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Mast Cells Modulate Pulmonary Acute Inflammation and Host Defense in a Murine Model

  1. Daniela Carlos1,
  2. Devandir Antonio de Souza Júnior2,
  3. Lúcia de Paula1,
  4. Maria Célia Jamur2,
  5. Constance Oliver2,
  6. Simone Gusmão Ramos3,
  7. Célio Lopes Silva4 and
  8. Dr. Lúcia Helena Faccioli1
  1. 1 Departamento de Análises Clínicas, Toxicológicas, e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil
  2. 2 Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Universidade de São Paulo, Ribeirão Preto, Brasil
  3. 3 Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil
  4. 4 Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil
  1. Reprints or correspondence: Dr. Lúcia Helena Faccioli, Dept. de Análises Clínicas, Toxicológicas, e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n Ribeirão Preto, SP, Brasil (faccioli{at}fcfrp.usp.br).
 
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Abstract

Background. Mast cells (MCs) participate in host resistance to several pathogens, but little is known about the role played by MCs in Mycobacterium tuberculosis infection.

Methods. Compound 48/80 (C48/80)-treated mice and nontreated mice were infected intratracheally with 1×105 viable M. tuberculosis bacilli (MTB; strain H37Rv).

Results. Infected BALB/c mice developed an acute pulmonary inflammation and had higher levels of tumor necrosis factor-α, interleukin-1, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and macrophage inflammatory protein-2 in the lungs by day 15. In vivo degranulation of MCs by C48/80 led to a reduction in the inflammatory reaction that was associated with a marked decline in lung proinflammatory cytokine and chemokine levels. The magnitude of the cellular immune response was also partially impaired in infected mice treated with C48/80. The number of Mycobacteria bacilli recovered from the lungs of infected mice treated with C48/80 was 1 log higher than that recovered from untreated infected mice. C48/80 treatment attenuated the granulomatous inflammation in the lung parenchyma seen in untreated MTB-infected mice.

Conclusions. These findings suggest that MCs participate in host defense against M. tuberculosis infection through the production and secretion of cytokines and chemokines that play a role in the recruitment and activation of inflammatory cells in this experimental model.

Tuberculosis is typically a disease of the lungs, which serve as a port of entry for the invasion of pathogens and a site of inflammation induced by the immune response directed against infectious agents [1]. Host protection against disease involves both innate and adaptive cell-mediated protective immune responses to arrest, kill, and remove multiplying intracellular pathogens such as Mycobacterium tuberculosis [2]. The major cell types involved in innate immunity include neutrophils [3], NK cells [4], and macrophages [5], which serve as a bridge to cell-mediated immunity in part by releasing cytokines and chemokines that are essential for mobilizing and recruiting various inflammatory cells to the site of infection [6]. Moreover, the release of cytokines and chemokines is also important for macrophage activation and the establishment of adaptive immunity. Lymphocytes and macrophages play an essential role in development of the Th1 cytokine response through the production of interleukin (IL)-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-a, providing the major mechanism of defense against mycobacterial infection [7].

Mast cells (MCs) are widely distributed in tissues, are abundant near surfaces exposed to the external environment (such as airways), and contribute to allergic diseases and chronic inflammatory processes [8]. Moreover, recent findings indicate that MCs are far more functionally diverse than previously imagined. They can produce an array of anti-inflammatory mediators [9] and function as immunoregulatory cells in T cell tolerance [10]. It is now clear that another important effector function of MCs is to promote innate immunity against microbial invasion [11, 12]. In vitro studies have demonstrated that MCs from different species are activated and release mediators on contact with bacteria [13, 14], including M. tuberculosis [15]. Although the study of the role played by MCs in innate immunity is relatively recent, there is substantial evidence that these cells play a critical role in host immune defense against bacterial infection [16, 17].

