differential cell counts were determined from Wright/Giemsa stained cytospins, counting 200 cells per slide.

In Vitro Assessment of Macrophage Phagocytosis
Resident peritoneal macrophages were harvested from uninfected wild-type and Fc{gamma}RIII–/– mice by lavage with RPMI at 4°C three times 4 ml. After lysis of red blood cells, macrophage preparations were routinely greater than 95% pure. Cells (1 x 106) were incubated with 1 x 107 CFU PsA PA01 expressing green fluorescent protein (GFP) in the presence of 10% serum obtained from Fc{gamma}RIII–/– or wild-type mice. After 1 hour at 37°C with gentle shaking the cells were washed, stained with DAPI, fixed with 4% paraformaldehyde, and counted by confocal microscopy. Cell-associated GFP-PsA was quantitated using ImagePro Software (Media Cybernetics, Bethesda, MD).

Production of Reactive Oxygen Species
ROS production by phagocytes was measured using dihydro-2'4,5,6,7,7'-hexafluorofluorescein (H2HFF) (FcOxyburst; Invitrogen, Carlsbad, CA). Peritoneal macrophages or bone marrow cells isolated from uninfected Fc{gamma}RIII–/– or wild-type mice (5 x 106) in PBS containing 1% BSA were incubated with 10 ng/ml PMA in the presence or absence of the inhibitor DPI (10 µg/ml). Fluorescence intensity was determined by flow cytometry (FACSCalibur; BD Biosciences, Franklin Lakes, NJ).

Cytokine and Anaphylatoxin Analyses
The BAL content of TNF-{alpha}, IL-6, and C5a was determined by ELISA according to the manufacturer's instructions (R&D Systems, Minneapolis, MN).

Fc{gamma}R Expression Analysis
Mice were infected intranasally with PsA as described above. Alternatively, C5a (200 ng per animal) in 50 µl PBS was administered intratracheally. Four hours later, lungs were harvested, processed for total RNA, and Fc{gamma}R levels quantitated by real-time RT-PCR (Taq-Man) using published Fc{gamma}R-specific primers (17).

Statistical Analyses
All data are expressed as the mean ± SEM. Survival curves were compared using Fisher's exact test. Comparison between groups was conducted using Student's t test, and differences were considered significant for P <= 0.05.


   RESULTS
Top
 Abstract
 CLINICAL RELEVANCE
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Fc{gamma}RIII Expression Confers Protection against Mortality Associated with P. aeruginosa Pneumonia
PsA lung infections cause severe bronchopneumonia, which previous studies have shown is controlled in part by functional expression of the complement C5a anaphylatoxin receptor (13). Mice deficient in either C5 or the C5aR exhibit exacerbated sequelae to PsA infection relative to wild-type animals, with increased mortality, decreased bacterial clearance, and an overabundance of infiltrating inflammatory cells (13, 14). In immune complex lung inflammation, C5a–C5aR interactions set the threshold for Fc{gamma} receptor–mediated responses by modulating the relationship of stimulatory Fc{gamma}RIII to inhibitory Fc{gamma}RII (17). To understand whether the Fc{gamma}RIII/Fc{gamma}RII ratio also plays a role in host defense against bacterial infection, we studied the responses of Fc{gamma}RIII-deficient mice compared with those of wild-type animals after lung infection with PsA. As shown by the data of Figure 1, Fc{gamma}RIII-deficient mice are significantly more susceptible to mortality after intranasal infection with 5 x 106 CFU of PsA. All of the Fc{gamma}RIII–/– mice died within 72 hours, whereas 50% of wild-type animals survived at least 8 days (n = 9–14 per group, P = 0.006).


Figure 1
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  		Figure 1. Fc{gamma}RIII-deficient mice are more susceptible to mortality from Pseudomonas aeruginosa (PsA) lung infection. Fc{gamma}RIII–/– (squares) and wild-type (triangles) mice were infected intranasally with 2 x 106 colony-forming units (CFU) PsA and monitored for survival (n = 9–14 mice per group, P = 0.002 for Fc{gamma}RIII–/– versus wild-type animals).

