What is the role of immunology in periodontal disease?
Schonfeld SE, Checchi L Review of immunology for the periodontist. J West Soc Periodontol Periodontal Abstr. 1985;33(2):53-64.
Nisengard RJ: The role of immunology in periodontal disease. J Periodontol. 1977 Sep;48(9):505-16.
Discuss the host response mechanism in periodontal disease including the production and role of inflammatory mediators like different cytokines and prostaglandins.
Genco RJ. Host responses in periodontal diseases: current concepts.J Periodontol. 1992 Apr;63(4 Suppl):338-55. Review.
Gemmell E, Seymour GJ: Modulation of immune responses to periodontal bacteria. Curr Opin Periodontol. 1994:28-38.
Gemmell Erica, Marshall R, Seymour GJ: Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease. PeriodontoIogy 2000. Vol. 14. 1997, 112-143
Ishikawa et al. Induction of the immune response to periodontopathic bacteria and its role in the pathogenesis of periodontitis. Periodontology 2000, VOI. 14, 1997, 79-1 11
Discuss the function and importance of Neutrophils (PMNs) in defense against periodontopathic bacteria?
Miyasaki KT. The neutrophil: mechanisms of controlling periodontal bacteria. J Periodontol. 1991 Dec ; 62(12):761-74. Review.
Dennison DK, Van Dyke TE: The acute inflammatory response and the role of phagocytic cells in periodontal health and disease. Periodontol 2000. 1997 Jun;14:54-78.
Van Dyke TE, Vaikuntam J: Neutrophil function and dysfunction in periodontal disease. Curr Opin Periodontol. 1994:19-27.
What is the role of lymphocytes as part of the cell-mediated adaptive immune system in periodontal disease?
Mathur A, Michalowicz BS: cell-mediated immune system regulation in periodontal diseases. Crit Rev Oral Biol Med. 1997;8(1):76-89. Review.
Seymour GJ, Taubman MA, Eastcott JW, Gemmell E, Smith DJ: CD29 expression on CD4+ gingival lymphocytes supports migration of activated memory T lymphocytes to diseased periodontal tissue. Oral Microbiol Immunol. 1997 Jun;12(3):129-34.
Reinhardt RA, et al. In Situ lymphocyte subpopulations from active versus stable periodontal sites. J. Periodontol. 59:656-670, 1988.
Kornman K, et al: Peripheral blood lymphocyte populations in ligature-induced periodontitis. J. Periodontal Res. 17:469 -471, 1982.
Wynne SE, et al. In situ demonstration of natural killer (NK) cells in human gingival tissue. J. Periodontol. 57:699-702, 1986.
What is the role of the humoral immunity as part of the adaptive immune system and the role of complement in periodontal disease?
Lovelace BM, Thompson JJ, Yukna RA. Evidence for local immunoglobulin synthesis in periodontitis. J. Periodontol. 53:626-630, 1982.
Ebersole J, et al. Humoral immune response and diagnosis of human periodontal disease. J. Periodontal Res. 17:478-480, 1982.
Ebersole JL, et al. Human serum antibody responses to oral microorganisms. IV. Correlation with homologous infection. Oral Microbiol. Immunol. 2:53-59, 1987
PD, Lin L, Gargiulo AW. Immunoglobulins and complement in human periodontitis. J. Periodontol. 49:631-634, 1978.
Lally ET, et al. Biosynthesis of complement components in chronically inflamed gingiva. J. Periodontal Res. 17:257-262, 1982.
Ebersole JL, Cappelli D, Holt SC: Periodontal diseases: to protect or not to protect is the question Acta Odontol Scand. 2001 Jun;59(3):161-6.
How does immune dysfunction affect the manifestation of periodontal disease?
Shenker B: Immunologic dysfunction in the pathogenesis of periodontal disease. J. Clin. Periodontol. 14:489, 1987. (Review)
Tolo K: periodontal disease mechanisms in immunocompromised patients. J Clin Periodontol. 1991 Jul;18(6):431-5. Review.
