Lymphocytes and monocytes form the core of a network of cells held together by several types of interactions, including (a) antigen presentation involving the MHC class II molecule of the APC interacting with the CD4 and TCR-CD3 complex on T-cells, (b) antibodies produced by B-cells and cells bearing Fc receptors, and (c) cytokines. The lymphocytes and monocytes perform three tasks with respect to the periodontium: (1) they protect the deep periodontal tissues from infection, (2) they orchestrate connective tissue destruction to prevent bone and systemic infection, and (3) they orchestrate connective tissue repair and healing.
There is very little evidence presently available which confirms that the lymphocyte-monocyte system participates in the defense of the periodontal tissues by direct interaction with bacteria. However, it seems highly plausible that locally produced specific antibodies can impart protection against specific bacteria and almost certain that the monocyte are important in the digestion of their molecules.
Experiment of Nature. Human Immunodeficiency virus (HIV) infection is an experiment of Nature in which both CD4+ T-cell and monocyte activities are altered. Individuals with HIV infection frequently exhibit severe, unusual periodontal inflammation (such as linear gingival erythema, HIV-gingivitis) and periodontal lesions in which large areas of soft tissue undergo necrosis and expose bone (necrotizing periodontitis or HIV-periodontitis) (Winkler et al., 1988. In: Robertson P.B. and J.S. Greenspan (ed) Oral Manifestation of AIDS. PSG Publishing Co., Inc. Littleton MA, pp 49-70). From the immunologic standpoint, this suggests that there is (1) an inadequate defense against mucocutaneous infection and (2) a disorganization of the local immune response. The disorganizational effect illustrates the grave consequences of soft tissue destruction proceeding at a rate that exceeds the rate of bone retreat. The student should appreciate that when I say that the chronic immune system destroys periodontal tissues, I view that as an important, physiologic host mechanism of preventing systemic and bone infection.
It may be argued that HIV infection (including AIDS) is not always associated with such periodontal lesions (Drinkard et al., 1991. Commun. Dent. Oral Epidemiol. 19:281-285). The student should recognize that this does not mean that the chronic immune cells do not function in tissue reorganization. What it simply indicates is that other factors are involved in periodontal pathogenesis. For example, we can speculate that such lesions would not occur unless there is an additional autoimmune neutropenia (Chapter 15). Moreover, 80% of the HIV cases showing ulcerative gingival lesions were smokers and 60% used recreational drugs (Winkler et al., 1988).
SCID Mice. Severe combined immunodeficiency mice are deficient in the VDJ recombinase system and therefore lack both mature B-cells and T-cells. Recently, Baker et al. (1994. Arch. oral Biol. 39:1035-1040) used this model to determine the role of B-cells and T-cells in responses to the periodontopathogen, P. gingivalis. Intriguingly, both SCID mice and normal mice develop bone loss when infected; however, normal mice develop more bone loss than SCID mice, indicating the importance of the chronic immune system in regulating bone loss. That SCID mice lost bone at all indicates that neither B-cells nor T-cells cells are absolutely required for bone loss to occur, and indirectly, this kind of implicates monocytes as having some role in periodontal bone loss.
Hypofunction of lymphocytes and monocytes does not appear to relate to severe forms of periodontitis as we observe in the case of hypofunction of neutrophils. Experimental lymphosuppression in animals with cyclosporin A or anti-thymocyte serum does not result in increased periodontal destruction. Similarly, there is no evidence that lymphosuppressed humans (azathioprine, corticosteroids, prednisone) have a greater level of periodontal destruction. On the contrary, there have been reports that hyporesponsiveness may be related to less gingival inflammation (Table 5).
| Table 5: Lymphocyte Disorders and Periodontal Disease | ||
| Immune disorder | Periodontal Status | Reference |
| Hypofunction IgA Deficiency Hypogammaglobulinemia Lymphosuppression azathioprine prednisone corticosteroids |
Less gingival inflammation Less gingival inflammation Normal Less periodontal disease Normal Normal |
Robertson et al., 1978 Robertson et al., 1980 Schuller et al., 1973 Tollefson et al., 1978 Oshrain et al., 1983 Sutton & Smales, 1983 |
| Hyperfunction Hyperproliferation of: peripheral blood lymphocytes to oral bacteria Levamisole |
Severe periodontitis Increased gingival inflammation |
McAnuity et al., 1985 Lehner et al., 1977 |
Increases in lymphocyte activity and susceptibility to periodontal disease. McAnulty et al., 1985 (Table 5) suggested that individuals with severe periodontitis had an intrinsic problem, HYPERfunction, of their peripheral blood lymphocytes. Thus, in their view, periodontal disease may partly be a result of predisposing factors residing within the lymphocyte-monocyte system. This idea is debatable, and although it makes sense theoretically, the overwhelming opinion is that individuals with periodontal diseases such as adult periodontitis or LJP have a normal lymphocyte system (Ranney, 1991). Levamisole, a drug which enhances T-cell activity, aggravates gingival inflammation in man (Invanyi and Lehner. 1977. Scand. J. Immunol. 6:219-226).
