Complement and acute phase proteins play an important role in the initiation of host defenses against local infection. Complement is believed to be important in periodontal infections as well. Actually, the only evidence that speaks compellingly for a role of complement in periodontal disease is that complement components and derived split products are found in abundance in the crevicular fluid. There are four conceivable areas wherein complement may play a significant role in periodontal infection: (1) neutralizing pathogens and their toxins; (2) recruitment of acute and chronic inflammatory cells; (3) opsonization; and (4) local hormone-like regulation of connective tissue changes.
Studies of peripheral blood complement. If we had to guess, it is likely that individuals with classical or alternative pathway deficiencies would be more susceptible to periodontal infection. Membrane attack complex deficiencies are not as likely to result in severe periodontal infections. No compelling studies have been reported examining either the effect of complement deficiency or complement pleomorphism (complotyping) on susceptibility to periodontal infection.
Gingival crevice and the gingival crevicular fluid (GCF). The gingival crevice is an unusual structure enabling certain biological activities (such as phagocytosis of bacteria by neutrophils) to occur outside the body. To understand how this can be, the dentist should know certain features of the gingival crevice. The mean temperature of the healthy gingival sulcus is 33.9° ± 0.4° C (Ng et al., 1978. J. Periodont. Res. 13:295-303); and this temperature elevates to 35-37° C as pocket depth (roughly equivalent to disease) increases (Mukherjee, 1981. J. Clin. Periodontol. 8: 17-20). Therefore, crevicular temperatures should support cellular function.
The electrolyte concentrations which have been measured in crevicular fluid are higher than in plasma, and these include sodium, potassium, calcium, and magnesium. Sodium levels can vary between 159 mEq/L and 222 mEq/L in gingival crevicular fluid, which is between 14% to 59% higher than in plasma (Abbott and Caffesse,1977. J Western Soc Periodontol 25: 164-178). The concentrations of electrolytes are at levels which should preclude cell lysis and support calcium-dependent cell function. The pH range in the gingival crevice reportedly varies from 6.5 to 8.5. Interestingly, alkalinization (higher pH) is correlated with increased inflammation. These pH ranges appear to moderately influence certain receptor-mediated activities of neutrophils, including chemotaxis and phagocytosis (Leblebicioglu et al., 1996. J. Periodontol67:472-477).
Oxygen is relatively diminished within the gingival crevice. This is indicated by both the types of bacteria that live in the crevice as well as actual measurements of crevicular pO2 and redox potentials. With respect to the types of organisms that grow in the crevice, we know that the black-pigmented organisms,Porphyromonas gingivalis and Prevotella intermedia, are moderate anaerobes which initiate growth in oxygen levels at 8% (although pO2 levels are usually reported in mmHg, I prefer the % conversion -- note: we breathe 20% oxygen). Other organisms are much more sensitive to oxygen, including the oral spirochetes, and require oxygen levels below 0.5%. Using a small oxygen electrode probe, the pO2 has been measured at 1.8% (Loesche et al., 1983. Infect. Immun. 42:659-667). Interestingly, the pO2 of the buccal vestibule has been measured and is LOWER (!!!), at about 0.6%. This may mean that the measurement of crevicular pO2 is fraught with problems OR that there actually is some infusion of O2 into the gingival crevice from the surrounding tissues.
Still, these oxygen concentrations are quite low. Will cells function under such hypoxic conditions? In this respect, the student should see the significance that monocytic phagocytes obtain almost half of their energy by oxidative phosphorylation (oxygen required), and that neutrophils obtain almost 100% of their energy by glycolysis (no oxygen required!). Additionally, if we believe the measured pO2 levels in the gingival crevice (and we may not really believe those measurements), we can surmise that since neutrophil oxidative killing mechanisms are relatively insensitive to hypoxia, they should be about 75% functional at the 1.8% concentration of oxygen measured within the gingival crevice (Gabiget al., 1979. Blood 53:1133-1139).
