Gingival Crevicular Fluid

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GCF is an inflammatory exudate originating from the leaky venules next to the oral sulcular and junctional epithelia. An increase in the flow rate of GCF has been associated with inflammatory changes in the gingival tissues, secondary to bacterial infection (reviewed in Tonetti et al., 1998). In addition to salivary PMN and macrophages that exude through the oral junctional and sulcular epithelia into the GCF, the GCF also contains relatively high levels of

Table 2.1. Oral Innate Effector Molecules with Anti-Candida Function



Mechanism of action


Salivary mucins and proteolytic derivatives







Secretory leukoprotease inhibitor

Mucous salivary gland cells

Salivary gland epithelium

Oral mucosal and salivary gland epithelia Neutrophils, monocytes, and oral mucosal epithelium Salivary gland acinar cells, neutrophils, and monocytes Salivary gland epithelium, neutrophils, and monocytes Acinar cells in major salivary glands, neutrophils, and monocytes Oral mucosal epithelium

Modulate adhesion, candidacidal activity via electrostatic interactions with yeast membrane Efflux of Candida ATP, deprivation of energy stores Pore-forming cationic peptides

Zinc deprivation

Oxidative damage

Insertion of cationic regions into yeast membrane

Possibly by iron deprivation

Candidacidal mechanism unknown de Repentigny et al. (2000), Gururaja et al.

Koshlukova et al. (1999) Lehrer and Ganz (1996) Sohnle et al. (2000)

Lehrer and Cline (1969)

During et al. (1999)

Wakabayashi et al. (1996)

serum-derived complement components and the antimicrobial enzymes lactoferrin and peroxidase, presumably derived from these leukocytes (Miyauchi et al., 1998; Tonetti et al., 1998).

In conjunction with PMN, the complement system may play an important role in the innate immune protection of the oral mucosa. Complement activation takes place in the gingival crevice via the classical and alternative pathways (Cutler et al., 1991). Although formation of membrane attack complex (MAC) on the surface of C. albicans has been demonstrated (Lukasser-Vogl et al., 2000), direct killing of pathogenic fungi through this mechanism has not been conclusively proven (Kozel, 1996). In addition, although C5-deficient mice were extremely susceptible to systemic challenge with C. albicans, they cleared the oral infection at the same rate as controls (Ashman et al., 2003). Therefore it appears that complement is less crucial in the clearance of oral infection than it is for disseminated disease, thus affirming the localized nature of protective host responses in Candida infections.

5. Cellular Components of Innate Defense Mechanisms against Oral Candidiasis

5.1. Oral Epithelial Cells

5.1.1. Immune Regulatory Function

In oral mucosal infections, C. albicans organisms colonize the uppermost layers of epithelium, rarely invading past the spinous cell layer (Reichart et al., 1995; Eversole et al., 1997). As a result, the oral mucosa is chronically inflamed with intense intraep-ithelial and subepithelial infiltration by leukocytes (Reichart et al., 1995; Eversole et al., 1997; Myers et al., 2003). Although the role of epithelial cells as an infection barrier against Candida is well recognized (Hahn and Sohnle, 1988), new information is emerging about the role of these cells in orchestrating the oral mucosal inflammatory response to this pathogen by synthesizing immunoregulatory cytokines.

Oral epithelial cells respond to infection with the release of a number of proinflamma-tory cytokines (Bickel et al., 1996), which can initiate and perpetuate mucosal inflammation. The response of oral epithelial cells to C. albicans infection in vitro includes an array of proinflammatory cytokines, namely inter-leukin (IL)-1a, IL-1ß, IL-8, IL-18, tumor necrosis factor alpha (TNF-a), and granulo-cyte-macrophage colony-stimulating factor (GM-CSF), which have been detected at the protein and/or mRNA level (Rouabhia et al., 2002; Schaller et al., 2002; Steele and Fidel, 2002; Dongari-Bagtzoglou and Kashleva 2003a,b; Dongari-Bagtzoglou et al., 2004). These cytokine responses of oral epithelial cells to C. albicans infection are strain-specific, require direct epithelial cell-fungal cell contact, and are optimal when viable yeast, germinating into hyphae, are used in cell interactions (Schaller et al., 2002; Dongari-Bagtzoglou and Kashleva, 2003a,b). Strong evidence also supports the fact that IL-1a, resulting from the interactions of oral epithelial cells with C. albicans, autoregulates other cytokines secreted in response to this pathogen (Dongari-Bagtzoglou and Kashleva, 2003a).