Experimentally, dinitrochlorobenzene (DNB, a skin contact antigen) has been used to induce cell-mediated immune lesions in the gingiva of gnotobiotic (rats) and conventional animals (dogs). The immunity to DNB could be passively tranferred by spleen cells but not serum. Painting the gingival margins with DNB in sensitized animals resulted in periodontal lesions. The lesions were extensive and histologically, resembled early gingivitis, and were dominated by mononuclear cells. No neutrophils participated in the lesion due to the relative absence of microbial chemotactic factors. Such investigations suggests that lymphocyte and monocytes are all that is needed to induce inflammatory lesions reminiscent of the established lesions of periodontal disease.
Increases in monocyte/macrophage activity as predisposing factors to periodontal disease. At present, there are several studies which begin to address the question as to whether increased monocyte activity may result in accelerated periodontal destruction. Peripheral blood monocytes from individuals with periodontal disease appeared to spontaneously release 2-3 times as much soluble IL-1b (remember, an old name for IL-1b was "osteoclast activating factor") than monocytes from individuals without periodontal disease (McFarlane et al., 1990. J. Periodont. Res. 25:207-214). The increased IL-1b release in monocytes from periodontitis patients was also observed when the monocytes were stimulated by lipopolysaccaride (LPS; a part of bacterial outer membranes).
Similarly, LPS-stimulated prostaglandin E2 (PGE2; a potent local bone resorbing hormone; see below) release is greater in monocytes from periodontitis cases and in localized juvenile periodontitis cases than normals (Garrison and Nicholls 1989. J. Periodont. Res. 24: 88-95; Shapira et al., 1994. J. Periodontol. 65: 139-146). The interpretation of these findings require much caution, since it is not clear whether the increased monocyte activity was a cause or an effect of severe periodontal destruction was secondary (Page, 1992. J. Periodontol. 63: 356-366). More study is required to determine whether monocyte hyperfunction can be related to periodontal disease as strongly as neutrophil hypofunction.
Peripheral lymphocyte blastogenesis. Numerous studies from the mid-1970s suggest an elevation of peripheral blood lymphocyte proliferative responses to dental plaque and certain oral microbial antigens can be associated with various forms of periodontitis. Although these findings may lead to a conclusion that there is an underlying lymphocyte hyperresponsiveness (as suggested in the McAnulty et al., 1985 study, cited above), this most likely signifies that the lymphocytes have been sensitized during the course of the disease. Importantly, it demonstrates that normal periodontal exposure of certain antigens to the host can result in systemic sensitization and memory (Lehner, T. 1982. Host-Parasite Interactions in Periodontal Diseases. Ed. R.J. Genco and S.E. Mergenhagen, Am. Soc. Microbiol., p202-216). Systemic immunity suggests that the antigen has gained access to the regional lymph nodes. Corroborating this bias is the observation that both B-cell and T-cell responses to oral bacterial antigens can be elicited in experimental gingivitis. Hyperresponsiveness can be developed subsequent to disease, but as yet, there is no convincing evidence that it can be developed prior to periodontal disease.
Serum antibodies. Seroconversion (appearance of antibodies in the serum in response to antigenic challenge) is usually good immunologic evidence that an infection has occurred which was severe and protracted enough to elicit a regional lymph node response. Serologic studies have shown a good correlation between microbiological culture of dental plaque in different periodontal diseases and serum antibody. Classically, individuals with AP possess antibodies to P. gingivalis and to a lesser extent, A. actinomycetemcomitans, and classically, individuals with LJP possess antibodies to A. actinomycetemcomitans and to a lesser extent, P. gingivalis (Gmür et al., 1986. Infect. Immun. 52: 768-776; Mouton et al., 1981. Infect. Immun. 31: 182-192; Tew et al., 1985. Infect. Immun. 48: 303-311; Gunsolley et al., 1990. J. Periodontol. 61: 412-419; Ebersole. 1990. Crit. Rev. Oral Biol. Med. 1:283-331).