MC activation and degranulation most commonly result from multivalent antigens binding to the IgE bound to the high-affinity IgE receptor (FcɛRI) on the surface, thus crosslinking FcɛRI. This activation results in noncytotoxic degranulation and the release of a variety of preformed and newly synthesized mediators [18–21]. In vivo studies have shown that compound 48/80 (C48/80) is a potent activator of MCs [22, 23]. C48/80 binds to G proteins in the signal transduction pathway, releasing MC mediators independently of FcɛRI activation [24]. In the present study, we have found that MC degranulation produces the initial signals responsible for regulating neutrophil and mononuclear cell recruitment in the bronchoalveolar space through release of both pro- and antiinflammatory mediators. Moreover, activation of lung MCs affected IL-12, IFN-γ, and IL-10 production, which led to an increased bacterial load in the lungs. These findings suggest that release of mediators afterMC activation plays an important role in modulating acute inflammation during M. tuberculosis infection.

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Materials and Methods

Experimental infection. Young adult BALB/c mice were obtained from the animal facilities of the Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo. All experiments were approved by and conducted in accordance with guidelines of the Animal Care Committee (protocol 04.1.374.53.4). Mice were either infected with 1×105 viable M. tuberculosis (strain H37Rv) or inoculated with 100 μL of PBS (uninfected mice) intratracheally under anesthesia (200 μL of tribromoethanol diluted in PBS).

Degranulation of MCs in vivo. The model of MC degranulation used in the present study was based on a well-characterized protocol [25]. Briefly, BALB/c mice received repeated intranasal doses (50 μg/20 μmL) of C48/80 (Sigma-Aldrich) to activate MCs and release their mediators. C48/80 was administrated 24 h before infection with M. tuberculosis and again at 4, 7, 10, and 13 days after infection. The following groups of mice were used in this study: control mice, which were mock inoculated with PBS and mock treated with 0.9% saline (saline + PBS); M. tuberculosis-infected mice that were mock treated with 0.9% saline (saline + MTB); uninfected mice that were treated with C48/80 (C48/80 + PBS); and M. tuberculosis-infected mice treated with C48/80 (C48/80 + MTB). Fifteen days after infection or administration of PBS, both untreated and treated mice were killed for analysis.

Collection of bronchoalveolar lavage fluid (BALF). The chest cavity of each mouse was carefully opened, and the trachea was exposed and catheterized. Sterile PBS/sodium citrate (0.5%) was infused through the catheter in 3 aliquots of 1 mL. Total cell counts from the BALF were obtained using a Neubauer chamber, and differential cell counts were obtained by Rosenfeld staining [26].

Measurement of cytokines and chemokines. Levels of TNF-α, IL-1, IL-2, IL-6, IL-12, IL-10, IL-5, IL-4, keratinocyte-derived chemokine (KC), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-2, and IFN-γ were determined in supernatants by ELISA (BD Pharmingen), in accordance with the manufacturer's instructions. Sensitivity of the assays was >10 pg/mL.

Histological analysis. Lung fragments were fixed in 10% formalin in PBS and embedded in paraffin. Sections (4–5 μm thick) were stained with either hematoxylin-eosin or Ziehl-Neelsen acid-fast stain. For MC detection, lung sections were stained with 0.1% toluidine blue in 1% acetic acid (pH 2.8) for 20 min. MC number was determined using 10 sections from each group of mice and 10 fields from each section. Sections were analyzed using a ×40 objective with an Olympus BX50 microscope (Olympus America) equipped with a Nikon DXM1200 digital camera (Nikon Instruments). Colony-forming unit determination. Lungs were removed aseptically from killed mice either treated or untreated with C48/80, and lung fragments were incubated in digestion solution. Serial dilutions were plated on supplemented 7H10 agar medium. Colonies were counted after 28 days of incubation at 37°C.

Statistical analysis. Each experiment was performed twice. The results of the experiments are expressed as mean ±SE values. Statistical variations were analyzed by 1-way analysis of variance followed by the Tukey test and Student's t test. The level of statistical significance was set at P < .05.