What is the role of immunology in periodontal disease?
Review of Immunology for the Periodontist
D: Discussion of complement, arachidonic acid cascade, hypersensitivity reactions and theory of clonal selection. Polyclonal response of B cells in response to antigen transforms B cells to plasma cell which produces immunoglobulins.
|
IgG |
IgM |
IgA |
IgD |
IgE |
|
Late in Ab response. Abs to toxins, bacteria, viruses |
Early in Ab response. Abs to infectious agents & polysaccharides |
Secretory antibody on mucous membranes |
No proved Ab activity. May act as a trigger |
Binds to mast cells. Important in allergic responses |
This can result in the precipitation of soluble antigens or in the agglutination of particulate antigens. This agglutinating or precipitating ability of antibodies is one of the major effects which antibody molecules produce in the immune response to foreign substances. Some of the effector functions, which are mediated by bound Ab, include: the complement system, opsonization by macrophage, tagging of cells, causes the release of inflammatory mediators, and neutralization of toxins by physically preventing the interaction between toxin and target.
Type Example Mediated by hypersensitivity reactions
|
I |
Anaphylaxis Wheal/Flare Rxn |
IgE |
|
II |
Humoral Autoimmunity |
IgG or IgM bound to Ag on host cell surfaces |
|
III Complement System |
Arthus Rxn Immediate Hypersensitivity |
Immune complexes caused by IgG combining with Ag |
|
IV |
Delayed Hypersensitivity |
Effector T-cells and Lymphokines |
The Complement System: Two pathways—Classical and Alternate.
Classical is initiated by the complexes of IgG and IgM and Ag with the C1.
Alternate pathway is initiated by the binding of endotoxins with a proactivator C3.
They both end with the formation of C5.
Arachidonic acid metabolites: prostaglandin has been shown to cause bone resorption.
Purpose: A review of basic immunologic responses, including a description of the principal two immune system responses (humoral and cellular), the complement cascade, and the protective and destruction potential of immune system responses. Immune responses to different types of periodontal disease were also discussed.
Discussion:
Destructive Immunologic Gingivitis and Periodontitis – Using Page and Schroeder stages of the disease permits a hypotheses to which host mechanisms may function at different stages of the disease
Initial lesion - migration of leukocytes into the gingival sulcus; complement activation in gingival crevice resulting from antibody-bacterial interaction and endotoxins; immediate hypersensitivity with release of histamine may result in increased vascular permeability
Early lesion: cell-mediated immunity with cytoxicity for fibroblasts, collagenase release from macrophages with further loss of collagen.
Established lesion: immune complex disease with perivascular infiltration, immediate hypersensitivity and collagenase activity
Advanced lesion: immune complex disease and cell-mediated immunity.
TYPES OF HYPERSENSITIVITY STAGES OF GINGIVITIS/PERIO DZ
I. Anaphylactic (IgE, Mast cells, Basophils) Initial 2-4 days
II. Cytotoxic (IgG/M autoimmune) Early 4-7 days
III. Immune Complex (IgG/M, Leukocytes) Established 2-3 wks
IV. Cell Mediated or Delayed (T cell) Advanced attachment loss
Disease may manifest itself only after overload of host defense mechanisms. Host defenses may include immunoglobulins, complement and other proteins in the crevicular fluid and PMN's, all of which may moderate the numbers and types of subgingival bacteria.
ANUG - usually occurs in patients with underlying gingivitis - cell-mediated immunity to F. fusiform may be responsible for conversion of gingivitis to ANUG.
Periodontosis - Neutrophil dysfunction with reduced phagocytic and chemotactic response as well as specific bacteria may be involved. This PMN dysfunction disrupts the protective host response to the bacteria.
Desquamative Gingivitis: Chronic desquamative gingivitis is a clinical entity with a number of underlying etiologies including dermatoses, hormonal factors and idiopathic factors. (Dermatoses include cicatricial pemphigoid, pemphigus, lichen planus, psoriasis.) Immunologic tests are important in diagnosis because some are autoimmune diseases while others have associated immunological findings.