IL-1a is a major constitutive and inducible proinflammatory product of epithelial cells, which can act as a key cytokine to amplify the inflammatory response by neighboring mucosal cells, or activate local leukocyte antifungal activities (reviewed in Dinarello, 1997). Studies screening cell supernatants or lysates of C. albicans-infected epithelia for various proinflammatory cytokines have identified IL-1a as one of the major cytokines upregu-lated at both the mRNA and protein levels (Schaller et al., 2002; Dongari-Bagtzoglou et al., 2004). Epithelial cell IL-1a has also been found to be present in human oral mucosal candidiasis lesions (Eversole et al., 1997). As our laboratory has shown, Candida-infected oral epithelial cells release this proinflammatory cytokine in its mature protein form in their microenvironment upon cell lysis. We have hypothesized that most of the IL-1a processing in the epithelial cell-C. albicans coculture system takes place at the plasma membrane where the cytolytic actions of C. albicans phospholipases and proteases trigger a release of membrane phospholipids. Membrane phospholipids may in turn activate the IL-1 convertase, which cleaves membrane-associated pro-IL-1a and triggers the release of the mature protein in culture super-natants (Kobayashi et al., 1990). Similarly, the ability of C. albicans to induce cleavage of the inactive IL-18 pro-peptide and trigger release of the active mature IL-18 protein has been demonstrated, an event temporally associated with the presence of the active form of the IL-1 convertase in these cells (Rouabhia et al., 2002).

IL-1 a released by injured epithelial cells increases the proinflammatory cytokine production (IL-8, GM-CSF) by neighboring uninfected mucosal and stromal cells (Dongari-Bagtzoglou et al., 2004). Such a mechanism could serve to amplify and extend the local inflammatory response, even in the absence of direct fungal invasion of the deeper mucosal and submucosal tissues. The local release of cytokines such as IL-1 a, IL-8, and GM-CSF by oral epithelial cells and fibroblasts could explain the histopathologic finding of neutrophilic microabscesses in these lesions (Eversole et al., 1997), since these cytokines are potent chemoattractants and/or activators of PMNs (Baggiolini et al., 1989; Blanchard et al., 1991). Recently, we established that the activation of PMN antifungal activity can take place in response to cytokines from C. albicans-infected oral epithelial cells in vitro. Hyphal growth inhibition experiments with human PMN from multiple donors revealed that the antifungal activity of PMN can be enhanced by two- to threefold over basal levels by C. albicans-infected oral epithelial cell supernatants, an effect largely dependent on the presence of bioac-tive IL-1a in these supernatants (Dongari-Bagtzoglou and Kashleva, in press).

We and other researchers have shown that only live, germinating organisms are capable of stimulating proinflammatory cytokine responses by oral epithelial cells, consistent with reports in endothelial cells (Orozco et al., 2000; Schaller et al., 2002; Dongari-Bagtzoglou and Kashleva, 2003a,b). C. albi-cans is a polymorphic organism which undergoes morphological transition between yeast, pseudohyphal, and hyphal forms. All three morphogenetic forms of C. albicans are frequently encountered in the oral mucosa (Cox et al., 1996) and in most oral infections both yeast and filamentous organisms can be found in the infected tissues (Olsen and Birkeland, 1977). Although in animal models of disseminated infection it has been established that the ability to change from yeast form to hyphae is crucial for virulence (Saville et al., 2003), the exact role of hyphal transition during the development of oral candidia-sis is still unclear. However, clinicopathologic findings have correlated the presence of filamentous forms with localized tissue invasion in oral candidiasis (Reinhart et al., 1995; Cox et al., 1996). Recently we studied the interactions of oral epithelial cells with the three different morphotypes of this pathogenic organism. More specifically, we compared the ability of yeast, pseudohyphal, and hyphal organisms to adhere to and lyse oral epithelial cells, as well as their ability to trigger a proin-flammatory cytokine (IL-8, IL-1 a) response. By using mutant strains with defects in hyphal transformation or by applying environmental pressure, which affected filamenta-tion in wild-type organisms, we found that morphogenesis is an important determinant of the outcome from the interactions between oral epithelial cells and C. albicans. When germination-deficient C. albicans mutants that form exclusively yeast (efgllefgll cphUcphl mutant, Lo et al., 1997) or pseudo-hyphae (tupl/tupl mutant, Braun and Johnson, 1997) were cocultured with oral epithelial cells, they exhibited a significantly reduced capacity to adhere to oral epithelial cells and disrupt their cell membrane (Fig. 2.1). Also, in sharp contrast to strains, which formed true hyphae under these coculture conditions, germination mutants and oral strains naturally deficient in germination, triggered essentially no proinflammatory cytokine responses by these cells (Villar et al., 2004). In addition to morphogenesis, invasion of oral epithelial cells and tissues is a critical determinant of the oral mucosal inflammatory response to infection. Highly invasive C. albicans strains trigger a wider array and overall greater levels of proinflammatory cytokines in oral epithelial cells compared to invasion-deficient organisms (Villar et al., in press).

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