The redox potential, or oxygen reduction potential, Eh, is perhaps more important a parameter to consider than pO2 levels when we attempt to reconstruct oxidative killing of neutrophils within the gingival crevice. The Eh of the gingival crevice has also been determined and was found to decrease slowly from about +250 mV to about -150 mV over a period of seven days after the insertion of the monitoring electrodes (Kenney and Ash, 1969. J.Periodontol. 40: 630-633). Also, periodontal pockets developed lower Eh than gingival sulci, and some microorganisms isolated from periodontal pockets appear to require Eh values less than -290 mV. Consider this: in order to reduce oxygen, the neutrophil must send electrons down an electrical potential gradient from -370 mV to -160 mV (chapter 4). Therefore, in order for the neutrophil to be able to reduce oxygen (ie., give oxygen an electron), it needs an Eh at or above - 160 mV. The Eh values measured within the gingival crevice suggest that regardless of the oxygen tensions, oxidative killing by crevicular neutrophils would be intact in health, but possibly impaired in periodontitis. If we use bacterial Eh requirements as an indicator, it is possible that the oxidative antimicrobial activity of neutrophils will be greatly impaired in disease states. We can conclude that the activities of the oxidative killing mechanisms may vary in rough accord with disease state (more specifically, the Eh values). It is known that in the absence of oxidative killing mechanisms, neutrophils take twice as long to kill periodontal pathogens (Miyasaki et al., 1986 Infect. Immun. 53: 154-160). The shut down of oxidative killing may be an important factor in the sequential, stepwise progression toward periodontal destruction. Luckily, neutrophils also possess a potent arsenal of non-oxidative killing mechanisms (chapter 4).
In health, complement levels in GCF are about 1/35 of serum, but a periodontal inflammation increases, there is a concomittant increase in complement levels to over 25% (certain components, such as factor B, C3, and C4, are up to 85%) of serum (Shenkein, 1991. Crit. Rev. Oral Biol. Med. 2: 65-81). The alternative and the classical pathways of complement activation should be sufficiently opsonic at 20% and 2% levels, respectively; nonetheless, in AP, it has been documented that complement-mediated opsonic activity is below normal. Therefore, one potential 'problem' in AP is the inability of GCF to adequately opsonize bacteria for phagocytosis. This may lead to the 'abnormal' ingestion of microbial pathogens into the phagocyte cytosol (Thompson and Wilton, 1991. Infect. Immun. 59:932-940) rather than the phagolysosome. This may not be so bad or abnormal, since certain bacterial pathogens cannot grow (and are killed) in the presence of phagocyte cytosol and its major protein complex, calprotectin (Miyasaki et al., 1993. J. Dent. Res. 72:517-523).
In adult periodontitis (AP), C3 and B cleavage in gingival fluids is observed. Both gingivitis and AP have been characterized primarily as involving alternative pathway activation. This is of some interest, since it suggests that even though pathogen-specific antibodies are formed in AP, the bulk of complement activation in this disease is still via the alternative pathway. In localized juvenile periodontitis (LJP), C3, B, and C4 cleavage is observed. The complement cleavage patterns observed in periodontal disease states also indicate greater classical pathway activation in LJP, suggesting a higher degree of antibody interacting with target antigen (probably, A. actinomycetemcomitans). Because serum antibody against A. actinomycetemcomitans does not form until the later stages of the disease process, it is possible that classical pathway complement activation only occurs in the later stages of LJP (ie., long after the periodontal lesions have formed). Thus, diagnostics aimed at detecting classical pathway complement activation may not prove to be predictive. It is as yet unclear when local antibodies are formed against A. actinomycetemcomitans in LJP.
Neutrophils work in conjunction with complement and can become target-specific with the involvement of antibody. In general, neutrophils are particularly important in host defense against bacterial infection. Are neutrophils important in the defense against periodontal bacteria? We can't answer that question. But, we can say that neutrophils protect the periodontium against periodontal destruction.
