Summary and Future Directions

Oral candidiasis is characterized by a recurrent, persistent, acute inflammatory reaction to Candida infection, which is limited to the uppermost epithelial layers of the oral mucosa. The inflammatory response to this pathogen elicits chronic pain and discomfort upon mastication, but it may also be responsible for activation of immunoef- fector cells and the prevention of invasive infection. Although this chapter has concentrated on the innate immune and nonimmune mechanisms of the oral mucosal...

Allergic Fungal Rhinosinusitis

Allergic fungal rhinosinusitis (AFRS or AFS in the literature) is a hypersensitivity disease of the paranasal sinuses afflicting patients who are immunocompetent albeit with a history of atopy and allergic rhinitis to fungi. The disease process begins as the fungi become entrapped within the nasal cavity, presumably because of ostium obstruction or mucociliary disorder, and initiate a hypersensitive immune response. Just as with the other forms of fungal sinusitis, A. fumigatus is the most...

Histatins

These are histidine-rich proteins, which originate in the salivary glands of humans and higher primates (Oppenheim et al., 1988). Histatins 1 and 3 are synthesized in the parotid and submandibular glands, and together with histatin 5, which is a prote-olytic product of histatin 3, represent about 80 of the total histatin content in human saliva (Edgerton and Koshlukova, 2000). Histatin 5 is the most effective candidacidal peptide within the histatin family, killing both yeast and hyphal...

Lysozyme and Lactoferrin

Salivary lysozyme is a product of the ductal epithelium of major and minor salivary glands, in addition to being potentially synthesized by sPMN. The muramidase activity of lysozyme causing degradation of the murein in bacterial cell walls is mainly responsible for its potent bactericidal activity, which has mostly been characterized for oral streptococci (Laible and Germaine, 1985). Recently, small cationic amphipathic regions were identified in the peptide sequence of lysozyme that exhibited...

Host Factors Predisposing to Oral Candidiasis

Oral candidiasis is a superficial mycosis and can present in a variety of clinical forms. The presence of Candida alone is not an indication of disease since yeasts can be found as a commensal in approximately 40 of the population. Candidiasis is essentially a disease of the diseased and reflects as much changes in host defences as increased pathogenicity of the organism. Oral can-didiasis has been associated with a variety of predisposing factors and these are summarised in Table 3.1.

Structure of the Oral Mucosa

The oral mucosa is a highly permeable tissue, with regional variations, as the type and keratinization status of the epithelial cell layer varies in different locations of the oral cavity. The oral cavity is lined by at least four different types of mucosa (Squier and Finkelstein, 2003). While nonkeratinized epithelium lines the majority of the oral cavity, covering the hard palate and gingiva is the masticatory mucosa, which receives the most severe mechanical forces and has stratified...

Cytokines

In animal models, however, there has been some intensive study of cytokines in relation to oral candidiasis in an attempt to answer questions of their relationship with protection. Farah et al. (2001a), in an irradiated mouse model, showed that CD4 cell depletion led to increased colonisation and infection with Candida. This showed that IL-12 from the draining submandibular lymph nodes was higher in these infected animals than in controls, suggesting that IL-12 might have a role in clearance of...

Conclusions

There are several soluble factors that may be active against oral candidiasis in the oral cavity. The major one of these is antibody but anti-Candida factors also include defensins, histatins, and cytokines. Analysing protective factors in the oral cavity is challenging since both systemic and mucosal immunity can play a role, and there are several different forms of oral candidia-sis where either yeast or hyphal forms predominate, and these infections may be acute or chronic. Review of the...

Salivary Histatins

Salivary histatins are a family of basic histidine-rich proteins in which therapeutic potency against oral candidiasis is apparent and thus have promise as therapeutic agents for humans with oral candidiasis. Salivary histatins appear to be particularly active against intact cells rather than hyphae (Edgerton et al., 1998) and appear to bind to a 67-kDa protein in the cell wall. Salivary histatin 5 (Hst5) is a potent toxin for C. albi-cans it induces non-cytolytic efflux of Candida cellular...

Innate Immune Effector Function

Oral epithelial cells are constantly exposed to microbial challenge and therefore play an important role as the first line of defense against infection. In addition to secretion of natural antibiotic peptides (i.e., calprotectin and defensins) with antifungal Figure 2.1. Yeast and pseudohyphal forms of C. albicans do not injure oral epithelial cells or trigger a proinflammatory cytokine response. SCC15 oral epithelial cells were cocultured with C. albicans SC5314 (wt.), or its congenic yeast...