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Results

Reduced number of leukocytes in BALF from infected mice treated with C48/80. To determine the effect of the mediators released by MCs on recruitment of cells to the inflammatory site, BALF was collected 15 days after MTB infection and repeated treatment with C48/80. Treatment with C48/80 did not change the total number of leukocytes in BALF from uninfected mice, compared with that in uninfected mice that did not receive C48/80. MTB infection alone increased the leukocyte number in BALF, but the total leukocyte number in BALF from infected mice decreased ∼50% after treatment with C48/80 (figure 1A). The neutrophil number increased significantly in BALF from infected mice in comparison with that in control and C48/80-treated mice. After infection, neutrophils comprised ∼25% of the total leukocytes found in BALF. With C48/80 treatment, the number of neutrophils seen in BALF from MTB-infected mice was <50% the number of neutrophils present in balf from infected mice that did not receive c48/80 (figure 1B). the number of mononuclear cells also increased in balf from infected mice, but the number of these cells was significantly less in balf from infected mice that received c48/80 (figure 1C). these data suggest that the mediators released by mcs stimulated with c48/80 modulate the recruitment of inflammatory cells to the lungs after infection with mtb.

Figure 1.
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Figure 1.

Effect of mast cell degranulation on inflammatory cell nos. in bronchoalveolar lavage fluid. Cells were obtained from BALB/c mice that were either untreated (saline) or treated with compound 48/80 (C48/80) and that were either not infected or infected intratracheally with 1×105 bacilli/100 μL (Mycobacterium tuberculosis bacilli [MTB] strain H37Rv). Control mice received 100 μL of sterile PBS by the same route. The no. of total leukocytes (A), neutrophils (B), and mononuclear cells (C) were counted after Rosenfeld staining. Data are mean ±SE values from 2 independent experiments (n=5 mice per group). Symbols indicate statistically significant differences for comparison with the control group (*), the C48/80 group (§), and the MTB-infected group (#). Statistical variations were analyzed by 1-way analysis of variance.

Significant reduction in the number of metachromatic MCs in the lungs of infected mice treated with C48/80. By toluidine blue staining, few metachromatic MCs could be identified in histologic sections of lung from uninfected mice, and these cells were localized adjacent to the pleural membrane (figure 2A). Metachromatic MCs were extremely rare in sections of lungs from mice that received C48/80 (figure 2B). The MCs that were present were degranulated, and the granule matrix was in extracellular space (figure 2B, inset). In contrast, many metachromatic MCs were seen in the lungs of MTB-infected mice, and these cells were also found near bronchioles (figure 2C). A few degranulated MCs were observed in the lungs of MTB-infected mice after treatment with C48/80 (figure 2D), and the granule matrix was in extracellular space (figure 2D, inset). In uninfected mice, C48/80 administration decreased the metachromatic MCs in the lungs by ∼69%, compared with that in untreated mice. MTB infection increased the number of metachromatic MCs by ∼23% relative to that in uninfected mice. In contrast, in MTB-infected mice that received C48/80, the number of metachromatic MCs were reduced by 63% (figure 3) relative to that in infected mice that did not receive C48/80. C48/80 treatment of the lungs degranulated MCs, which resulted in a lack of toluidine blue staining of granule matrix proteoglycans.

Figure 2.
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Figure 2.

Light microscopy of metachromatic mast cells (MCs) in pulmonary parenchyma. Lung sections were stained with toluidine blue. Metachromatic MCs (arrows) were evaluated in untreated and uninfected lungs (A), uninfected lungs treated with compound 48/80 (C48/80) (B), untreated infected lungs (C), and infected lungs treated with C48/80 (D). The insets in panels B and D show degranulated MCs in lungs after treatment with C48/80. Original magnification, ×400 (panels) and ×600 (insets).

Figure 3.
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Figure 3.

No. of metachromatic mast cells (MCs) in lung parenchyma. Cells were obtained from BALB/c mice that were either untreated (saline) or treated with compound 48/80 (C48/80) and that were either not infected or infected intratracheally with 1×105 bacilli/100 μL (Mycobacterium tuberculosis bacilli [MTB] strain H37Rv). Control mice received 100 μL of sterile PBS by the same route. The nos. of metachromatic MCs present in the lungs were determined 15 days after infection or administration of PBS. Symbols indicate statistically significant differences for comparison with the control group (*), the C48/80 group (§), and the MTB-infected group (#). Statistical variations were analyzed by 1-way analysis of variance.