Serum antibody and disease. The next bit is rather convoluted, so get some coffee. The student should recall that different isotypes (subclasses) of immunoglobulins exhibit different functions. Therefore, one may envision two individuals, one that produces one subclass of antibody (say 'IgG1') against an antigen and another that produces a different subclass of antibody against that antigen (say 'IgG2'). One of these individuals may be susceptible to disease and the other, not susceptible. I'm talking like this because I am trying to introduce you to an emerging hypothesis: ie., that susceptibility to EOPs such as LJP can relate to some genetic variable controlling the subclass of antibody that one may produce, and that we may actually gain some insight into disease susceptibility by examining certain serological parameters. With this in mind, it has been observed that many antibodies against A. actinomycetemcomitans in LJP are of the IgG2 subclass (Wilson and Hamilton. 1992. Infect Immun 60: 1806-1812; Gmür and Baehni. 1997. Oral Microbiol. Immunol. 12:1-10) and are directed against a 100 Kda carbohydrate "serotype-defining antigen" believed to be a high molecular weight form of lipopolysaccharide (Califano et al., 1989. Infect Immun 57:1582-1589; Wilson and Schifferle, 1991. Infect Immun 59:1544-1551).
I know you're thinking "Gee, Ken, isn't the neutrophil chemotaxis defect enough of an explanation for LJP?" Well, it is possible that other factors may be involved since only 75% of LJP cases exhibit neutrophil defects. Worse yet, I also have friends with "defective" neutrophil chemotaxis and perfectly healthy gums.
One of the factors may relate to the ability to opsonize A. actinomycetemcomitans adequately due to the isotype of IgG produced. First, as stated several pages ago, we know that (1) A. actinomycetemcomitans is serum-resistant (can't be killed by complement or antibody plus complement), and (2) antibody is required for the phagocytic killing A. actinomycetemcomitans. In African-Americans that are susceptible to LJP, there appears to be a predisposition to form IgG2 (Zhang et al., 1996. Infect. Immun. 64: 2004-2009), and it has been hypothesized that this predisposition to IgG2 responses may relate to the heightened disease susceptibility in that population. Mark Wilson, at the State University of New York at Buffalo, says this: My suspicion, based on available evidence, is that African-Americans may be at increased risk for development of LJP because they tend to produce IgG2 antibodies against A. actinomycetemcomitans preferentially over other IgG subclasses (though they do produce measurable quantities of IgG1 and IgG3). The problem may be that their phagocytes express a form of IgG Fc receptors which doesn't bind IgG2 particularly well.
The Fc receptor responsible for binding IgG2 is FcgRII (CD32). There is an allele of FcgRII which binds IgG2 with relatively low affinity (check the glossary term "FcgRII.") Let us say an individual has the low affinity receptor, this individual may be at risk since the IgG2 will only be opsonic at very high concentrations, which may be achieved in the later disease stages, but too late to prevent disease. Mark Wilson continues: We are presently genotyping African-American LJP subjects to determine if they do, indeed, express the "wrong" form of CD32, i.e, the R131 allotype, on their phagocytes. So far, this appears to be the case, with 73% of our patients being R131/R131 homozygous. Stay tuned.
Correlation. The strength of the correlation between serum antibodies and microbial culture was determined (Ebersole et al. 1987. J. Periodont. Res. 22: 184-186). Serum antibody appeared to correlate with microorganisms cultured from sites approximately 80% of the time when the lesion was deemed active, but correlated with microorganisms only 20% of the time when the lesion was deemed inactive. The strongest correlation was made among antibodies to A. actinomycetemcomitans, LJP, and the culture of A. actinomycetemcomitans. LJP lesions appear to occur prior to seroconversion, but nevertheless, probably progress (without treatment) in the face of high serum titers. Some investigators feel that the localized nature of LJP can be attributed to the chronic immune system capacity to synthesize specific antibody. The synthesis of antibody may be delayed until localized destruction is severe, since A. actinomycetemcomitans appears to elaborate an immunosuppressive factor (Shenker et al., 1982. J. Immunol. 128: 148-154). However, once antibody production occurs (perhaps at the systemic level, the invasiveness of A. actinomycetemcomitans may subside. Interestingly, recent serologic data suggests that even LJP involves P. gingivalis (Zafiropoulos et al., 1992. J. Periodontol. 63: 80-86). Specific antigens dominate the immune response. In LJP, high titers against serotype-specific carbohydrate antigens, LPS and certain outer membrane proteins are observed.