Evidence that neutrophils are protective against periodontal destruction. Three lines of evidence support the proposal that neutrophils protect the periodontium by as yet unidentified activities. First, primary neutrophil or myeloid abnormalities have been associated with severe periodontal destruction. Second, otherwise healthy individuals with severe periodontal problems appear to have subtle defects in their neutrophils. Third, experimental neutropenia in animals leads to rapid periodontal infection.
Several rather gross abnormalities of neutrophils are initially diagnosed by physicians and subsequently referred to dentistry for oral problems (Table 3). These conditions are generally rare; however, they are important for the student to know not only as experiments of Nature, but also because it is possible that you will be required to provide service for such cases in your future.
Neutropenia and agranulocytosis. Neutropenia and agranulocytosis are signs of underlying diseases or disease processes. An individual is said to be neutropenic if his neutrophil counts are below 1500 mm3 and exhibit agranulocytosis if the counts drop below 500 mm3 (normal individuals have neutrophil counts between 5000-10000/mm3). Some of the known causes of neutropenia include myelosuppression, drugs (idiosyncratic), infections, and autoimmune disorders in which the neutrophil is the target. For example, infection by the human immunodeficiency virus (HIV) results in an increase in autoimmune neutropenia (as well as thrombocytopenia) a form of antibody-mediated cytotoxic autoimmunity (type II immunopathology). Paroxysmal nocturnal hemoglobinuria (PNH), a deficiency of phosphatydylinositol glycans (see chapter 3, complement) also can result in neutropenia.
Hyper-IgE (Job's syndrome, HIE). HIE is a rare, complex disorder (possibly localized to chromosome 7q21) characterized by the marked elevation of IgE, chronic dermatitis (eczematoid rash), "coarse facies (what the heck does THAT mean?!)," and serious, life-long bouts of recurrent infections by opportunistic organisms (Staphylococcus aureus and Candida albicans) which result in skin abscesses remarkable in their lack of erythema ("cold" abscesses). Abscesses could involve any organ. Invariably, infections are noted within the first six weeks of life. The term, "Job's Syndrome" was coined as a Biblical reference to Job, who was smote by boils from head to foot. Coarse facial features include broadened nasal bridge and irregularly proportioned cheeks and mandible. The cause of hyper IgE is unclear, but it has been suggested that the balance between the T-cell elaboration of cytokines IL-4 and IFNg is a defective (two hormones involved in the regulation of IgE production: IL-4 is protagonistic and IFNg is antagonistic). Recent data suggests that cyclooxygenase pathway products can also produce osteoporotic changes in subjects with HIE (Leung and Geha. 1988. Hematol./Oncol. Clinics N. Am 2:81-100). Circulating immune complexes (IC) -- which appear to be IgG anti-IgE complexed against IgE Fc -- are observed in the sera of afflicted individuals. The IC can impair leukocyte chemotaxis, and some patients with HIE exhibit impaired leukocyte chemotaxis. Other investigators have evidence suggesting that mast cells, armed with IgE against inappropriate bacterial targets, release histamine when confronted by bacteria. The histamine apparently impairs neutrophil function. Mononuclear cells from the blood of patients with HIE also release a 60 kda factor that inpairs neutrophil function. Periodontal disease in individuals with HIE has been noted, and the above summary of HIE should suggest at least a few of the underlying mechanisms for this (you decide, the actual reason is unknown).
Chediak-Higashi syndrome (CHS). CHS is a rare disease with an autosomal recessive mode of inheritance (possibly localized to chromosome 1q43). A structural defect, the fusion of azurophil and specific granules into giant granules called "megabodies," is characteristic of neutrophils from individuals with this disease. Neutropenia, depressed inflammation, and the relative lack of neutral serine proteases are observed in CHS. Depressed inflammation is thought to be due to decreased chemotaxis and secretion, not the neutropenia. The formation of reduced oxygen metabolites is greatly exaggerated. Oral manifestations of this disease include severe periodontitis and oral ulceration.