Influence of treatment with C48/80 on levels of cytokines and chemokines in the lungs. To assess whether the reduction in pulmonary inflammation was correlated with levels of cytokines and chemokines in the lungs, TNF-α, IL-1, IL-6, KC, MCP-1, and MIP-2 were measured in homogenates of lungs from infected mice and from uninfected mice either treated with C48/80 or not treated (figure 4). Only KC levels in the lungs increased in uninfected mice treated with C48/80. In infected mice, levels of all proinflammatory mediators increased significantly, with the exception of IL-6. TNF-α levels decreased in the lungs of infected mice treated with C48/80 relative to those in uninfected mice treated with C48/80. Levels of TNF-α, IL-1, KC, MCP-1, and MIP-2 decreased in the lungs of infected mice treated with C48/80, compared with those in untreated and infected mice. In contrast, IL-6 levels increased in the lungs of infected mice treated with C48/80, compared with those in the other groups. These data indicate that MC degranulation and mediator release modulated the levels of cytokines and chemokines in the lungs.

Figure 4.
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Figure 4.

Effect of mast cell (MC) degranulation on chemokine and proinflammatory cytokine levels in the lungs 15 days after infection or administration of PBS. Shown are levels of interleukin (IL)-1, tumor necrosis factor (TNF)-α, IL-6, keratinocyte-derived chemokine (KC), monocyte chemotactic protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 in lung homogenates from BALB/c mice that were either not treated (saline) or treated with compound 48/80 (C48/80) and that were either not infected or infected intratracheally with 1×105 bacilli/100 μL (Mycobacterium tuberculosis bacilli [MTB] strain H37Rv). Control mice received 100 μL of sterile PBS by the same route. Data are mean ±SE values from 2 independent experiments (n=5 mice per group). Symbols indicate statistically significant differences for comparison with the control group (*), the C48/80 group (§), and the MTB-infected group (#). Statistical variations were analyzed by 1-way analysis of variance.

Influence of treatment with C48/80 on Th1 and Th2 cytokine responses in the lung. The effect of MC mediator release on Th1 and Th2 cytokine responses was evaluated by measuring IL-12, IFN-γ, IL-2, IL-10, IL-4, and IL-5 levels in the lungs after infection with MTB and treatment with C48/80 (figure 5). Cytokine levels were not altered by C48/80 treatment itself. Levels of Th1 cytokines (such as IL-12, IFN-γ, and IL-2) increased in lungs of infected mice relative to those in uninfected mice treated or not treated with C48/80. However, levels of Th1 cytokines were greatly reduced in infected mice treated with C48/80, compared with those in infected mice that were not treated with C48/80. When infected mice treated with C48/80 were compared with uninfected mice treated with C48/80, only IL-2 levels were diminished. Levels of Th2 cytokines (such as IL-4 and IL-5) were not altered in the lungs of the different groups of mice. However, IL-10 levels in the lungs of infected mice treated with C48/80 were higher than those in other groups. These data suggest that mediators released by MCs can down-regulate the levels of Th1 cytokines and increase the level of the Th2 cytokine IL-10.

Figure 5.
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Figure 5.

Effect of mast cell (MC) degranulation on Th1 and Th2 cytokine responses in lungs 15 days after infection or administration of PBS. Shown are levels of interleukin (IL)-12, interferon (IFN)-γ, IL-2, IL-4, IL-10, and IL-5 in lung homogenates from BALB/c mice that were either not treated (saline) or treated with compound 48/80 (C48/80) and that were either not infected or infected intratracheally with 1×105 bacilli/100 μL (Mycobacterium tuberculosis bacilli [MTB] strain H37Rv). Control mice received 100 mL of sterile PBS by the same route. Data are mean ±SE values from 2 independent experiments (n=5 mice per group). Symbols indicate statistically significant differences for comparison with the control group (*), the C48/80 group (§), and the MTB-infected group (#). Statistical variations were analyzed by 1-way analysis of variance.