Longitudinal aspects. It is unclear at what point in the infection and subsequent disease process that initial seroconversion occurred, and it is also unknown how long serum titers remain elevated after the infection has subsided. In an attempt to address the latter issue, Ebersole et al. (1987) examined the serum response in a longitudinal manner following subgingival scaling and aggressive treatment (multiple-site surgery + antibiotics). Interestingly, 73% of patients manifested an INCREASE in antibodies against certain pathogens after scaling (Figure 8). "sc" = scaling; "st" = surgery plus antibiotics, dots = appointments). The increase in antibody titers began to peak 100-200 days after scaling. The reason for the antibody increase is unclear, but it may relate to the inoculation of microorganisms into the host tissues resulting from scaling or perhaps the elimination of an immunosuppressive microorganism. It may represent a more complex process involving a simplification of the microbial challenge. Surgery + antibiotics led to a gradual decline in antibody. The decline in antibody titers took at least 1 year.Regardless of whether you choose to believe Seymour or Page and Schroeder, the goal of periodontal therapy can be the conversion of the B-cell lesion to a T-cell lesion. Page and Schroeder would suggest that this is overkill, since in their model, there are stable B-cell lesions; however, they probably would not be opposed to the attainment of such a goal. In clinical practice, of course, it is impossible to monitor an intragingival B-to-T conversion.
Changes in intragingival T-cell subpopulations. The persistence of the T-cell populations in periodontitis and the increase in B-cell activity led to a postulation that T-cell regulation of B-cells was altered (dysfunctional) in periodontal disease. Were this true, it may be possible to observe phenotypic variation in the T-cell subpopulations, since phenotype and T-cell function should be related. Taubman et al. (1988. Adv. Dent. Res. 2: 328-333) examined the alterations in lymphocytes and mononuclear cells in the periodontium in two different periodontal disease entities, juvenile periodontitis and adult periodontitis. The number of lymphocytes recovered from periodontally-diseased tissues is almost 3 times greater than that from normal tissues (Fig. 11A; PB=peripheral blood, JP = juvenile periodontitis, AP = adult periodontitis). Taubman and his colleagues (especially, G.J. Seymour) found that CD4+ helper/suppressor-inducers and CD8+ cytotoxic/suppressors usually are in a ratio of 2:1 in gingivitis of children (Armitt et al., 1986. J. Periodontol. 57: 3-7) and in health. This ratio was 1:1 in both AP and JP (Fig. 11B). This suggested an immunoregulatory change and it clearly reveals that JP is similar to AP with respect to mononuclear cell (monocyte/lymphocyte) activity. Although we try to avoid preconceived notions, the shift in CD4:CD8 ratios from 2:1 to 1:1 seem paradoxical since there is an increase in B-cell activation.Resolution of the B-cell paradox. There are two explanations to this paradox. First, and most likely, it can reflect a sampling error; ie., it is difficult to sample a lesion during a destructive period and consequently, lesions are usually sampled during a period of healing and suppression. Second, but only within the 'realm of possibility,' this paradox can be explained in terms of subpopulations of CD4+ T-cells (Taubman et al., 1988). CD4 cells are not just "helper cells (~TH2 cytokine profile)," but also "suppressor-inducer cells (~TH1 cytokine profiles)." CD4+ suppressor-inducers may directly suppress B-cells or activate CD8 suppressors. Thus, although the CD4 cells are lower in proportion, this may reflect a decrease in the suppressor-inducer CD4 subpopulation. This could lead to relatively "unchecked" B-cell activation.