Specific granule deficiency (SGD). SGD is a rare disease which was originally described as a disease in which neutrophils lacked specific granules. Now, it is clear that SGD represents a failure to package in granules whole groups of proteins (both specific and azurophil granule proteins). Specific granule proteins which are missing include lactoferrin, cobalophilin, cytochrome b, the FPR, C5a receptor, and CR3. If you consider these components alone, it will be clear to you that an SGD neutrophil will have depressed respiratory burst activity, diminished ability to respond to chemoattractants, and poor phagocytosis. Not only are specific granules affected, but the packaging of defensins into azurophil granules is also defective. Therefore, intraphagolysosomal killing is predictably sluggish. Decreases in inflammation may also be predicted on the basis of the deficiency of chemoattractant receptors, both because these cells are less responsive, chemotactically, and because they do not secrete inflammatory mediators at normal levels. The disease is probably autosomal recessive, although there have been too few cases to analyze thoroughly. Oral manifestations of this disease include severe periodontitis and oral ulceration.
Papillon-LeFèvre syndrome (PLS). PLS features rapid generalized destruction of alveolar bone (both primary and secondary dentitions affected) and palmar-plantar hyperkeratosis. At present, the exact immunologic abnormality (if any) which contributes to this condition is unknown; however, one report indicates that PLS may be associated with diminished neutrophil activity (Van Dyke et al., 1984. Clin. Immunol. Immunopathol. 31: 419-429). Neutrophils from an individual with PLS had decreased receptor affinity for chemotaxins such as formyl peptides. Recent studies suggest that another systemic immunologic abnormality is the increase of circulating NK cells, although the periodontal lesions associated with PLS appear to be a fairly typical plasma cell-dominated lesion (Çelenligil et al. 1992. J. Clin. Periodontol. 19: 392-397).
Chronic granulomatous disease (CGD). CGD is a group of diseases characterized by the inability of the phagocyte to reduce oxygen. CGD is clinically diagnosed by the presence of recurrent, indolent, pyogenic infections by catalase + bacteria (which do not secrete reduced oxygen -- hydrogen peroxide -- because they possess catalase [see chapter 4]). Because the host phagocytes are unable to mount a normal respiratory burst (ie., reduce oxygen) they have difficulty controlling organisms which do not release reduced oxygen metabolites themselves. Apparently, catalase negative bacteria release enough hydrogen peroxide to assist neutrophils perform oxidative killing. The inability to rapidly dispatch bacteria which gain access to the connective tissues leads to the formation of granulomas by the chronic immune cells. There are several biochemical defects of the NADPH oxidase system which have been associated with CGD. The X-linked form involves a mutation in the gene encoding the heavy subunit of cytochrome b (p91phox). An autosomal recessive form of CGD which mimics the X-linked form (ie., the absence of cytochrome b) involves the mutation of the small subunit of cytochrome b (p22phox) and is encoded on chromosome16q24 (Dinauer et al., 1990. J. Clin. Invest. 84: 1729-1737). Two forms of CGD do not show diminished expression of cytochrome b, but lack certain cytosolic proteins which shuttle electrons from NADPH to cytochrome b. These autosomal recessive forms have been associated with a defect in neutrophil cytosolic factors 1 and 2 (NCF-1 and NCF-2, aka, p47phox and p67phox). The deficiency in NCF-1 has been localized to chromosome 7 and the deficiency in NCF-2 to chromosome 1 (The human genome. 1992. J. NIH Res. 4: 153-170). It is interesting that CGD is not more strongly associated with periodontitis. It suggests that phagocyte defense against facultative bacteria invading the normoxic connective tissues is not as important as defense against anaerobic bacteria in the hypoxic gingival crevice.