Salivary IgA Subclass Antibodies to Candida

IgA subclass antibodies have been reported in a few studies in patients with CAC. IgA antibodies and IgA1 antibodies were increased in comparison with the controls (Ivanyi and Ivanyi, 1990). However, it is possible that some of this IgA1 antibody might have been derived from inflammation in the oral cavity itself. However, Coogan et al. (1994) showed that in HIV infection IgA1 and IgA2 subclass antibodies against Candida were raised in both whole and parotid saliva compared with controls. This...

Saliva

Whole saliva is comprised of a mixture of molecules and cells derived from the major and minor salivary glands, with mucosal epithelium and the serus exudate originating in the gingival crevices (gingival crevicular fluid (GCF)). Collectively, these components form a strong innate defense barrier to infection. Abnormal salivary function, caused by reduced salivary flow or altered composition, leads to increased levels of C. albicans in the oral cavity, often culminating in overt OPC (Fotos and...

Epithelial Cell Factors TLR etc

This aspect is covered in more detail elsewhere. However, one of the exciting new areas of immunology has been the recognition that epithelial cells play an active part in innate immunity and that epithelial cells can produce factors interactive with the immune system upon contact with bacteria and other antigens. Some of these factors appear to be microbicidal to Candida. For example, Pivarcsi et al. (2003) showed that antimicrobials induced from epithelial cells can kill Candida. This...

General Considerations for Oral Mucosal Immunity to Candida

Theoretically, SIgA, serum IgG transu-dating through the mucosa, and cellular immunity might all play a role in protection of mucosal surfaces against Candida infections. Animal models have largely concentrated on systemic candidiasis possibly because of the difficulties in obtaining reproducible and relevant models of mucosal candidiasis. Evidence suggests a role for CMI, even at mucosal surfaces. Infection with C. albicans is an almost universal finding in patients with severe...

Other Soluble Factors

There are additional soluble factors in saliva, which have been shown to have antiCandida activity. Earlier work had reported that lysozyme in parotid saliva was increased in relation to the oral Candida load (Yeh et al., 1997) though the pathway of such stimulation was not identified. Statherin mediates a dose-dependent adhesion of C. albicans to epithelial cells (Johansson et al., 2000). This adhesion could be inhibited by specific IgG antibodies to statherin, suggesting that antibodies...

Classification of Oral Candida Infections

Candida species can be found as commensals in the mouths approximately 40 of normal subjects in amounts up to approximately 800 colony forming units (CFU) ml. There is usually some underlying precipitating factor for oral candidiasis, often an immunodeficiency and in patients with various forms of candidiasis (Table 3.2), salivary counts of greater than 20,000 CFU ml may be found. Oral candidiasis is a common condition, especially in patients with xerostomia, those taking immunosup-pressive...

Defensins

Defensins are pore-forming cationic pep-tides with broad antimicrobial activity against bacteria and fungi (reviewed in Lehrer and Ganz, 1996 Diamond and Bevins, 1998). There are 28 types of human beta defensins, but only four have so far been fully characterized. Defensins are divided into a and P classes. The a defensins are expressed in neutrophils and intestinal Paneth cells, whereas the P defensins are expressed by epithelial cells of multiple organs, including but not limited to the lung,...

Other Cell Types

Quantification of immunolabeled cells in lesions from HIV+ persons with OPC showed that the inflammatory infiltrate consisted mainly of CD1a+ Langerhans cells and macrophages, both of which moved from the lamina propria into the basal epithelial cell layer (Romagnoli et al., 1997). In this study, CD1a+ cells were the only cell type, which increased considerably in numbers, as compared to healthy controls (Romagnoli et al., 1997). A significant increase in the number of CD8+ cells was observed...

Neutrophils

Neutropenia has long been recognized as the primary risk factor for invasive candidiasis, the mortality rate of which rises up to 90 , even with maximal antifungal treatment (Rodriguez-Adrian et al., 1998). Recently it has become evident that apart from neutropenia, a decrease in function of circulating neutrophils may also be responsible for reduced resistance to infection, thus cytokine treatment combined with white blood cell transfusions have been successfully tested in neutropenic patients...

Functional Aspects of Serum and Salivary Antibodies to Candida

There have been many attempts to identify functional activity of serum or salivary antibodies in vitro and in addition some conclusions can be drawn from in vivo models. (Table 3.4) Thus Holmes et al. (2002) showed that while whole saliva promoted the binding of C. albicans to epithelial cell lines, human Candida-specific IgA antibodies could inhibit the adhesion. These antibodies could be absorbed by both Candida or by an anti-IgA. These findings seem to suggest that IgA in the human oral...

