INTRODUCTION

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The indigenous microbiota plays an important role in health and diseases of humans and animals. It contributes to the development of the immune system and provides resistance to colonization by allochthonous or pathogenic microorganisms (95, 299, 323, 420, 495). It also constitutes a reservoir of potentially pathogenic bacteria that may infect host tissues (44, 299, 495).

In the oral cavity, indigenous bacteria are often associated with the etiology of two major oral diseases, which are endemic in industrialized societies and are increasing in developing countries (514). Oral diseases seem to appear after an inbalance among the indigenous microbiota, leading to the emergence of potentially pathogenic bacteria. To define the process involved in caries and periodontal diseases, it is necessary to understand the ecology of the oral cavity and to identify the factors responsible for the transition of the oral microbiota from a commensal to a pathogenic relationship with the host (299, 322). The regulatory forces influencing the oral ecosystem can be divided into three major categories: host related, microbe related, and external factors (299).

Secretory immunoglobulin A (SIgA) constitutes the predominant immunoglobulin isotype in secretions, including saliva. It is considered to be the first line of defense of the host against pathogens which colonize or invade surfaces bathed by external secretions (320, 328). The main function of SIgA antibodies seems to be to limit microbial adherence as well as penetration of foreign antigens into the mucosa (59, 320, 323, 328). Naturally occurring SIgA antibodies reactive with a variety of indigenous bacteria have been detected in saliva (55, 59, 108, 174, 293, 296). Furthermore, indigenous bacteria of the oral cavity have been found to be coated with SIgA (55, 108). The role of these antibodies in the colonization and the regulation of the indigenous microbiota is still controversial. Despite the presence of SIgA antibodies, a resident microbiota persists in the oral cavity. Indigenous bacteria can survive in the oral cavity because they are less susceptible to or can avoid immune mechanisms (30, 44, 87, 141, 142). It is also possible that SIgA has an effect on indigenous bacteria but that it is only a minor force among the multiple factors that maintain the homeostasis of the indigenous microbiota (87).

Since caries and periodontal diseases are associated with indigenous bacteria, defining the role of SIgA in the control of the oral indigenous microbiota is a prerequisite for the elaboration of effective vaccines against these diseases. Until now, studies that evaluated the role of SIgA in the microbial ecology of the oral cavity gave contradictory results. In vitro experiments have shown that SIgA may inhibit (222, 383) or promote (222, 270) the adherence of oral bacteria to teeth. Experiments with animal models showed that salivary IgA induced against Streptococcus mutans leads to a reduction in the colonization of this bacterium and to the prevention of caries (328). More recent studies indicate that the immunity is not maintained (392). IgA-deficient humans were found to be more or less susceptible to caries and periodontal diseases (90, 393, 394).

The present review describes the oral ecosystems, the major factors that might control the oral microbiota, the basic aspects of the secretory immune system, and the biological functions of SIgA and finally focuses on experiments related to the role of IgA in the microbial ecology of the oral cavity. To present an overall picture of the current knowledge of oral microbial ecology, this review is not limited to human studies but includes in vitro systems such as the chemostat and the artificial mouth, as well as results obtained with animal models, such as rodents and primates, including our study on a murine model.

Ecology is the science that studies interrelationships between organisms and their living (biotic) and nonliving (abiotic) environment (20).

An ecosystem consists of the microbial community living in a defined habitat and the abiotic surroundings composed of physical and chemical elements. In its simplest expression, the oral ecosystem is thus composed of the oral microorganisms and their surroundings, the oral cavity (495).

Within an ecosystem, the development of a community usually involves a succession of populations. The process begins with the colonization of the habitat by pioneer microbial populations. In the oral cavity of newborns, streptococci (S. mitis biovar 1, S. oralis, and S. salivarius) are the pioneer organisms (73, 367a). Pioneer microorganisms fill the niche of this new environment and modify the habitat, and as a result, new populations may develop. As the process continues, the diversity and the complexity of the microbial community increase. Succession ends when no additional niche is available for new populations. At this stage, a relatively stable assemblage of bacterial populations is achieved. It is called a climax community.

