Role of Chronic Systemic Diseases and Impaired Host Factors
Chronic systemic disease
Of the systemic diseases, by far the greatest caries risk is associated with rheumatoid conditions, particularly Sjogren's syndrome, because of its severe depressive effect on the salivary secretion rate as well as the quality of the saliva. The most severe xerostomia is seen in patients with Sjogren's syndrome. Other systemic and chronic diseases that cause salivary gland hypofunction and xerostomia and are thereby regarded as risk factors and prognostic risk factors are listed in Box 9. Chronic diseases such as psychogenic disorders (eg, depression), allergies, hypertension, and so on, should also be regarded indirectly as risk factors and prognostic risk factors because of the associated long-term medication with significant depressive effects on SSR (see Box 10).
Some diseases impair the immune system generally, eg, leukemia or specifically acquired immunodeficiency syndrome (T cells). Other diseases, such as early-onset (juvenile) diabetes and Down's syndrome, are often associated with hypofunction of the phagocytozing polymorphonuclear neutrophil leukocyte cells, which represent the first line of nonspecific defense in the gingival crevice.
Host resistance
In principle, dental caries, like other diseases caused by microorganisms, is characterized by microbial attack and host resistance; for dental caries, however, both processes are very complex and difficult to define. Thus, the microbial attack cannot be defined as the mere presence and activity of a certain pathogenic microorganism.
Although there is substantial evidence that mutans streptococci (primarily Streptococcus mutans and Streptococcus sobrinus) are important etiologic agents of human dental caries, disease may develop without their presence. The number of cariogenic bacteria and the volume and microbial composition of the plaque in which they are present are also important factors. Furthermore, other factors, for example, the pattern of sugar intake, determine both the amount and nature of the acids released by mutans streptococci and other plaque bacteria, and thereby their cariogenic
potential (see chapter 2).
Host resistance is even more difficult to define. Unlike resistance to many infectious diseases, resistance to caries is not determined solely by nonspecific antibacterial compounds and the alertness of the immune system at a given time. Nevertheless, an important conclusion can be drawn: Given the high potential for caries development in part of the population, the alertness developed by the immune system under natural conditions is inadequate for protection at the population level. That there are marked variations at the individual level, however, was shown in the Vipeholm study (Gustavsson et al, 1954); in the most extreme interventional test group, about 20% of the subjects failed to develop any new carious lesions (see chapter 2).
Several studies have shown (for review, see Kilian and Bratthall, 1994) that dental caries does not lead to acquired immunity. In this respect, dental caries is different from almost all other diseases caused by microorganisms. There may be two reasons. First, the mucosal immune system has evolved to maintain a natural balance with members of the commensal microflora of the body and not to eliminate them. Second, like some other members of the oral microflora, S mutans releases a protein with immunosuppressive properties.
Immune factors
The soft and hard tissues of the oral cavity are protected by both nonspecific and
specific immune factors, which limit microbial colonization of the oral surfaces and
prevent the penetration of noxious substances and ensuing damage to the underlying
tissues. The nonspecific immune factors present in saliva include lysozyme, the
lactoperoxidase system, lactoferrin, various little-known antibacterial compounds, and
high-molecular weight glycoproteins and other salivary components, that may act as
bacterial agglutinins (see Box 13). Unlike antibodies, these nonspecific factors lack
immunologic memory and are not subject to specific stimulation. However, several of
the nonspecific immune factors may interact with salivary immunoglobulins, resulting
in a mutual amplification of their respective activities.
Infection and disease caused by cariogenic microorganisms occur in an environment
containing a variety of specific host immune factors, derived from several sources.
The major and minor salivary glands constitute one such source, contributing
essentially all the secretory IgA to whole saliva, together with lesser amounts of IgM
and IgG. Secretory IgA mediates its protective effect mainly through primary binding
of antigen. Binding can inactivate toxins, inhibit enzyme-based systems, and affect
many other mechanisms involved in microbial colonization. Binding of several
organisms results in their agglutination and consequent clearing from the mouth.
Other immunoglobulin isotypes may also participate in these mechanisms.
An additional source of immune factors is the gingival crevicular fluid: This
contributes most of the IgG, as well as some monomeric IgA. The crevicular fluid
also contains many of the complement components and cell types that, together with
IgG or IgM antibody, can inactivate or opsonize bacteria. Thus, the potential exists for
several specific host immune mechanisms to intervene in the colonization and/or the
pathogenic activity of cariogenic microorganisms. These specific host immune factors
in whole saliva are assisted by the phagocytozing nonspecific polymorphonuclear
neutrophil leukocyte cells migrating from the gingival crevice.
Numerous studies in animals and humans have shown that increased antibody levels,
either secretory IgA or IgG, to S mutans can enhance its elimination and/or interfere
with its cariogenic activity. However, the exact molecular mechanisms are only partly
understood. Some of the potential mechanisms are summarized in Box 14.