Secretory Leukoprotease Inhibitor

SLPI is a natural anti-inflammatory and antimicrobial peptide found in mucous secretions of the oral, respiratory, and genital mucosa, and is secreted by epithelial cells lining these mucosal surfaces (reviewed in Tomee et al., 1998). SLPI is a relatively small cationic peptide (12 kDa), which acts primarily as an endogenous inhibitor of neutrophil elastase, thus limiting tissue injury and inflammation (Bingle and Tetley, 1996). In addition, SLPI has antiretroviral activity and can kill...

Summary

Fungal sinusitis is an emerging family of fungal diseases, which has been thus far understudied. Though widely recognized in clinical setting and thoroughly reported in the literature, studies to corroborate these observations are yet to be done. In addition, few or no animal models have been developed to study the pathogenic process of fungal sinusitis. Future studies will need to explore the underlying host defense anomalies that predispose individuals to fungal infection of the sinuses and...

Clinical Features of Oral Candidiasis

All Candida species form the same type of oral lesions clinically (Redding, 2001). However, recent evidence suggests that mixed infections with more than one species may be associated with more severe symptoms and are more difficult to treat (Redding et al., 2002). There are three main clinical variants of oral candidiasis the pseudomembranous (also known as thrush), the hyperplastic, and the erythematous (Axell et al., 1997). The hyperplastic form is accompanied by extensive epithelial...

Noninvasive Fungal Masses Fungal Balls

Fungal balls of the paranasal sinuses are commonly referred to as mycetomas in the literature (though this is a misnomer as mycetomas technically represent superficial fungal infections on the feet) (Ferguson, 2000c). Fungal balls are noninvasive, non-immunogenic types of fungal sinusitis. Patients are immunocompetent and generally are neither atopic nor do they suffer from other disorders specific to the respiratory tract. The masses themselves are mycelial mats which can rest in the sinus...

Physiology in Immunity

This mechanism accounts for how a majority of foreign debris is cleared from the nasal region, though the process is hindered when the ostium becomes blocked or the mucus becomes too viscous to move. Particulates are inhaled and become trapped in the viscous mucus overlaying the respiratory epithelium. Using coordinated mucocil-iary beat, the mucus is swept through the cavities and is pushed into the nasopharynx where it is then swallowed and digested (Baraniuk, 1994 Herbert, 1999). This...

Gingival Crevicular Fluid

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...

Histopathologic Characteristics

Chronic hyperplastic or pseudomembra-nous candidiasis is a form of infection with distinct clinical and histopathological characteristics. The histologic features of this infection include a hyperplastic and parak-eratotic response of the surface epithelium, which is invaded by hyphal organisms. The inflammatory infiltrate consists primarily of PMN, which form microabscesses within the epithelium, whereas very few PMN are found within the lamina propria in association with blood vessels...

Humoral Immunity against Oral Candidiasis

A variety of studies have attempted to address the question of whether antibodies might be protective, in which case they might be expected to be higher in controls than in patients, or whether antibodies might reflect the antigenic load in which case they would be expected to be higher in patients than in controls. Studies of antibodies in humans in oral candidiasis have used both serum and saliva, with the main objectives of identifying responses in relation to clinical disease or sometimes...

Peroxidase and Myeloperoxidase

Peroxidase originates from two main sources in the oral cavity. Salivary peroxidase is synthesized by acinar cells in major salivary glands and myeloperoxidase (MPO) is derived from the neutrophil primary granules. Monocytes also contain MPO in their primary granules, whereas macrophages are known to lack this enzyme (Marodi et al., 1991). These enzymes combine with H2O2 and thiocyanate or iodide ions to produce hypothiocyanate, or hypoiodite, which are powerful oxidizing agents. In the...

The Paranasal Sinuses

Located within this framework of cartilage, bones, and turbinates are the four sinus cavities of the paranasal region. They function to humidify incoming air, filter out particulate matter present in respiration, aid in resonance, lighten the weight of the skull, and protect the brain and tissues from direct trauma. All the paranasal sinuses are connected to the nasal cavity via an opening in their tissue called the ostium. This small aperture allows for release of pressure and for drainage of...

Saps and Oral Humoral Immunity

The Saps appear to play a major role in virulence by mediating adherence, causing tissue damage, and evading of host immune responses (reviewed by Naglik et al., 2003b). Ten SAP genes have been identified that encode a proteinase family between 35 and 50 kDa (Hube, 2000), which include two major subfamilies based on nucleotide acid sequences identity (SAP1-3 and 4-6). The contribution of the Saps to C. albi-cans pathogenesis has been clearly demonstrated using SAP-deficient mutants and...