Periodontal lesions were examined using monoclonal antibodies designated "2H4" and "4B4." 2H4 identifies CD45RA, a molecule associated with naive or virgin cells [prior to activation by exposure to antigen]. 4B4 reacts with CDw29, which was believed to characterize previously activated (memory) cells. Naive cells have also been functionally associated with suppressor inducer activity. Both a decrease in proportion of CDw29+ T-cells and a takeover by double-labelled CD45RA/CDw29 cells was observed (Fig. 11C). The function of the double-labelled cell type is unknown; but it has been suggested that these cells are functionally immature memory T-cells. The increased polyclonal activity of B-cells in the presence of increased CD8+ T-cells cannot be related to increases in either the CDw29 or the CD45RA phenotype. The data is not definitive, since the memory T-cells may differentiate either in the Th1 or Th2 direction (Fig. 12), but it does suggest that on occasion, both B-cells and CD8+ T-cells can proliferate together.Gingival cytokines production. Given the B-cell nature of the periodontal lesion, it has been proposed that individuals susceptible to periodontal disease may have a TH2 response, whereas resistance to periodontal disease may relate to a TH1 cytokine profile (Gemmell and Seymour, 1994. Curr. Op. Periodontol.1994:28-38). Although suggestive information has been generated regarding the cytokine profiles associated with periodontal disease, the student should remember that periodontal inflammation does not occur in just a single stage; thus, cytokine profiles will vary with respect to when sampling was performed and the frequency of bone-resorptive events. Thus, observations which seem paradoxical may have very logical explanations. For example, the observation that "normal" gingivae transcribe detectable levels of IL-8 mRNA but periodontally diseased gingivae does not (Tonetti et al., 1993. J. Periodont. Res. 28:511-513) seems contrary to what one may predict. Periodontally diseased tissue may be beyond the point of using IL-8 and at a point of either using cytokines which more specifically recruit chronic inflammatory cells or at a point of shutting down the recruitment phase of the lesion.
A recent study demonstrates the absence of mRNA for IL-2 and IL-4 production but significant levels of mRNA for IL-5 and IL-6 production in gingival mononuclear cells isolated from lesional sites of adult periodontitis (Fujihashi et al., 1994. Molecular Pathogenesis of Periodontal Disease. ASM, Washington DC pp135-145). The presence of production of IL-5 and IL-6 suggests that TH2 CD4+ T-cells may dominate the periodontal lesion (Fig. 13). Both IL-5 and IL-6 are important cytokines in the later differentiation steps of B-cells. The absence of IL-2 would be an indication of the absence of TH0/TH1 CD4+ cells (although IL-12 was not examined), and the absence of IL-4 would suggests that certain TH2 activities may not be occurring, such as the activation of resting B-cells. Thus, the TH1/TH2 picture is not clear -- we don't know the precise subset responsible for the production of IL-5 and IL-6 (but no IL-4). Indeed, Taubman et al., (1994. Molecular Pathogenesis of Periodontal Disease pp 147-157) find evidence for both TH1 and TH2 T-cells. This makes it somewhat difficult to understand why periodontal lesions are dominated by B-cells. Taubman et al., also point out something that may be important: IL-4 downregulates the production of IL-1 and upregulates the production of IL-1 receptor antagonist (IL-1ra) in macrophages. Therefore, if IL-4 is diminished at lesional sites, IL-1ra may also be diminished and IL-1 mediated bone resorption may be favored.Potential results of B-cell activation. Although we generally view B-cells as primarily important as antibody-producing cells, activated B-cells also are major producers of interleukin-1b (IL-1b) within the gingiva.
Polyclonal B-cell activation. T-cell "dysregulation" of B-cells may be compounded by the activation of B-cells in a "polyclonal manner." Although it is clear that antibody within the periodontal tissues can be antigen-specific and react with such putative pathogens as A. actinomycetemcomitans, the vast majority of the immunoglobulins found in the periodontal tissues do not appear to be reactive to the antigens of the specific putative pathogens. Polyclonal B cell activation can also explain this observation as well as the B-cell aspect of the periodontal lesion. Importantly, the polyclonal nature of the antibody response in periodontitis has been suggested to preclude the formation of extensive insoluble immune complexes (Clagett and Page. 1978. Arch. Oral Biol. 23: 153-165). Perhaps a more important aspect of polyclonal B-cell activation is that it can lead to the production of IL-1, which activates osteoclasts and impede immunologic clearance of the offending pathogen.
Polyclonal B-cell activation may result from B-cell mitogens (or polyclonal B-cell activators; PCBA) PCBA are usually mitogenic (cause cell division with or without T-cell help) and are usually T-independent antigens (can activate B-cells specifically without T-help). The mechanism of interaction of PCBA probably differs with different activators. Some may be lectins which interact with B-cell surface glycoproteins. Others may be charged carbohydrates. Usually, the B-cell mitogen is polyvalent. Dental plaque contains a number of components which can activate B-cells in a polyclonal manner; eg., Lipopolysaccharides, A. viscosus, F. nucleatum, Porphyromonas gingivalis, are B-cell mitogens (Lehner, 1982). Often, polyclonal B-cell activation can lead to polyclonal antibody production, and although immunoglobulin levels are elevated, there may not necessarily be observed an increase in antibody titers against selected antigens. Interestingly, the PCBA of dental plaque appear to be T-cell dependent (ie., require cytokines from T-cells such as IL-2 and IL-6).