Conclusion: Many factors, both immunological and bacterial may be involved in periodontal diseases. Elimination or suppression of a single factor will probably have little impact on the disease process.
Discuss the host response mechanism in periodontal disease including the production and role of inflammatory mediators like different cytokines and prostaglandins.
Purpose: Review article on the host responses in periodontal disease.
Conclusions:
2 types of lymphocytes (B-cells and T-cells): B cells develop in the marrow and subsequently develop into plasma cells, producing antibodies. T-cells develop in the Thymus and occur as either helper (assist B-cells in Ab production) or cytotoxic (upregulate microbiocidal activity of other cells (PMN’s)).
Periodontal bacteria trigger inflammatory host responses, which lead to tissue destruction. Tissue products such as the metalloproteinases, elastase, cytokines, prostaglandins, antibodies, and complement components all provide the basis for possible diagnostic indicator tests.
Data from clinical and in vitro studies suggest that the neutrophil/antibody/complement interplay is critical for protection against periodontal disease. Abnormalities in these ratios often lead to increased susceptibility to periodontal disease. This understanding can be used in the development of diagnostic tests, which assess function of phagocytes and their accessory factors. These include:
1. Assessment of macrophage production in cytokines
2. Measurement of the process of emigration by neutrophils to the site of inflammation
3. Assessment of factors influencing opsonization and killing of bacteria by phagocytes.
The role of periodontal bacteria may well be to stimulate chronic inflammatory cells of the gingiva and fibroblasts to produce cytokines including IL-1, TNF, IL-6, and others which act to stimulate osteoclastic bone resorption. These cytokines mediate their activity through the arachidonic acid metabolites, mainly prostaglandins, but also possibly the prostacycline and lipoxygenase products to increase osteoclastic activity, which in turn results in bone resorption.
There are healing periods following periods of active tissue destruction in specific sites. Measurement of factors which are responsible for healing such as the negative regulators of inflammation including TGF-B, gamma-interferon, IL-4, and IL-1receptor antagonist may provide an assessment of periodontal disease in remission or in the healing phase.
Genetic factors, which are responsible for increased susceptibility, provide indicators for those in the population who are at high risk to develop severe periodontal disease. To date, factors such as human leukocyte antigen (HLA) associations with periodontal disease, leukocyte adherence defects, and leukocyte functional abnormalities such as seen in LJP cases may have a genetic basis.
Purpose: Review article on the modulation of immune responses to bacteria.
Discussion: Modulation of PMN function: PMNs and the innate immune system are the first line of defense against infectious agents. PMNs comprise more than 90% of the leukocytes in gingival fluid. PMNs show both destructive and protective influence on periodontium. Some periodontal bacteria as P.g., A.a. and F.n. may jeopardize the protective functions of PMNs by inhibition of phagocytosis, production of superoxidase dismutase and direct leukotoxicity. MacFarlane demonstrated impaired phagocytosis of PMNs in patients with refractory periodontitis. PMNs have a regulatory role by secreting a range of regulatory cytokines including IL-1 and IL-1 receptor antagonist. Adaptive immune responses: Studies have shown phenotypic and functional immunoregulatory imbalance in adult periodontitis (reduced CD4/CD8 ratios in patients with periodontitis). Most data show that T-cell response in adult periodontitis is antigen specific. Polyclonal B-cell responses have been cited to be important in the pathogenesis of periodontitis but there is also the possibility of local activation of memory B-cells in the periodontal tissues. Different lymphocyte clones may home in the different disease states (gingivitis or periodontitis) in the gingival tissues, but this difference is not