Reduction of granuloma formation by treatment with C48/80. To investigate the effects of the mediators released by MCs on the initial formation and subsequent development of granulomas, histological sections from lungs were analyzed. On day 15 after MTB infection, the lung parenchyma exhibited perivascular and peribronchial granulomatous inflammation (figure 6A). Lungs of infected mice treated with C48/80 showed a reduced inflammatory response (figure 6B). In nontreated infected animals, bacilli could be detected by acid-fast staining in lung parenchyma (figure 6C). Lungs of infected mice treated with C48/80 showed an increase in the number of bacilli in the parenchyma (figure 6D). These findings suggest that MC degranulation results in attenuation of inflammation and inhibition of granuloma formation.

Figure 6.
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Figure 6.

Histological analysis of the lungs of mice 15 days after intratracheal infection with Mycobacterium tuberculosis bacilli (MTB). Shown are results for mice that were either not treated (saline) (A and C) or treated with compound 48/80 (C48/80) (B and D). Untreated infected mice had extensive granuloma formation (A; hematoxylin-eosin). In comparison, infected mice treated with C48/80 showed reduced granuloma formation (B; hematoxylin-eosin). Moreover, untreated infected mice had a greater bacterial load (C, arrows; Ziehl-Neelsen acid-fast stain) than the infected mice treated with C48/80 (D; Ziehl-Neelsen acid-fast stain). Original magnification, ×400 (A and B) and ×640 (C and D).

Increase in mycobacterial burden after C48/80 treatment. To investigate whether MC activation and degranulation are important in host defense, live mycobacterial bacilli were recovered from the lungs of infected mice either treated or not treated with C48/80 (figure 7). Fifteen days after infection, there was a significant increase (1.0 log) in the number of mycobacteria in the lungs of infected mice treated with C48/80 in comparison with that in untreated infected mice. These data suggest that mediators released by MCs result in impairment of bacterial clearance.

Figure 7.
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Figure 7.

Bacterial load in the lungs of mice infected with Mycobacterium tuberculosis bacilli (MTB) and either not treated (saline) or treated with compound 48/80 (C48/80). Shown are colony-forming unit counts of bacilli recovered from the lungs of mice infected intratracheally with 1×105 bacilli/100 μL (MTB strain H37Rv) and then either not treated or treated with C48/80 after 15 days of infection. Data are mean ±SE values from 2 independent experiments (n=5 mice per group). The asterisk (*) indicates a statistically significant difference between infected mice treated with C48/80 and those infected with MTB and not treated. Statistical variations were analyzed by Student's nonparametric t test.

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Discussion

The present study has demonstrated that MC numbers are increased in the lungs 15 days after MTB infection and that treatment with C48/80 modulates the inflammatory process associated with MTB infection. Pharmacological treatment of mice with C48/80 triggers MC activation and the release of preformed mediators (such as histamine, tryptase, chemokines, and interleukins [27]) that are important in the initial events of the inflammatory response. Because rat peritoneal MC regranulation occurs ∼72 h after stimulation with C48/80 [28], a model in which animals received repeated intranasal administration of C48/80 was used. Under the conditions used in the present study, MCs are repeatedly stimulated to release mediators.

MTB infection induced an intense inflammatory reaction in the lungs and an increase in the levels of neutrophils and mononuclear cells in BALF. Degranulation of MCs by C48/80 resulted in a decrease in the recruitment of mononuclear cells and neutrophils to the bronchoalveolar space during the first 2 weeks of infection. Studies in MC-deficient (W/Wv) mice have also shown a reduction in neutrophil migration during infection with Escherichia coli and Klebsiella pneumoniae. The inability to rapidly recruit neutrophils to the infectious focus observed in these animals seems to be a consequence of a reduction in the level of TNF-α [29, 30]. In the present study, the levels of TNF-α and IL-1β detected in lung homogenates were significantly reduced in infected mice treated with C48/80, suggesting that the role played by MCs in neutrophil recruitment may be attributed to the modulation of inflammatory cytokine levels at the site of the infection. Injections of TNF-α increased neutrophil recruitment and survival rates in W/Wv mice during acute bacterial peritonitis [31]. Moreover, a reduction in the number of MCs by C48/80 prevented neutrophil-migration failure during sepsis, which resulted in a reduction in the bacterial load in the peritoneal cavity and was accompanied by an increase in TNF-α and IL-1β levels in serum [32].