The concept of a stable or climax community does not imply static conditions. The stability is based upon homeostasis, which implies compensating mechanisms that act to maintain steady-state conditions by a variety of controls aimed at counteracting perturbations that would upset the steady state. The concepts of homeostasis and bacterial succession are important in oral microbiology. Some factors, such as a high-sucrose diet, may cause an irreversible breakdown in the homeostasis of the oral ecosystem, resulting in the initiation of caries (299).

ORAL ECOSYSTEM OF MAMMALS

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Habitats

The oral cavity is a moist environment which is kept at a relatively constant temperature (34 to 36°C) and a pH close to neutrality in most areas and thus supports the growth of a wide variety of microorganisms. However, the mouth must not be considered a uniform environment. There are several habitats in the oral cavity, each being characterized by different physicochemical factors and thus supporting the growth of a different microbial community. This is partly due to the great anatomical diversity of the oral cavity and the interrelationship between the different anatomic structures. The oral cavity possesses both hard (teeth) and soft (mucosa) tissues. The tooth can be described as a nonshedding hard surface that offers many different sites for colonization by bacteria below (subgingival) and above (supragingival) the gingival margin. In contrast, the oral mucosa is characterized by a continuous desquamation of its surface epithelial cells, which allows rapid elimination of adhering bacteria. The mucosa that covers the cheek, tongue, gingiva, palate, and floor of the mouth varies according to the anatomical site. The epithelium may be keratinized (palate) or nonkeratinized (gingival crevice) (495). The tongue, with its papillary surface, provides sites of colonization that are protected from mechanical removal. The area between the junctional epithelium of the gingiva and teeth, referred to as the gingival crevice, also provides a unique colonization site that includes both hard and soft tissues.

The oral surfaces are also constantly bathed by two important physiological fluids, the saliva and the gingival crevicular fluid. These fluids are essential for the maintenance of the oral ecosystems by providing water, nutrients, adherence, and antimicrobial factors. The supragingival environment is bathed by saliva, while the subgingival environment (gingival crevice) is bathed mainly by the gingival crevicular fluid. Saliva is a complex mixture that enters the oral cavity via the ducts of three pairs of major salivary glands, the parotid, the submandibular, and the sublingual, and the minor salivary glands. Saliva contains 99% water but also contains glycoproteins, proteins, hormones, vitamins, urea, and several ions. The concentrations of these components will vary according to the salivary flow. Generally, a slight increase in the secretion rate leads to an increase in sodium, bicarbonate, and pH and a decrease in potassium, calcium, phosphate, chloride, urea, and proteins (103, 347). At higher secretion rates, the concentrations of sodium, calcium, chloride, bicarbonate, and proteins increase while the concentration of phosphate decreases. Saliva helps maintain tooth integrity by providing ions such as calcium, phosphate, magnesium, and fluoride for the remineralization of tooth enamel.

Gingival fluid is an exudate originating from plasma that passes through the gingiva (junctional epithelium) to reach the gingival crevice and flows along teeth. The diffusion of gingival fluid in healthy gingiva is slow but increases during inflammation. The composition of the gingival fluid is similar to that of plasma; it contains proteins, albumin, leukocytes, Igs, and complement.

Humans. The oral microbiota of humans is highly complex and diverse. It is composed of more than 300 bacterial species, to which may be added protozoa, yeasts, and mycoplasmas. Some of the more frequently isolated microorganisms are listed in Table 1. Their distributions vary qualitatively and quantitatively according to the habitat. Mutans streptococci (S. mutans, S. sobrinus, S. cricetus, and S. rattus) and S. sanguis are found in larger numbers on teeth, while S. salivarius is isolated mainly from the tongue (446). S. mutans and S. sanguis appear in the oral cavity only after eruption of the teeth (446).

(i) Teeth. On teeth, microorganisms colonize in a dense mass forming dental plaque (299, 350, 495). Dental plaque consists of microbial communities organized in a complex matrix composed of microbial extracellular products and salivary compounds. The microbial composition of dental plaque varies according to the site and the sampling time. Dental plaque develops preferentially on surfaces protected from mechanical friction, such as the area between two teeth (approximal surface), the subgingival area (gingival crevice), and the pits and fissures of the biting surfaces. The predominant organisms isolated from supragingival dental plaque are gram-positive, facultatively anaerobic bacteria, particularly Actinomyces spp. and streptococci (299, 350, 495). Gram-negative bacteria of the group Veillonella, Haemophilus, and Bacteroides are regularly isolated but in lower proportions (45, 495).