Leukocyte adhesion deficiency, type I (LAD-I). LAD-I is characterized by the inability of individuals to express the "b2 subunit (CD18)" common to the leukocyte integrins, LFA-1, Mac-1, and p150/95. The deficiency is profound, and individuals with LAD express leukocyte integrins at levels less than 6% of normal. All leukocyte integrins are heterodimers consisting of an a subunit (CD11a, CD11b, or CD11c) and the common b2 subunit. LFA-1 is important for a neutrophil diapedesis and lymphocyte scanning of antigen-presenting cells. Like LFA-1, Mac-1 (CR3) is important for adhesion to endothelial cells, both Mac-1 and p150/95 (CR4) are the crucial complement receptors involved in phagocytosis. The level of periodontal disease is related to whether one or two defective alleles are present (Waldrop et al. , 1987. J. Periodontol. 58:400-416). Homozygotes exhibit generalized prepubertal periodontitis (GPP) afflicting both the deciduous and the permanent dentition. Heterozygotes appear to have normal prepubertal periodontal status. However, postLJP-like lesions seem to appear at some point postpubertally.
Histologically, LAD-I periodontal lesions show a dense plasma cell infiltrate with copious immunoglobulin production (which appear histologically as Russell bodies: a 10-15 µm diameter, round, extracellular bit of fluid). Virtually no extravascular neutrophils are observed (Figure 4, Waldrop et al., 1987). We will make very little issue of the plasma cell infiltrate, only stating that this is remeniscent of typical, adult periodontitis (although it may be exaggerated).
Leukocyte adhesion deficiency, type II (LAD-II). Recently, another adhesion deficiency disease, LAD-II, has been identified. Patients with this defect exhibit pronounced neutrophilia (ie., blood neutrophil levels 5-10 times higher than normal) and recurrent bacterial infections at an early age (prepubertal, even within a year after birth). They may also show severe mental retardation. Their leukocytes fail to express the natural ligands for P and E-selectins (sialo-Lewis X, gp150-Lewis X (CD15), and CLA (an epithelial antigen). Neutrophils from such individuals have difficulty forming initial rolling interactions with the endothelium. LAD-II has been associated with severe periodontitis (I'm not sure whether a dentist made this clinical call, and the physicians probably do not distinguish between gingivitis and periodontitis) in five year old child (Price, et al., 1994. Blood 84:1635-1639).
Chronic inflammatory adult periodontitis (AP) is a disease characterized by loss of attachment ranging between 0.072-0.36 mm/year when averaged over many years, and is usually associated with plaque and calculus. Several severe forms of periodontal diseases show much greater rates of attachment loss with less associated plaque and calculus (Table 4). There have been several attempts to categorize the severe forms of periodontal disease, and table 4 does not reflect the latest recommendations by the American Academy of Periodontology (which does not distinguish rapidly progressing adult periodontitis from generalized juvenile periodontitis).
Localized juvenile periodontitis (LJP) is a severe form of early onset periodontitis afflicting teenagers (usually post-pubescent, age range is described as 12-26 years). LJP appears to afflict females more than males. Racial discrepancies also exist, and recent surveys suggest that the frequency in Caucasians is 0.02%, the frequency in Asians is 0.2-0.47%, and the frequency in people of African decent is 0.8% (Boughman et al., 1990. Crit. Rev. Oral Biol. Med. 1: 89-99). This disease is characterized by attachment loss (rate of loss estimated to be 1.08-1.8 mm/year) mainly about the secondary first molars and incisors (possibly reflecting eruption sequence) and very little macroscopic plaque. In 70-80% of cases, LJP is characterized by a neutrophil chemotaxis defect (without any noticeable defect in random migration). In some instances, an increase in respiratory burst activity has been observed, leading to the speculation that neutrophils may participate in tissue destruction by oxidative pathways. In about 75% of cases, LJP is associated with a massive, tissue-invasive infection by the serum-resistant organism, A. actinomycetemcomitans. When neutrophils are defective, the organisms