 
Fc{gamma}RIII Expression Contributes to Clearance of Pseudomonas
To determine whether expression of Fc{gamma}RIII facilitates clearance of PsA infection, the number of viable bacteria recovered 12 or 24 hours after inoculation of 5 x 106 CFU was determined. As shown in Figure 2, almost 2-fold more bacteria were recovered from the lungs of Fc{gamma}RIII-deficient mice compared with wild-type animals 24 hours after infection (1.04 ± 0.41 x 105 CFU/g lung tissue for Fc{gamma}RIII–/– versus 1.96 ± 0.61 x 104 CFU/g lung tissue for wild-type mice, P = 0.022, n = 10–11 mice per group). A significant reduction in clearance was also observed at 12 hours (data not shown).


Figure 2
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  		Figure 2. Fc{gamma}RIII deficiency impairs clearance of pulmonary PsA infections. Fc{gamma}RIII–/– and wild-type mice were infected intranasally with 5 x 106 CFU PsA. After 24 hours, animals were killed and lung homogenates assessed for bacterial content. Data are the mean CFU ± SEM per gram lung, P = 0.022 for n = 10–11 mice per group.

 
Fc{gamma}RIII–/– Mice Exhibit Increased Inflammation after PsA Infection
Histologic analysis of the lungs 24 hours after infection showed evidence of diffuse bronchopneumonia for both mouse strains, with no apparent difference between the two (Figure 3). Analysis of cellular infiltrates in BAL fluid, however, revealed a significant increase in cellularity, composed primarily of polymorphonuclear leukocytes (PMNs) and macrophages (Table 1). Both PMNs and macrophages were elevated by approximately 30% in the Fc{gamma}RIII–/– mice with no significant difference in lymphocytes.


Figure 3
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  		Figure 3. Histologic appearance of lung tissues from Fc{gamma}RIII–/– and wild-type mice 24 hours after PsA infection. Twenty-four hours after intranasal infection with 5 x 106 CFU PsA, mice were killed and lungs processed for histology. Both mouse strains exhibited diffuse inflammatory infiltrates. Sections are representative of three independent experiments, hematoxylin and eosin (original magnification: x200).

 

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  		TABLE 1. FC{gamma}RIII-DEFICIENT MICE HAVE GREATER PULMONARY INFLUX OF LEUKOCYTES AFTER PSEUDOMONAS AERUGINOSA INFECTION

 
As shown in Figure 4, BAL levels of the proinflammatory cytokines, IL-6, and TNF-{alpha} were also elevated in PsA-infected Fc{gamma}RIII–/– mice compared with wild-type animals (IL-6, 460 ± 52 pg/ml for Fc{gamma}RIII–/– versus 270 ± 74 for wild-type mice, P = 0.025; TNF-{alpha}, 276 ± 86 pg/ml for Fc{gamma}RIII–/– versus 108 ± 46 pg/ml for wild-type mice, P = 0.048, n = 9–11 mice per group). The extent of complement activation was determined by evaluating levels of the anaphylatoxin C5a/C5adesArg in BAL fluid, and was not significantly different for the two mouse strains (4.21 ± 0.41 ng/ml for Fc{gamma}RIII–/– versus 3.0 ± 0.064 ng/ml for wild-type mice, P = 0.08, n = 9–11 mice per group).


Figure 4
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  		Figure 4. Lung cytokines are elevated in Fc{gamma}RIII-deficient mice after PsA infection. The concentrations of IL-6, TNF-{alpha}, and C5a present in bronchoalveolar lavage (BAL) fluid 24 hours after PsA lung infection were assessed by enzyme-linked immunosorbent assay. Data are the mean ± SEM concentrations, P = 0.025 for IL-6, P = 0.048 for TNF-{alpha}, NS for C5a (n = 9–11 mice per group).

 
The change in permeability resulting from PsA infection was assessed from the extravasation of Evans blue dye (Figure 5). At 24 hours after infection, permeability in both Fc{gamma}RIII–/– and wild-type mice mouse lungs was significantly elevated compared with uninfected controls (P < 0.05, n = 3–6 mice per group). Permeability in PsA-infected Fc{gamma}RIII–/– mice was approximately 4-fold greater than for PsA-infected wild-type mice (P = 0.012, n = 5–6 mice per group).