(ii) Mucosal surfaces. Little information is available on the microbiota of mucosal surfaces. The oral mucosa of the gingiva, palate, cheeks, and floor of the mouth are colonized with few microorganisms (0 to 25 CFU/epithelial cell) (495). Streptococci constitute the highest proportion of the microbiota in these sites, with a predominance of S. oralis and S. sanguis. The genera Neisseria, Haemophilus, and Veillonella have also been isolated (495). On the tongue, a higher bacterial density (100 CFU/epithelial cell) and diversity is found (44, 495). In all studies, Streptococcus spp. (S. salivarius and S. mitis) and Veillonella spp. were the predominant members of the microbiota (44, 495). Other major groups isolated include Peptostreptococcus spp., gram-positive rods (mainly Actinomyces spp.), Bacteroides spp., and other gram-negative rods. Black-pigmented obligate anaerobic rods and spirochetes, which are closely associated with periodontal diseases, have been recovered in small numbers (511). It has been suggested that the tongue could act as a reservoir for microorganisms that are implicated in periodontal diseases (511).

Animal models. Animal models have been widely used in dental research (347, 350, 475). In general, information on their resident oral microbiota has been only partial or has been obtained during experimental protocols (44, 347, 350, 533). However, some studies have characterized the oral resident microbiota of monkeys (26, 61, 438), rats (204), and mice (150, 396, 500) more extensively. These results are summarized in Table 1. It is interesting that two genera, Lactobacillus and Streptococcus, are common to all laboratory animals.

It is now well established that caries and periodontal diseases are infectious diseases associated with resident microorganisms of the dental plaque (299). In deciding upon therapy, such as vaccination, it is important to determine if one or several microorganisms cause the diseases. There are two major hypotheses about the role of plaque in oral diseases (301). The specific plaque hypothesis proposes that only a few microorganisms are involved in the oral disease process, while the other hypothesis (nonspecific) considers that diseases result from the interaction of the whole plaque with the host. Several experiments have attempted to describe the oral microbiota associated with caries and periodontal diseases and to identify the specific etiological agents. The current knowledge of the microorganisms involved in caries and periodontal diseases process has been obtained from the studies of humans and of laboratory animals, such as monkeys, hamsters, rats, and mice.

Caries. Dental caries is a bacterial disease of the dental hard tissues; it is characterized by a localized, progressive, molecular disintegration of the tooth structure. The development of caries is associated with dental plaque of smooth coronal surfaces, pits, and fissures. Caries may also appear on root surfaces that are exposed to the oral environment as a result of gingival recession. The demineralization of teeth (enamel, dentine, and cementum) is caused by organic acid produced from the bacterial fermentation of dietary carbohydrates. The frequent ingestion of carbohydrates may lead to the selection of bacteria that are acidogenic (capable of producing acid from carbohydrates) and aciduric (capable of tolerating acid) and concurrently to a low-pH environment. These conditions favor the solubilization of tooth minerals. The pH at which this demineralization begins is known as the critical pH and ranges between pH 5.0 and 5.5 (275).

Periodontal diseases. Periodontal diseases is a general term describing the inflammatory pathologic state of the supporting tissues of teeth. Periodontal diseases can be grouped into two major categories, gingivitis and periodontitis. Each can be further divided according to the age of the patient (prepubertal, juvenile, adult), disease activity and severity (rapid, acute, chronic), and distribution of lesions (localized or generalized) (299, 439). Gingivitis is defined as an inflammation of gingival tissues which does not affect the attachment of teeth. Periodontitis involves the destruction of the connective tissue attachment and the adjacent alveolar bone (439). In periodontitis, the gingival crevice is deepened to form a periodontal pocket due to the apical migration of the junctional epithelium along the root surface (495). The induction and progression of periodontal tissue destruction is a complex process involving plaque accumulation, release of bacterial substances, and host inflammatory response (156, 157, 299). Although bacteria rarely invade tissues, they may release substances that penetrate the gingivae and cause tissue destruction directly, by the action of enzymes and endotoxins, or indirectly, by induction of inflammation. The host inflammatory response to bacterial antigens is both protective and destructive in periodontal diseases. Tissue damage may be caused by the release of lysosomal enzymes from phagocytes and by the production of cytokines that stimulate connective tissue cells to release metalloproteinases (including collagenases) or cytokines that activate bone resorption. Among the bacteria regularly isolated from periodontal pockets, those producing such virulence factors are generally gram-negative rods and include Porphyromonas, Prevotella, Fusobacterium, Actinobacillus actinomycetemcomitans, Capnocytophaga, and Wolinella.