may overwhelm acute phase defenses. The plaque spreads as a thin (20-200 µm), non-mineralized front apically along the tooth and within the adjacent gingival tissues (Waerhaug, 1976; Saglie et al., 1982). This results in excessive tissue destruction, probably regulated by the chronic immune cells. At present, the reason that LJP is limited to certain sites is unknown. However, it has been proposed that the site limitation is a result of a time-dependent "window of opportunity." The window opens as a general periodontal infection during the mixed dentition period (at this time, the permanent first molars and incisors have erupted) and closes with the formation of protective antibodies. Antibody (with complement) is absolutely required for the opsonization of A. actinomycetemcomitans (Baker and Wilson, 1989. Oral Microbiol. Immunol. 3:98). This indicates that antibody responses must be initiated before neutrophils can kill this microbe. The time required to produce antibodies of the proper isotype, specificity, and affinity may be prolonged by immunosuppressive factors elaborated by the microbe (Shenker et al., 1990. Infect. Immun. 58: 3865-3862). At present, one form of periodontal therapy have been shown to stimulate antibody production against periodontal pathogens such as P. gingivalis and A. actinomycetemcomitans. As you may have guessed, that form of therapy is the old, tried-and-true, scaling and root planing (Sjöström et al., 1994.Infect. Immun. 62: 145-151)! The exact significance of this is quite debatable, since LJP is not particularly "curable" with scaling and root planing alone, and since not all seronegative individuals seroconvert with scaling and root planing.
More than one type of LJP. The student probably recognizes that clinical entities often encompass several different biochemical lesions. For example, there are at least 4 forms of CGD, two forms of LAD, and 5 forms of SCID. Three biochemically-distinct types of LJP have been partially described. We will refer to them as "LJP-1, LJP-2, and LJP-3."
LJP-1. Neutrophils from individuals with the classic form of LJP, ie. "LJP-1," are characterized by a decrease in chemotactic responses to a variety of chemotactic factors, including C5a, FMLP (N-formyl-methionyl leucyl phenylalanine) and leukotriene B4 (Offenbacher et al., 1987. J. Periodontol. 58:602-606). The neutrophil dysfunction in LJP-1 is associated with a functional decrease in chemotaxin receptors on the PMN surface. The defect does not affect the individual receptors (eg., the C5a receptor, the FPR, etc.), as such, LJP-1 is a pan (global) - receptor defect. Seventy to eighty per cent of the clinical cases of LJP appear to be LJP-1.
It is difficult to conceive of one genetic lesion affecting many different, monomeric cell surface receptors. Van Dyke et al. (1987. Infect. Immun. 55: 2262-2267) have described about a 40% deficiency in a membrane 110 kdal glycoprotein which may explain the pan-receptor defect in LJP (Figure 5). The exact function of GP110 is unknown. Because GP110 is expressed late in cell differentiation at about the time that chemotaxin receptor expression occurs, it has been proposed that GP110 is functionally related to the chemotaxin receptors. GP110 may be (a) a transductory element, (b) involved in receptor cycling (perhaps important in anchorage to cytoskeletal elements), (c) a fibronectin receptor which binds fibronectin in the connective tissues and provides a signal which upregulates the chemoattractant receptors, (d) a subunit common to all chemotaxin receptors or (e) an epiphenomenon, indicative of the state of neutrophil maturity. The inheritance mode of is still unclear, and although some data suggests that LJP is inherited in an autosomal recessive manner, others suggest an autosomal dominant mode of inheritance, localization to chromosome 4, and linkage to the gene involved in dentinogenesis imperfecta (Boughman et al., 1986. J. Craniofacial Genet. Dev. Biol. 6:341-350).LJP-2. "LJP-2" manifests with identical clinical lesions as LJP-1; however, neither decreased chemotaxis, FMLP or C5a receptors, nor GP-110 are observed in laboratory studies of patient neutrophils. We may speculate that LJP-2 may be distributed regionally, and may explain the inability of Finnish studies to confirm a chemotaxis defect in LJP.