reflected to the pattern of adhesion molecule expression. Cytokines in adult periodontal disease: Elevated levels of IL-1, IL-5 and IL-6 are found in patients with periodontitis but lower levels of IL-1 and IFN-γ. IL-4 is also increased and enhances anitbody production (IgG4). There are discrete T-cells subsets with different cytokine profiles and protective capabilities. For example, CD4 Type 1 cells produce IL-2 and IFN-γ and their major function is delayed-type hypersensitivity, whereas Type 2 T-cells produce IL-4 and IL-10 and their major function is regulation of antibody production. The outcome of the infection is dependent on which T-cell subset is stimulated. Stimulation of Th-1 leads to resistance and Th-2 susceptibility. Endogenous cytokines levels control which subset predominates. IL-12 or NK cell stimulatory factor is produced by monocytes, macrophages, B cells, and other accessory cells in response to bacteria, bacterial products, or parasites. It induces IFN-γ productions and is necessary for Th1 induction. It provides a link between natural resistance and adaptive immunity. Differences in the regulation of the immune response to specific plaque bacteria result in differences in host reactivity. Some individuals are susceptible to periodontal breakdown and others manifest a disease that over their lifetime progresses very slowly. T-cells are depressed in progressive lesions and B-cells predominate and differentiate. Cytokine profiles that confer resistance or susceptibility to periodontitis have not been defined, However, it was reported that in leprosy which clinically presents as both stable and progressive forms, mRNAs for IL-2, INF-γ were most evident in the resistant forms and for IL-4, IL-5 and IL-10 in the susceptible form. Cytokine therapy may be an option in the future for certain diseases.
Title: Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease.
Keywords: cytokines; prostaglandins; homeostasis
Purpose: A study of cytokines involved in periodontal disease lesions may explain the variation with respect to frequency/rate of progression and suggest future lines of therapy.
Discussion:
Periodontal disease results from the interaction of the host defense mechanisms with microorganisms in plaque.
Patient susceptibility is most likely very important in determining the outcome of the disease, but a predictive screening of periodontal disease progression has not been formulated.
Immune homeostasis: the importance of cytokines induced locally is paramount as they effect the cells in the immediate area, therefore they determine the course of response and resistance/susceptibility to the pathogen
Cytokines:
Cell regulators that influence production and activation of different effector cells in immune response. Production of “appropriate” cytokines is essential for protective immunity.
Cytokines interact in a network: induce each other, modify cell surface receptors, cause synergistic, additive or antagonistic interactions on cell function. This allows the immune system to have multiple mechanisms for dealing with pathogens, then restoring homeostasis.
Cell-mediated immunity: induction of CD4+ and CD8+ T cells
Humoral immunity: B-cells antibody production.
Multiple regulatory mechanisms that could be a defense against pathogen interference and be essential in the preservation of homeostasis.
Immune response to infection is regulated by the balance between Th1 and Th2 cytokines. There is a question as to whether this classification is correct; possible that there is not two distinct subpopulations predetermined to produce a specific cytokine pattern, but rather acquired at time of differentiation cells.
Th1: Cell-mediated inflammation. Express/secrete IL-2, IFN-γ, TNF-β, IL-3, TNF-α, granulocyte-macrophage colony stimulating factor (GMCSF). Increase ability of macrophages to kill pathogens and mediate delayed-type hypersensitivity reactions. IFN-γ, IL-12 induces Th1 response.
Th2: Antibody production and allergic response. Express/secrete IL-4, IL-5, IL-6, IL-10, IL-13, IL-3, TNF-α, GMCSF. Stimulate mast cells, esosinophils and IgE. Stimulate B cell production/differentiation: IgM, IgG4, IgA & IgE. IL-4, IL-10, IL-13 favor Th2 response.