The formation of dental plaque on smooth surfaces has been widely studied in vitro and in vivo and represents a good example of the force involved to maintain the homeostasis of the oral ecosystems. The development of dental plaque follows a general bacterial succession pattern under the control of several factors (reviewed in reference 353). After tooth brushing, dental plaque is initiated by the deposition of an acellular proteinaceous film, termed the acquired pellicle (353). The major constituents of the pellicle are components of saliva and gingival crevicular fluid such as proteins (albumin, lysozyme, proline-rich proteins), glycoproteins (lactoferrin, IgA, IgG, amylase), phosphoproteins, and lipids. Bacterial components such as glucosyltransferase are also present. The bacteria colonize the pellicle within the first 2 to 4 hours after cleaning. The pioneer microorganisms consist mainly of streptococci (S. sanguis, S. oralis, and S. mitis) and, in smaller numbers, Neisseria and Actinomyces. The bacteria with low affinity for the pellicle are eliminated by salivary flow. After initial colonization, the pioneer microorganisms grow rapidly, forming microcolonies that are embedded in an extracellular matrix composed of bacterial and host molecules. During this process, the alteration of the environment by pioneers allows the colonization by other bacterial groups such as Veillonella and Haemophilus (48 h after tooth brushing). Several bacterial interrelationships including coaggregation, production of antibacterial substances, and food chains contribute to increase the diversity of the bacterial community. Also, the consumption of oxygen by aerobic species favors the colonization of obligately anaerobic microorganisms such as Fusobacterium, Bacteroides, and spirochetes (1 to 2 weeks). If the plaque is left to accumulate, the complexity of the microflora increases until a climax community has been established (2 to 3 weeks). As described above, an inbalance in the plaque ecosystem may lead to the development of oral diseases. For example, the uncontrolled development of supragingival plaque in the absence of oral hygiene may cause gingivitis and subsequent colonization of the subgingival crevice by periodontopathogens. A high sucrose intake may lead to a higher colonization of plaque by S. mutans and Lactobacillus and to the development of caries.

In the following sections, each factor that may influence the physicochemical environment and the colonization of the oral cavity will be described in detail. All these factors are interrelated and depend on host and microbial activities as well as external factors such as diet or oral hygiene. For better clarity, these factors have been divided into four categories: physicochemical, host related, microbial, and external.

The physicochemical factors result from the combined action of host, microbial, and external factors. In all in vivo and in vitro systems, the growth of microorganisms is influenced by five important variables: temperature, pH, availability of water, availability of nutrients, and oxidation-reduction potential (20). As the mouth is constantly bathed by saliva and crevicular fluid, water is not considered to be a limiting factor.

Oxidation-reduction potential and anaerobiosis. Many enzymatic reactions are oxidation-reduction reactions in which one compound is oxidized and another compound is reduced. The proportion of oxidized to reduced components constitutes the oxidation-reduction potential or redox potential (E_h). The E_h is greatly influenced by the presence or absence of molecular oxygen, which is the most common electron acceptor. Anaerobic bacteria need a reducing environment (negative E_h) for growth, while aerobic bacteria need an oxidizing environment (positive E_h). The mouth is characterized by a wide range of oxidation-reduction potentials, allowing the growth of aerobic, facultative anaerobic, and anaerobic bacteria (495). In general, the dorsum of the tongue and the buccal and palatal mucosa are aerobic environments with positive E_h, thus better supporting the growth of facultative anaerobic bacteria. The gingival crevice and the approximal surfaces of the teeth (surfaces between teeth) possess the lowest E_h and the highest concentration of obligately anaerobic bacteria. The E_h values vary between +158 to +542 mV in saliva but may reach 300 mV in gingival crevices (495). The E_h also varies during plaque formation, changing from positive values (+294 mV) on clean tooth surfaces to negative values (141 mV) after 7 days (218). The fall in E_h during plaque formation is the result of oxygen consumption by facultative anaerobic bacteria as well as a reduction in the ability of oxygen to diffuse through the plaque. This explains in part the increased in number of obligately anaerobic bacteria during plaque formation.