LJP-3. Finally, there is a report that in one case, LJP may be associated with a defective formyl peptide receptor, FPR (Perez et al., 1991. J. Clin. Invest. 87: 971-976). Neutrophils were defective in their ability to migrate in response to FMLP, but normal in their ability to respond to C5a. Further, both secretory and respiratory burst activity were normal in response to FMLP. Fewer isoforms of the FMLP receptor were observed in this individual. This unusual form of LJP is inconsistent with previous observations of a pan-receptor defect, diminished GP-110, and genetic localization to chromosome 4 (the FPR is encoded on chromosome 19). However, it is an enormously interesting observation. First, this case of LJP vindicates the position that a subtle neutrophil chemotaxis defect may result in LJP (ie., the the neutrophil defects described for LJP-1 are likely to be real). Second, the normal secretory and respiratory burst activities and the reportedly fewer isoforms of the FPR suggest that the chemotactic function of the FPR may be crucial. LJP-3 may be a cleaner model and show that the important lesion of LJP-1 is really the decreased expression of the FPR chemotaxin receptor (ie., all the other problems are epiphenomenal). The possible relationship between LJP-1 and LJP-3 is shown in Fig. 6.
Neutrophils and LJP, summary. At present, it is unclear whether (a) infection by A. actinomycetemcomitans associates exclusively with LJP-1 and not LJP-2 or LJP-3 (b) to what extent serum-derived inhibitors of leukocyte function may be involved, or (3) whether LJP-2 neutrophils kill A. actinomycetemcomitans at a slower rate. It is also unclear as to why a chemotaxis defect should should be associated with severe periodontal disease. That is, it is unknown whether decreased chemotactic ability is the critical factor which results in decreased capability of neutrophils to control the periodontal microbiota or chronic inflammatory cells. Phagocytic killing may be an important factor, but in that case, it is difficult to understand how a defect in the FPR or GP110 would effect the process. It has been suggested that neutrophils have many biochemical problems related to a single, as yet unidentified, underlying defect.
The distinction between generalized juvenile periodontitis (GJP) and rapidly progressing adult periodontitis (RAP) is conceptually clear but clinically a bit more difficult to distinguish. GJP has been described as afflicting young adults and/or post-pubescent individuals (Research, Science, and Therapy Committee, Amer. Acad. Periodontol. 1991. Periodontal Diseases of Children and Adolescents). GJP is a generalized, severe form of periodontitis afflicting all of the permanent dentition which has been associated with plaque and calculus suggesting a different microbial etiology than LJP. Neutrophils from such individuals appear to exhibit chemotaxis disorders and no alteration in GP-110. The chemotaxis disorders may result from some other phagocyte problem. It is likely that GJP represents a grab bag of diseases.
Rapidly progressing adult periodontitis (RAP) is a form of severe periodontitis which also has not been well-defined. In general, individuals "afflicted" with RAP have a mean age of about 40 (range 30-62). The chief criterion appears to be subjective, and is often based upon the opinion of the referring dentist that the amount of attachment loss is inconsistent with the age and plaque levels. One of the earliest studies found that in 16% of the cases studied (3 out of 19), intrinsic defects in leukocyte chemotaxis could be observed (as in LJP-1). On the other hand, 32% (6/19) exhibited factors in the patient's serum which impaired leukocyte function. Some of these factors were immunoglobulins which functioned as cell-directed inhibitors (CDI) of chemotaxis rather than as autoantibodies (Lavine et al., 1979. J. Periodont. Res. 14:10-19). The difference between a CDI and an autoantibody is that the CDI functions via its Fc region rather than its Fab region by as yet unexplained mechanisms (however, given the domain structure of immunoglobulin, it is not difficult to envision some biologic function attributed to some domain other than the variable domain). In one case, a factor was elevated in serum which led to inactivation of the chemotaxin; this factor is known as a chemotactic factor inactivator (CFI). Extrinsic and intrinsic defects in cell function were not observed in 53% of the cases (this doesn't necessarily mean that they aren't there). Recently, it was reported that serum from individuals with RAP did not support phagocytosis of A. actinomycetemcomitans as well as serum from non-diseased individuals (Sjöström et al., 1992. Infect. Immun. 60:4819-4825).