Figure 5
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  		Figure 5. Fc{gamma}RIII-deficient mice exhibit increased pulmonary vascular permeability after PsA lung infection. Fc{gamma}RIII–/– and wild-type mice were infected intranasally with 5 x 106 CFU PsA or administered an equal volume of PBS. Permeability was assessed 24 hours later by extravasation of Evans blue dye into BAL fluid. Permeability index was determined from the dye content of BAL compared with plasma, P < 0.05 for infected versus PBS, P = 0.012 for PsA-infected Fc{gamma}RIII versus wild-type, n = 3 mice per group for PBS controls, n = 5–6 per group for PsA-infected animals.

 
Role of Phagocytes in Defense against PsA Pneumonia
In light of the absence of Fc{gamma}RIII on inflammatory cells in the knockout mice, we assessed their phagocytic ability in vitro. Peritoneal macrophages from uninfected Fc{gamma}RIII–/– or wild-type mice were incubated with GFP-labeled PsA and the number of internalized bacteria evaluated by confocal microscopy. Cells from both mouse strains contained a similar number of engulfed bacteria (7.00 ± 0.43 per cell for wild-type and 6.29 ± 0.38 per cell for Fc{gamma}RIII–/–) (Figure 6). We also compared the bactericidal competence of Fc{gamma}RIII–/– phagocytes with those of wild-type mice by assessing their ability to produce reactive oxygen species. Cells from both mouse strains produced similar amounts of ROS after stimulation with phorbol myristate acetate (data not shown). These results indicate the lack of Fc{gamma}RIII does not significantly alter the intrinsic inflammatory cell function.


Figure 6
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  		Figure 6. Phagocytosis of PsA by alveolar macrophages from Fc{gamma}RIII–/– and wild-type mice. BAL macrophages were isolated 1 hour after intranasal inoculation with GFP-tagged PsA. Phagocytosis was determined by fluorescent microscopy as the number of bacteria per cell and was comparable for Fc{gamma}RIII–/– and wild-type animals.

 
Pseudomonas Infection Alters the Fc{gamma}RIII/Fc{gamma}RII Ratio via a C5a/C5aR-Dependent Mechanism
Activation of Fc{gamma}R-expressing cells by ligation of C5a and C5a receptor has been shown to modulate the relative cell surface levels of Fc{gamma}RII and Fc{gamma}RIII. In models of immune complex injury, this activation determines the subsequent inflammatory response (12, 17). As activation of complement and generation of C5a is one response to bacterial infection, we evaluated alterations in the relative expression of Fc{gamma}RII and Fc{gamma}RIII in PsA-infected mouse lungs. Wild-type and C5aR-deficient mice were infected intranasally with PsA, and 4 hours later the lung mRNA levels of Fc{gamma}RII and Fc{gamma}RIII were analyzed by RT-PCR. As shown in Figure 7, PsA infection in wild-type mice revealed a significant increase in the Fc{gamma}RIII/Fc{gamma}RII ratio, but no change was observed in C5aR-deficient animals (P = 0.04 for PsA infected versus uninfected wild-type mice, n = 4 per group). The change in Fc{gamma}RIII/Fc{gamma}RII ratio was similar after intratracheal administration of recombinant C5a (P = 0.009 for wild-type mice with versus without C5a administration, n = 4 per group). Thus generation of C5a by infecting PsA regulates Fc{gamma}R expression levels as it does in immune complex injury.


Figure 7
Figure 7
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  		Figure 7. Lung expression of Fc{gamma}RII relative to Fc{gamma}RIII is reduced following PsA infection and by C5a administration. (A) Recombinant C5a (200 ng/mouse) or PBS was administered intratracheally to wild-type or C5a receptor–deficient mice and the expression of Fc{gamma}RII and Fc{gamma}RIII assessed 4 hours later by quantitative PCR. (B) Wild-type or C5a receptor–deficient mice were infected intranasally with 5 x 106 CFU PsA, and 24 hours later lung expression of Fc{gamma}RII and Fc{gamma}RIII was assessed by quantitative PCR. Data are expressed as the ratio of Fc{gamma}RII to Fc{gamma}RIII, P = 0.01 for C5a-treated versus PBS control, P = 0.04 for PsA-infected versus PBS control wild-type mice, NS for C5aR–/– animals, n = 4 mice per group.

 
Presence and Induction of Anti-PsA Antibodies
Since ligation of Fc{gamma}RIII requires the presence of immune complexes, we questioned whether PsA-reactive antibodies were detectable in uninfected mice. Naïve mice of both mouse strains were found to exhibit low but detectable levels of anti-PsA reactive IgGs, but no difference was detected in either the total or subclass distribution between the two. Within 24 hours of PsA infection, both Fc{gamma}RIII–/– and wild-type mice exhibited increases in the titers of PsA-specific IgG1 and IgG2b, but not IgG2a (n = 7–8 mice per group).