Nutrients. Chemostat studies (42, 145, 186, 316) and a study with mice (34) suggest that the levels of most bacterial populations are strongly controlled by substrate availability. Each bacterial species must be more efficient than the rest in utilizing one or a few particular substrates under certain conditions. According to Liebig's law of the minimum, the growth of each organism is limited by the required substrate that is present in the lowest concentration (20). In the oral cavity, microorganisms living in the supragingival environment have access to nutrients from both endogenous (saliva) and exogenous (diet) origin. Saliva is an important source of nutrients and can sustain normal growth of microorganisms in the absence of exogenous nutrients (105, 454). Saliva contains water, carbohydrates, glycoproteins, proteins, amino acids, gases, and several ions including sodium, potassium, calcium, chloride, bicarbonate, and phosphate. Among exogenous dietary components, carbohydrates and proteins have the greatest influence on the composition of the oral microbiota (34, 335, 457).

Hormonal changes. It is well known that in humans, puberty and pregnancy are characterized by increased levels of steroid hormones in plasma and subsequently in the crevicular fluid and saliva (130, 252). It is also well documented that pregnancy and puberty are associated with an increase in gingival inflammation which is accompanied by an increase in gingival exudate (539). It has been proposed that the exacerbations in gingival inflammation may be due to hormone-induced alterations in the microbiota of the gingival crevice (211, 241, 539). Microorganisms in the subgingival area that use hormones as growth factors may be favored during the period of hormone increase associated with puberty and pregnancy (242). Several investigators have described a transient increase in the number of black-pigmented gram-negative anaerobic bacteria in the subgingival microbiota during puberty (107, 180, 337, 529) or pregnancy (211, 242). Kornman and Loeshe (242) reported an increased proportion of Prevotella intermedia in the subgingival microbiota of pregnant woman, corresponding to an increased levels of estrogens and progesterone in plasma. They also demonstrated in vitro that progesterone or estradiol can substitute for vitamin K as an essential growth factor for P. intermedia (242). In contrast, other studies were unable to find any changes in the subgingival microbiota during puberty (536) and pregnancy (212).

Stress. Host stress may be associated with changes in hormones, salivary flow, dietary habits, and immune response (23, 51, 104, 254, 503). Few studies on the effect of stress on the indigenous microbiota have been performed, and most data have been obtained from studies of the intestinal microbiota of rodents. Stress in rodents is considered to be related to stimulation of the hypothalamic-pituitary-adrenocortical axis, which can lead to an elevation in corticosterone concentration. Crowding, fighting, and husbandry changes are some of the factors that are known to induce an increase in cortisol levels in plasma in mice and might play an important role in animal stress (51, 197, 254, 368, 503). These factors affect the behavior of mice in terms of feeding, sexual habits, grooming, rearing, and biting (503). The composition of the intestinal microbiota of rodents may be altered by a variety of unrelated disturbances, such as changes in environmental temperature, crowding in cages, and fighting among animals (239, 424). These changes in the intestinal microbiota include a reduction in numbers of lactobacilli (424, 474) as well as fusiform and segmented filamentous bacteria (230, 231, 239). In our studies, some evidence suggested that the oral microbiota of mice may also be influenced by stress. Various factors such as shipping to our animal facility, husbandry modifications, and low temperature (in nude mice) led to decreases in the proportions of Lactobacillus murinus among the total cultivable oral microbiota (150, 294, 295).

Genetic factors. The genetic background appears to influence the susceptibility to caries (249, 379) and periodontal diseases (161). This could in part be because the host genetic factors select for a microbiota with varying potential for causing oral diseases. The selection of a certain microbiota by the host is dependent on inherited immune factors, physiology, metabolism, mucus composition, or receptor-ligand interactions (337). Malamud et al. (289) produced evidence for the inheritability of agglutinin activity and parotid flow rate. Genetic factors also seem to influence the intestinal (230, 231, 308, 506) and oral (337, 425, 476) microbiota. Moore et al. (337) reported that the composition of subgingival microbiotas of monozygotic twins (11 to 14 years of age) was more similar than that of dizygotic twins. In contrast, we found that the genetic background does not seem to be an important factor in the composition of the oral microbiota of mice and that its influence is probably masked by environmental and husbandry factors (150). On the other hand, the oral indigenous microbiota of SPF mice is simple and the effect of the genetic background is perhaps observed only when the host is exposed to a more complex microbiota.