|
Cytokine |
Source |
Functions |
|
Interferon-gamma |
T cells NK Cells |
Induction of Th1 cells Inhibts interleukin 4 activities Enhances IL12 production Stimulatues macrophage activity and cytolytic T lymphocytes and NK cells upregulation of MHC I and II |
|
IL-4 |
T cells Mast cells basophils |
Induction of Th2 cells Inhibts interleukin 2 activities and INF-gamma Inhibts interleukin 12 production Induces proliferation and differentation of B cells Inducsed the proliferation of T cells Downregulations of monocytes production of IL1, TNF-a, IL 6 |
|
IL-10 |
T cells B cells Monocytes and macrophages |
Promotes Th2 response while supresses Th1 cell-mediated responses Supressess proliferation and cytokine production by activated T cells Suppressess macrophages function and IL 12 production Inhibits macrophage-derived IL1, IL6, IL8 Enhances B cell proliferation and differentiation |
|
IL-12 |
B cells Monocytes Macrophages Dendritic cells Keratinocyctes Langerhans cells neutrophils |
Plays a key role in Th1 induction Stimulates growth of NK and T cells Link between natural resistance mediated by phagocytic cells and natural killer cells and adaptive immunity mediated by T-helper cells, cytolytic T lymphocytes and B cells |
|
IL-13 |
T cells |
Similary functions to IL 4 Downregulates IL 12 production and may favor Th2 development Co-stimulator for B cells but does not affect T cells Modulates monocyte and macrophage function including inhibition of cytokine production |
Suppression of immune system and inflammation:
IL-4, IL-10 and IL-13. The link between innate and adaptive immunity is IL-12 (activates NK cells, which then influence whether Th1 or Th2). Stable periodontal lesions have high T cell predominance- Th1: increase of IFN γ and IL-2. Progressive lesions have increased B cells/plasma cells- Th2: increase of IgG4 and IL-4. However, full range of cytokine producing T cells was all found in both gingivitis and periodontitis.
Progressive periodontal lesions:
Antibodies are important to eliminate organisms, but could cause continued CT breakdown. Systemic involvement: serum with high titers of anti-P.g antibodies can inhibit in vitro bone resorption. However, humoral response can’t clear P. g from pocket.
Tissue destruction:
Caused mainly by IL-1, TNF-α , and IL-6. These increase collagenase production, increase CT destruction, bone demineralization and cytokine production, stimulating osteoclast differentiation and inducing bone resorption. These destructive cytokines are seen in gingivitis and active periodontitis, but generally not in health.
Suppression of tissue destructive cytokines:
IL-1ra (binds IL-1 receptors without inducing cell activation), IL-10, IL-4 and Transforming growth factor (TGF)-β all downregulate IL-1 and TNFα, and induce IL-1ra secretion, death of LPS stimulated monocytes, and stop bone resorption.
Prostaglandins:
Cleavage of phospholipase A2 to generate arachidonic acid and then goes thru COX pathway (activated by IL-1 & TNF α) converting it to prostaglandins (PGs) and thromboxanes. PGs mediate bone resorption and have synergistic effect involving inflammation. Corticosteroids and NSAIDs are able to control inflammation by blocking parts of this pathway. PGs are secreted by several tissue components in the periodontium. PGE2 is stimulated by LPS and is important in periodontal disease. There is an increase in PGE2 in inflamed gingival tissues.
Cytokine therapy:
Makes sense conceptually, but is difficult to achieve clinically. Cytokines as a whole are essential for the immune system to function, so widespread suppression would be bad. Also, since cytokines are continuously produced, long-term blockage would be necessary.
Gene therapy:
Treat disease by correcting genetic defects in somatic cells. As many precursors are dormant in tissues difficult to alter these cells. A vector is needed to carry and insert new material. To date, retroviruses, adenoviruses, liposomes and direct DNA injection have been approved
P: To summarize the immune response to periodontopathic bacteria and its role in the pathogenesis of periodontitis.
Porphyromonas Gingivalis: earlier known as B. asaccrolyticus
-Pts with adult periodontitis had higher levels of IgG antibodies to P. gingivalis in serum and GCF.
-Fimbriae – Curled, single-stranded filaments implicated in adherence of bacteria to gingival tissue. Fimbriae are found in P. gingivalis and Aa.
-P. gingivalis has a dense amorphous capsule around the outer membranes. Pt with periodontitis appear to have very low levels of antibody to the capsular polysaccharide (resists desiccation and phagocytosis from PMNs).
-P. gingivalis lipopolysaccharide shows very little endotoxic activity although it is significantly mitogenic. Highest antibody tilters to P. gingival is LPS were associated with LJP (only SS compared to the control group).