On the other hand, the fact that people who lack a functioning secretory immune
system have significantly more dental caries than do their age-matched counterparts
seems to implicate salivary antibody in some aspect of the modification of the
cariogenic potential of the oral microbiota. Therefore, individuals with complete
secretory immunodeficiency (total absence of both secretory IgA and IgM) would
constitute one group at greater risk of developing dental caries. There are currently no
available analyses of caries experience in patients with IgG or selective IgG subclass
deficiencies. Secretory IgA has a different molecular structure from serum IgA. While
serum IgA occurs mainly in the classic monomeric form characteristic of other
immunoglobulin classes, IgA in saliva and other exocrine secretions occurs as a larger
complex, composed of dimeric IgA linked with a specific salivary glycoprotein, the
secretory component. This complex is known as secretory IgA. Apart from providing
active transport of the immunoglobulin molecule across secretory epithelia, the
secretory component gives the secretory IgA molecule greater resistance to
proteolytic enzymes than serum IgG, IgA, and IgM, thus enhancing its function in the
enzymatically hostile environment of the oral cavity and other mucosal surfaces.
Two subclasses of IgA¾IgA1 and IgA2¾have been identified in human serum and
secretions. The subclass IgA1 accounts for 80% to 90% of serum IgA, whereas in
external secretions the proportions of IgA1 differ at different mucosal sites. Salivary
secretory IgA usually contains 65% to 75% IgA1, but there are significant individual
variations.
There is only limited information about differences in biologic functions of the two
IgA subclasses. However, the distinction is important because IgA1 is susceptible to a
group of bacterial enzymes, labeled IgA1 proteases, while IgA2 is resistant to such
proteases. These enzymes are excreted by the streptococcal species that initiate dental
plaque formation: Streptococcus oralis, Streptococcus mitis, and Streptococcus
sanguis.
The secretion of the IgA2 subclass is delayed in a significant number of infants,
sometimes into the period of tooth eruption. The early deficit in the IgA2 subclass
may limit the spectrum of antibody specificities available for reaction. In addition, S
mitis and S sanguis each have strains that secrete IgA1 proteases; both streptococcal
species are prominent colonizers of the mouth in the first year of life. If, because of
poor oral hygiene, the early flora is rich in IgA1 protease-secreting strains, then the
child could be at increased risk because IgA1-specific defense mechanisms would be
susceptible to inactivation.
This may partly explain why, in the studies by Wendt (1995), discussed in chapter 2,
children whose oral hygiene was poor at the age of 1 year developed multiple carious
lesions during the following 2 years, while children whose teeth were clean at the age
of 1 year because of regular cleaning by their parents remained caries free at the age
of 3 years. However, in the first year of life, there is significant individual variation in
the response to oral antigens. Longitudinal studies [au: Reference?]have also
demonstrated that children develop responses to the same antigens at different rates. If
responses are poor or of low affinity, or if responses to critical antigens are not
mounted early enough, then a different sequence of colonization might occur, which
could be detrimental to the host. Thus, the ability to identify the longitudinal
development of immune responses to critical antigens could predict future caries risk.
Early immune responses to some antigens that may participate in plaque formation
have been studied. Gahnberg et al (1985) measured the presence of salivary IgA
antibody to glucosyltransferases from S sanguis and S mutans in the first 4 years of
life. Glucosyltransferase was selected because it participates in the glucan-mediated
processes of plaque formation by mutans streptococci. Streptococcus sanguis can be
recovered from nearly all children by the end of their first year of life. Antibodies to S
sanguis glucosyltransferase were detected by the end of the second year, but
antibodies to S mutans glucosyltransferase could be detected in fewer than 15% of
children as old as 4 years, even though more than 50% had been colonized by mutans
streptococci.
The apparent delay in antibody formation to this potentially important antigen may
diminish the immune protective effect, at least with respect to initial colonization.
Longitudinal studies could reveal whether the children who had developed salivary
antibody to this (or other) important antigens before significant colonization were also
those who subsequently had little or no experience with caries. Such information
could be vital in assessing future caries risk.
Because placental transfer of IgG antibodies may regulate the early immune responses
of the offspring, elevated maternal levels of serum IgG (especially IgG1) antibody to
critical colonization antigens may indicate decreased risk for dental caries in the
primary dentition. Similarly, in contrast to bottle-feeding, breast-feeding allows the
passive transfer of similar secretory IgA antibody specificities, which, if continued
during the period of early challenges by cariogenic streptococci, may delay
colonization and thus decrease the risk of disease.
Theoretically, it would seem that a vigorous set of immune responses, active during
the period of initial colonization of newly erupted tooth surfaces, should influence the
composition of the microbiota on those surfaces. A lag in the expansion of
lymphocytes of a particular IgA subclass may delay the synthesis of antibody to
certain types of important oral antigens and create an increased risk of caries. The
early expansion of clones that will differentiate into plasma cells secreting salivary
IgA or serum IgG antibody to bacterial components critical to some phase of
pathogenesis may decrease eventual caries risk. Thus, early identification of these
specificities may be predictive of future caries experience. The significance of the role
of infective dose in early immune stimulation is unclear, but it is likely that artificial
triggering of the secretory or systemic antibody compartment to synthesize
appropriate antibody prior to infection would significantly modify the caries
experience of the child.
While definitive immune predictors of caries risk are incompletely defined, Smith and
Taubman (1991) have presented some guidelines (Table 14).