Adherence. To get established in the oral cavity, microorganisms must first adhere to teeth or to mucosal surfaces. Adherence is essential for providing resistance to the flow of saliva. Adherence is mediated by adhesins on the surface of bacteria and by receptors on the oral surface. Microbial adhesins consist of polysaccharides, lipoteichoic acids, glucosyltransferases, and carbohydrate-binding proteins (lectins). These adhesins are found as cell wall components or are associated with cell structures, such as fimbriae, fibrils or capsules. The receptors may be salivary components (mucins, glycoproteins, amylase, lysozyme, IgA, IgG, proline-rich proteins, and statherins) or bacterial components (glucosyltransferases and glucans) that are bound to oral surfaces (160, 405, 422). The adherence may result from nonspecific physicochemical interactions between the bacteria and the oral surfaces. For example, lipoteicoic acids on microbial surfaces may interact with negatively charged host components through calcium ions or through hydrogen or hydrophobic bonding. However, these interactions cannot alone explain the selective attachment of bacteria to various oral surfaces. It is believed that another mechanism accounts for this selective colonization, perhaps involving specific or stereochemical interactions between bacterial adhesins and host receptors. In this case, the same physicochemical forces intervene but now act between extremely small, highly localized, spatially well organized opposing molecular groups (70). It is probable that the bacteria first adhere by nonspecific interactions which are followed by stronger stereochemical interactions. A number of specific interactions have been identified in adhesion to human tooth surfaces (reviewed in reference 422). The stereochemical interactions involved in bacterial adhesion in the oral cavity are analogous to the interactions between antigen and antibody or between an enzyme and its substrate. For example, type 1 fimbriae of Actinomyces naeslundii genospecies 2 and surface antigen I/II (protein P1) of S. mutans can bind to proline-rich proteins (407), Streptococcus gordonii can bind to -amylase (423), and A. naeslundii genospecies 2 and Fusobacterium nucleatum can interact with statherin (159, 160, 535). Another adherence strategy involves a lectin-like bacterial protein with the complementary carbohydrate receptor located on glycoproteins (344). The interaction may be inhibited in vitro by adding the specific carbohydrate. S. sanguis can bind to sialic acid-containing oligosaccharides of the low-molecular-weight salivary mucin (MG2) (345). Type 2 fimbriae of Actinomyces binds to the beta-linked galactose glycoprotein on epithelial cell surfaces (60).

Diet. It is well documented that frequent consumption of a high-sucrose diet enhances the development of S. mutans and Lactobacillus (335, 347, 457). The fermentation of sucrose into lactate generates a low pH, favoring acidogenic and acidophilic bacteria. The substitution of sucrose with weakly fermentable sugar alcohols such as xylitol results in a reduction of S. mutans numbers and caries (205, 287). Xylitol appears to selectively inhibit carbohydrate metabolism in S. mutans, which reduces acid production and thereby stabilizes the composition of the oral microbiota (49). Apart from the effect of sucrose, very few studies have addressed the effect of other dietary components on the oral microbiota. During our research on the effects of various dietary components on the oral microbiota of mice (34), we found that a high-starch diet favored an increase in the proportion of Enterococcus faecalis while a high-protein diet favored an increase in Lactobacillus murinus. Variations in the vitamin, lipid and mineral content of the diet had no direct effect on the oral microbiota of mice.