   DISCUSSION
Top
 Abstract
 CLINICAL RELEVANCE
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this investigation of mechanisms of host defense against P. aeruginosa lung infections, we found that mice lacking Fc{gamma}RIII have significantly reduced survival and bacterial clearance compared with wild-type animals. Despite the increased mortality, Fc{gamma}RIII–/– mice exhibit elevated numbers of inflammatory cells in BAL fluid. They also exhibited enhanced pulmonary vascular permeability and increased levels of IL-6 and TNF-{alpha} in BAL fluid compared with PsA infected wild-type mice. Comparison of levels of the C5a anaphylatoxin generated in the two strains indicated no significant difference in complement activation.

In probing the mechanism of Fc{gamma}RIII-mediated protection against PsA infection, we assessed the presence of pathogen-specific IgG and found detectable levels in both mouse strains before infection, with no apparent difference in the total levels or the IgG subclass distribution. Within 24 hours of infection, the levels of PsA-specific IgG increased in both mouse strains, supporting a role for an immune complex–mediated component in the PsA lung infections, and suggestive of a scenario similar to that found in chronic bacterial lung infections in humans.

Previous studies have shown that the relative expression of Fc{gamma}RIIb and Fc{gamma}RIII is important for determining the nature of responses in immune complex–mediated inflammation, such that increased Fc{gamma}RIII promotes inflammation and decreased Fc{gamma}RIII promotes tolerance (17). These studies have also demonstrated a link between complement activation–mediated generation of C5a, triggering of the C5aR, and increases in the ratio of Fc{gamma}RIII to Fc{gamma}RIIb (17). Indeed, C5aR-deficient mice, present a phenotype similar to Fc{gamma}RIII-deficient animals with respect to pulmonary infection with PsA (13). In our original report of this phenotype we did not ascribe a mechanism to this finding, and the relationship of the C5a receptor to Fc{gamma} receptor expression was not known. Similarities in the phenotype of C5aR–/– and Fc{gamma}RIII–/– mice with respect to PsA lung infection, in concert with an appreciation of C5a-mediated regulation of Fc{gamma} receptor balance provide a compelling explanation for the complex interactions involved. Thus, deficiency in any component is likely sufficient to set the net response awry and lead to an impairment in host defense. Incomplete overlap of each of the components, however, may be reflected by distinctions among mouse strains in their responses to PsA infection. In particular, Fc{gamma}RIII–/– mice exhibited an approximately 30% increase in the influx of inflammatory cells, whereas C5aR–/– animals experienced a massive (~ 300%) infiltration of neutrophils into the lungs (13).

Consistent with previous reports, intratracheal administration of exogenous C5a led to an increase in the ratio of Fc{gamma}RIII to Fc{gamma}RII. In C5aR-deficient mice, this shift was not observed. PsA lung infection resulted in a similar change in the Fc{gamma}RIII to Fc{gamma}RII ratio in wild type mice, but not in C5aR–/– animals. Thus, in both Fc{gamma}RIII- and C5aR-deficient mice, increased susceptibility to PsA pneumonia may be related in part to an inability to appropriately regulate Fc{gamma} receptor expression.

The extent to which interaction between Fc{gamma}RIII and pre-existing anti-PsA–specific antibodies contribute to the phenotype is not clear. We observed increases in PsA-reactive IgG1 and IgG2b after infection. Studies have suggested that the inflammatory potential of immune complexes mediated by distinct IgG subclasses is related to their binding affinities for specific Fc{gamma} receptors (18). Other studies have demonstrated that patients with cystic fibrosis who have chronic PsA lung infections exhibit a correlation between lung function and levels of specific IgG subclasses (19–21). Additional studies are needed to define the relationship between immune complexes, Fc{gamma} receptors, complement, and the host response to bacterial pathogens.


   Footnotes
 
This work was supported by NIH HL51366 (to C.G.).

Originally Published in Press as DOI: 10.1165/rcmb.2007-0309OC on November 1, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form August 22, 2007

Accepted in final form September 29, 2007


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 MATERIALS AND METHODS
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 DISCUSSION
 References
 

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