References

Abiko, Y., Suraweera, A.K., Nishimura, M., Arakawa, T., Takuma, T., Mizoguchi, I., and Kaku, T. (2001). Differential expression of human beta-defensin 2 in keratinized and non-keratinized oral epithelial lesions immunohis-tochemistry and in situ hybridization. Virchows Arch. 438 248-253. Abiko, Y., Jinbu, Y., Noguchi, T., Nishimura, M., Kusano, K., Amaratunga, P., Shibata, T., and Kaku, T. (2002). Upregulation of human beta-defensin 2 peptide expression in oral lichen planus, leukoplakia and...

Host Immune Responses to Saps

Very few studies have investigated the interaction between Saps and the host immune response. While high titres of anti-Sap IgG antibodies have been demonstrated in sera of candidiasis patients Macdonald and Odds, 1980 Riichel and Boning, 1983 Ruchel et al., 1988 , few detailed studies on mucosal antibody responses, using saliva or vaginal secretions, against the Saps have been performed. However, recently two reports have addressed this. In a small study of six patients with oral candidiasis...

Cellular Anatomy and Physiology

The nasal cavity, turbinates, and paranasal sinuses are lined with mucosa comprised of four distinct nasal epithelium populations olfactory epithelium OE , stratified squa-mous epithelium SE , respiratory epithelium RE , and nonciliated cuboidal columnar epithelium NCE , also known as transitional epithelium. Each type has its own unique cell populations and distribution throughout the nasal cavity. SE lines the external nares and vestibule of the nose, RE covers most of the nasoturbinates,...

Stephen J Challacombe Durdana Rahman Mukesh Mistry and Julian R Naglik

Host Factors Predisposing to Oral 3. Classification of Oral Candida 4. General Considerations of Oral Mucosal Immunity to 5. Humoral Immunity against Oral 5.1. Saps and Oral Humoral 5.2. Host Immune Responses to 5.3. Functional Aspects of Serum and Salivary Antibodies to Candida 46 5.4. Oral Immunity to Candida in HIV 5.5. Serum Antibodies Responses to Oral Candida Infection in Humans 47 5.6. Salivary IgA Subclass Antibodies to 6. Innate Factors against Oral Candidiasis 6.1. Epithelial Cell...

Tobias E Rodriguez12 Jack R Harkema3 and Gary B Huffnagle

The Nasal 2.2. The Paranasal 2.3. Cellular Anatomy and 2.4. The Role of Nasal Physiology in 3. Classifications of Fungal Sinusitis 3.1. Noninvasive Fungal Masses Fungal 3.2. Invasive Fungal 3.3. Chronic Rhinosinusitis 3.4. Allergic Fungal 4. Summary

The Nasal Cavity

Sinus Drainage And Oral Thrush

The nasal cavity connects the nares to the nasopharynx by way of the posterior nasal aperture Cooper, 1994 . In humans the nasal cavity is estimated to be 16 cm3 in volume Harkema, 1992 . The cavity is divided laterally by the nasal septum, which is comprised of cartilage more distally and bone more proximally. The cavity itself is enclosed by the lateral walls, a complicated structure containing portions of several bones three of which form the foundation for the nasal turbinates see Fig. 1.1...

Calprotectin

Calprotectin is a protein complex consisting of two noncovalently linked peptide chains that are abundantly synthesized by neutrophils, monocytes, certain subpopulations of macrophages, and squamous epithelia, such as oral epithelium and activated epidermal keratinocytes reviewed in Brandtzaeg et al., 1995 . In situ hybridization studies revealed that calprotectin is synthesized in the upper and middle spinous cell layers in the oral mucosa in oral can-didiasis as well as normal tissues, with...

Oral Microbial Ecology

The oral mucosa is colonized by over 200 microbial species. Thus, the potential for bacterial and fungal infections is high, with a need for innate defense mechanisms. The oral cavity is comprised of at least four microbial ecological niches with a certain degree of variability in the composition of their indigenous flora the saliva, the tongue, and the tooth-associated supragingival and subgingival plaques Slots, 1992 . The most predominant indigenous bacterial flora in saliva, tongue and...

Invasive Fungal Sinusitis

Within invasive fungal sinusitis there are two distinct subtypes, acute and chronic. Acute sinusitis occurs in immunocompro-mised hosts bone marrow transplant patients, HIV, etc. and generally lasts for less than 4 weeks. In the literature it is commonly referred to as fulminant sinusitis, conveying the rapid disease progression and destruction affiliated with the infection Ferguson, 2000a . Characteristically the disease progresses in a matter of days, with hyphal growth and extension pushing...