Oral hygiene and antimicrobial agents. Oral hygiene is one of the most important factors in the maintenance of oral homeostasis and oral health. The mechanical removal of plaque by tooth brushing and flossing can almost completely prevent caries and periodontal diseases (307, 460). The addition of antimicrobial agents to dentifrices, mouthwashes, and varnishes increases the effect of mechanical oral hygiene procedures. Antimicrobial agents may assist in protection by reducing bacteria adhesion to the tooth surface, by reducing the growth of microorganisms and plaque accumulation, by selectively inhibiting only those bacteria directly associated with oral diseases, or by inhibiting the expression of virulence determinants, such as acid production or protease activity (302). Fluoride is found in most toothpastes and mouth rinses and is well known for its anti-caries properties. The principal caries-preventive effect of fluoride is attributed to the formation of fluoroapatite and calcium fluoride, which lead to an increase in the resistance of enamel to demineralization (48). It can also inhibit bacterial growth by reducing the sugar transport, glycolytic activity, and acid tolerance of many gram-positive species (48, 301). Fluoride can help stabilize the composition of the microflora by reducing the rate of acid production and the fall in pH during frequent carbohydrate intake (43). Other agents that have been formulated for commercial toothpastes and/or mouth rinses include chlorhexidine, quaternary ammonium compounds, plant extracts, metal ions, and phenolic compounds (97, 304). These antimicrobial agents have been shown to reduce dental plaque formation, caries, and gingivitis (97, 302).

Drugs and diseases. Salivary gland hypofunction and xerostemia may result from the intake of xerogenic medication, irradiation treatments for head and neck cancer, and Sjøgren's syndrome. Patients with xerostomia have a decrease capacity to eliminate sugars and buffer the acids found in plaque. In addition to suffering from the reduction in saliva protection, patients with xerostomia generally consume soft, high-sucrose diets and suck sour candies to keep their mouths moist (299). Patients suffering from xerostemia have higher levels of mutans streptococci, lactobacilli, staphylococci, and Candida, while the levels of S. sanguis, Neisseria, Bacteroides, and Fusobacterium are reduced compared with those in a healthy individual. They are also more susceptible to dental caries and candidiasis (63, 273).

Other factors. Many other external factors may affect the oral microbiota; these include the wearing of dentures or partial dentures (305), smoking, oral contraceptives usage (539), malnutrition (474), host macroenvironment (150, 294, 295), and various exposures to exogenous bacterial species (150, 396).

SECRETORY IGA SYSTEM

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IgA Structure

SIgA is the principal immunoglobulin isotype found in saliva and all other secretions. It exists as a polymeric molecule composed of two (or more) IgA monomers (300,000 Da), a J (joining) chain (15,600 Da), and a secretory component (SC) (70,000 Da) (reviewed in references 54, 81, and 220) (Fig. 1). Each monomeric IgA is formed of four polypeptides, two -heavy chains and two light chains (kappa or lambda) linked covalently by disulfide bonds. The J chain and SC are disulfide linked to the Fc region of the IgA molecule (220). The J chain is a polypeptide synthesized within plasma cells that is involved in initiating the polymerization of IgA. The SC is a heavily glycosylated protein produced by mucosal epithelial cells. The SC stabilizes the structure of polymeric IgA and protects the molecule from proteolytic attack in secretions (224). It is referred to as the polyimmunoglobulin receptor (PIgR) in its membrane-bound molecular form. It is present on basolateral epithelial cell membranes and acts as a receptor for transepithelial transport of polymeric IgA (and IgM) (81, 497).

View larger version (17K): [in this window] [in a new window]   FIG. 1.   Schematic representation of SIgA. SIgA consists of at least two IgA monomers linked to a J chain and a secretory component (SC). The J chain and SC are disulfide linked to the Fc region of the IgA molecule. Each IgA monomers consist of two -heavy chains and two light chains linked covalently by disulfide bonds. The wavy line represents the SC.

In humans, there are two IgA subclasses, IgA1 and IgA2, which occur in similar proportions in saliva and other secretions. The IgA1 and IgA2 heavy chains differ in only 22 amino acids, predominantly due to a deletion of 13 amino acids in the hinge region of IgA2; these amino acids are present in IgA1 (220, 498, 501). This structural difference renders IgA2 resistant to the action of a number of bacterial proteases that specifically cleave IgA1 in the hinge region (220). These IgA1 proteases are produced by several mucosal pathogens as well as by a large number of resident bacteria of the oral cavity and are thought to interfere with most of the protective properties of IgA antibodies (224). Salivary IgA antibodies against proteins and carbohydrates of bacteria occur predominantly in the IgA1 subclass, and the antibodies against lipoteichoic acid and lipopolysaccharide are more prevalent in the IgA2 subclass (64).