It is well known that MCs are an important source of other chemotactic mediators, such as IL-1β [33], IL-8, MCP-1, and MIP-2 [34]. In addition, other studies have shown that W/Wv mice infected with Listeria monocytogenes had decreased neutrophil recruitment associated with reduced levels of IL-6, compared with that in wild-type mice [35]. The present study showed an increase in IL-6 levels in the lungs of infected mice treated with C48/80. In contrast, the levels of KC, MCP-1, and MIP-2 were diminished in the lungs of these mice. Furthermore, by use of histidine-decarboxylase-deficient mice in an air pouch-type inflammation model, it has been shown that the increase in the number of infiltrating leukocytes was due to the high levels of MIP-2. These findings suggest that histamine also plays a regulatory role in the recruitment of inflammatory cells [36]. The results presented here may also be due to an indirect effect of the release of mediators by MCs on the production and release of cytokines and chemokines by other cells. Histamine, the main preformed mediator stored in MC granules, stimulates alveolar macrophages to release neutrophil and monocyte chemotactic factors [37].

During M. tuberculosis infection, bacilli are phagocytized by alveolar macrophages and dendritic cells (DCs), which secrete IL-12 and stimulate the adaptive immune response [38, 39]. A reduction in IL-12 levels in homogenates of lungs from infected mice was detected after C48/80 administration. Recent studies have demonstrated that mediators released by MCs (such as TNF-α, IL-1β, and MCP-1) may modulate the migration, maturation, and functional activity of DCs at inflammatory sites [40, 41]. Thus, it is possible to suggest that mediators released by MCs stimulated with C48/80 can negatively interfere with the activation and release of IL-12 by DCs during MTB infection. High levels of IL-12 are required during M. tuberculosis infection to ensure adaptive immunity and immunological control [42]. The presence of IL-12 in inflamed tissues drives effector cells (such as CD4 T lymphocytes) toward a Th1 pattern, and they then produce IL-2 and IFN-γ. The present study has shown that treatment of infected mice with C48/80 also significantly reduced the production of IL-2 and IFN-γ. These results can be explained by a failure to activate CD4 T lymphocytes because of the low levels of IL-12 produced by DCs. The differentiation of naive T cells into Th1 effector cells requires the presence of DCs, because these cells have the capacity to regulate T cell polarization, which is dependent on prior MC activation at the site of immunization [43].

The role played by Th2 cytokines in the suppression of cellmediated responses was also investigated. In infected mice treated with C48/80, we observed increased levels of IL-10 only. Other studies have shown that the absence of IL-10 accelerated the formation of focus granulomas in lung parenchyma, probably because of an exacerbated production of IFN-γ [44]. We observed that lung tissue of infected mice treated with C48/80 had few granulomatous inflammation sites, compared with lung tissue of untreated infected mice. Degranulation of MCs by C48/80 also resulted in an increase in the number of bacilli recovered from lungs of mice infected with MTB. These results suggest that MC activation is important in the regulation of the inflammatory response, which is crucial to the destruction and elimination of bacilli and, consequently, to host defense against infection.

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Acknowledgments

We thank Elaine Medeiros Floriano and Vani Alves Correia (Faculdade de Medicina de Ribeirão Preto) for their assistance with the histological material. We also thank Carlos Artério Sorgi for his willingness to help in the cytokine assays. We are grateful to Izaíra Tincani Brandão, Erika Vitaliano Garcia da Silva, and Ana Paula Masson for technical assistance.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Fundação de Amparo à Pesquisa do Estado de São Paulo (grant 03/12885-5).

  • Received August 22, 2006.
  • Accepted April 4, 2007.
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  1. J Infect Dis. (2007) 196 (9): 1361-1368. doi: 10.1086/521830
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