Cytophilic antibody, C3dg, and immune complexes. There are three other mechanisms of increasing the number of B-cells which activate in response to antigen. B-cell activation depends upon the cross-linkage of membrane receptors. The cross-linkage configurations which lead to B-cell activation are (1) BCR to BCR or (2) BCR to "coreceptor." BCR to BCR cross linkage can occur in the presence of multivalent antigens (such as polymeric flagellin or carbohydrates; ie., the T-independent antigens) or by the formation of antigen-antibody complexes (immune complexes, IC). In the case of IC, a second antibody can cross-link an antigen with another antigen and render it multivalent.
B-cells possess two coreceptors which can lead to enhanced B-cell activities, the Fcg-receptor (FcgRII) and complement receptor 2 (CR2). First, a "cytophilic" antibody (IgG1 or IgG3) with a different specificity than the BCR of the B-cell may bind to an antigen that possesses two different epitopes: one for the BCR and one for the cytophilic antibody. If the BCR binds to one epitope and FcgRII binds to the cytophilic antibody, a response may occur. This response would not occur in the absence of the cytophilic antibody since the antigen was univalent with respect to the BCR of the B-cell. To elicit polyclonal B-cell activation via the FcR-bound (cytophilic) antibody, the antibody must be present in sufficient density to permit receptor cross-linking and the antigen must possess two different epitopes. Finally, as discussed in the section on complement, the B-cell also possesses receptors for C3dg. An antigen may which had activated the complement system can bear the complement split product, C3dg. C3dg is the ligand of the coreceptor, CR2. B-cell enhancement can occur if the B-cell were to bind antigen via the CR2 coreceptor and the BCR.
Localized gingival antibody production. It was believed in the 1970s that the gingival crevicular antibody was a serum exudate. It became apparent in the later 1970s that this was not so. Lally et al., 1980, showed that gingival explants were capable of producing immunoglobulins in organ culture. Martin et al., 1988 have demonstrated that organ culture antibody specificity is distinct from serum antibody specificity. Thus, both the subclass and specificity of the antibody response in periodontal tissues is distinct from that in serum. The periodontal lesion, as described above, has a B-cell nature. Fifty-seven per cent of the lymphocytic infiltrate in the connective tissues are plasmacytes. The gingiva in periodontitis therefore constitutes an organ of localized antibody production. Gingival tissues are impregnated with very high levels of immunoglobulins. Mackler and coworkers have demonstrated that there are differences in the immunoglobulin subclasses present in the inflamed gingivae and those present in serum (Table 6).
| Table 6: Serum vs. Gingival Immunoglobulin Subclass | ||||
| Subclass | Serum % | Gingival % | T1/2(days) | Functions |
| IgG1 | 70 | 40 | 20 | Cytophilic, Fix C |
| IgG2 | 18 | 2 | 24 | Plysaccharides, LTA |
| IgG3 | 8 | 28 | 7 | Cytophilic, Fix C |
| IgG4 | 4 | 30 | Variable | Homeostatis? |
There is an enormous disparity between the relative proportions of IgG2 and IgG4. The amount of cytophilic antibody is about the same, but IgG3 is in relatively higher proportion in the gingivae. The relatively low proportion of IgG2 suggests that antibodies to polysaccharides aren't so prominent within the gingiva. These data clearly point to a significant separation of serum and gingival compartments. The presence of IgG1 and IgG4 also suggest that immunoglobulin production is not a matter of simple polyclonal B-cell activation (in which case the IgM isotype should be in greater proportion) but rather, that the B-cell response is regulated by T-cells. The isotype patterns themselves have been ascribed to the Th2-nature of T-cell help within the gingiva. Th2 T-cell-derived "B-cell factors," IL-4, IL-5, and IL-6, has been suggested to cause B-cells to switch to IgG4 (and IgA1) isotypes (Kiyono and McGhee, 1991), but it is probable that IgG4 and IgG1A represent a late stage, anti-inflammatory event asociated with Th1 cytokines (Chapter 11). These are anti-inflammatory antibodies which either fix complement poorly or do not bind to FcR, thus tend to block antigen-specific inflammation. This suggests that most antibodies (in this study, at least), occurred in the later stages of the inflammatory response.
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