Intrinsic neutrophil defects have also been described in RAP. As found previously, abnormalities in leukocyte (neutrophil and monocyte) motility have been observed in some cases (Altman et al., 1985.J. Periodont. Res. 20: 553-563). In Japan, no defects in leukocyte motility could be observed in 13 RAP patients (Katsuragi et al., 1988. Adv. Dent. Res. 2: 359-363).
Refractory periodontitis is another poorly-defined clinical condition characterized by normal-to-increased rates of disease progression and resistance to resolution by conventional forms of periodontal therapy. Individuals with refractory periodontitis exhibit normal neutrophil chemotaxis but depressed neutrophil phagocytosis (MacFarlane et al., 1992. J. Periodontol. 63: 908-913). Although the underlying cause of this proposed defect is still unclear, 90% of individuals with clinically-defined refractory periodontitis were smokers in the study cited, obviously suggesting that tobacco may adversely effect neutrophil behavior and thereby promote periodontal disease. Can neutrophil behavior be influenced by smoking? Yes, definitely. In vitro studies clearly show that unsaturated aldehydes derived from tobacco smoke can impede neutrophil chemotaxis (Bridges et al., 1977. Infect. Immun. 16: 240-248); but more importantly, neutrophils derived from smokers show diminished phagocytosis relative to neutrophils from nonsmokers (Kenney et al., 1977. J. Periodontal Res. 12: 227-234). Although the inability to clearly define "refractory periodontitis" limits the value of these observations, it strongly suggests that smokers are at risk and that at least in part, this may be attributable to defective neutrophil phagocytosis.
A number of pathogens secrete leukotoxins, immunoglobulin proteases, lymphosuppressive factors, high molecular weight chemotaxis inhibitors (pertussis and cholera toxins, which ADP-ribosylate G-proteins), low molecular weight chemotaxis inhibitors, LPS and polysaccharides, all of which can affect immune function. Thus, the bacteria themselves can produce the dysfunction within the immune system. Of particular interest are the low molecular weight inhibitors. It has been reported that the periodontal organism, Capnocytophaga, can induce chemotactic defects in vivo (Shurin et al., 1979. New Eng. J. Med. 301: 849-854). Although the factors responsible for this induced defect have never been identified, it has been suggested that Capnocytophaga and other oral Gram negative bacteria produce low MW factors which inhibit the binding of the chemotaxin, FMLP, to the formyl methionyl peptide receptor (FPR) and additionally, inhibit neutrophil chemotaxis (Van Dyke et al., 1982. J. Periodontol. 53: 502-508). Other acquired disturbances may be hormonal, drug-induced, radiation-induced, viral, immune, and autoimmune. For example, estradiol (but not progesterone) inhibits neutrophil chemotaxis (Miyagi et al., 1992. J. Periodontol. 63:28-32). As mentioned in the section on phagocytes, both antihistamines and "tranquilizers" can impede neutrophil phagolysosomal fusion, thus phenothiazines (such as promethazine - an antihistamine, and trifluoperazine - a tranquilizer) can block specific granule fusion (Meers et al., 1987).
Crevicular neutrophils have been examined for several reasons. At one time, it was felt that crevicular neutrophils represented a special subpopulation of blood neutrophils. Indeed, it had been reported that oral neutrophils (largely of crevicular origin) seem to possess elevated levels of Fc receptors for IgA (Fanger et al., 1983. Mol. Immunol. 20: 1019-1027). To date, there has been no overwhelming evidence to suggest that crevicular neutrophils are different from neutrophils from other tissues. Crevicular neutrophils are less responsive than peripheral blood neutrophilsin vitro, but this is probably due to the prior stimulation of crevicular neutrophils by microbial and host-derived inflammatory compounds within the crevice. Crevicular neutrophils exhibit a decrease in function of iC3b receptors (CR3 and CR4; Wilton, 1976).
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