-P. gingivalis produces a wide variety of enzymes, collagenase and trypsin like proteases are very specific to P. gingivalis. This makes P. gingivalis easy to distinguish from other black-pigmented anaerobic rods.
-P. gingivalis produces enzymes that degrade most serum proteins, including immunoglobulins and complement proteins. They release gingipains ( esp argingipains) that degrades collagen I and IV and IgG extensively.
Tannerella forsythus: earlier known as B. forsythus
-B. forsythus is the organism most commonly found in refractory periodontitis.
-Serum IgM antibody levels to AA LPS were increased in pts with periodontitis.
Aggregatibacter acetinomycetemcomitans: earlier known as Actinobacillus acetinomycetemcomitans
-Aa strongly associated with Localized Juvenile Periodontitis
- Aa has a lipopolysaccharide that is also found in other gram-negative bacteria. The lipopolysaccharide has a broad spectrum of immunobiological and endotoxic activities.
-Aa possess fimbriae
-Large number of Plasma cells accumulate in localized gingival tissues with chronic inflammation
-IgA is found in saliva and humoral immune response at the mucosal level. It is capable of moving across mucosal membranes to prevent entry of infectious organisms.
-IgG antibodies to AA were significantly elevated in pts with juvenile perio (Aggressive) and IgG levels were significantly elevated in pts with moderate to severe perio.
-Aa and its antigens can invade tissues
-IgG2 is the major subclass in response to Aa
-The death of macrophages induced by Aa occurs through apoptosis (Aa must inter into these cells to induce this mode of killing)
-IL-1β (released from stimulated macrophages) stimulates bone resorption and is significantly increased in periodontal tissues and GCF from diseased sites. TNF α also stimulates bone resorption but is less potent than IL-1β.
-Monocytes from pts with early onset perio responded LPS with elevated amounts of Prostaglandin E2, and TNF α.
-Natural killer cells were found to decrease after OH training and/or professional therapy. There are more natural killer cells present as perio lesions deteriorate.
Discuss the function and importance of Neutrophils (PMNs) in defense against periodontopathic bacteria?
Purpose: To review the role of Neutrophils in periodontal disease.
Discussion:
Myeloid part (Neutrophils, monocytes and other granulocytes) of the immune cells is more protective with respect to periodontal pathogenesis. For example, cyclic neutropenia is associated with excessive periodontal destruction, whereas lympho-suppressive therapy isn't.
Host defense strategy:
Serum Complement (GCF)Neutrophil (gingival crevice)Monocyte/Macrophage (migrate into CT)Lymphocytes (will be presented Ag by MHC)
Monocytes/macrophages and lymphocytes predominate in the CT
Neutrophils predominate in the JE and the gingival crevice
Neutrophils concentration in periodontal tissue exceeds the concentration in blood. Neutrophils actually form a "leukocyte wall" between the periodontal plaque mass and JE (as opposed to a homogenous bacteria/leukocyte mixture). This wall acts as a secretory and digestive organ.
Neutrophils are terminally-differentiated cells and no longer concerned with their own survival. Therefore, they are free to use antimicrobial delivery modes that can be suicidal.
Neutrophils deliver antimicrobial substances by 4 different mechanisms:
Oxygen metabolites via a process known as "respiratory burst”, creating superoxide O2 -, and H2O2 -
Secretion via fusion of the cytoplasmic granule with either the plasma or phagosomal membranes
Phagocytosis via fusion of a phagosome with a lysosome forming a phagolysosome. This delivers very high concentrations of antimicrobial substances by intraphagolysosomal secretion and respiratory burst activity.
Death by cytolysis and/or apoptosis, this is very important in controlling muco-cutaneous candidiasis.
Neutrophils can kill microbes through two major pathways:
Oxidative killing: NAPDH Oxidase (in the cytosol phosphoproteins, or membrane specific granules: cytochrome b, and flavoprotein) or Myeloperoxidase found in the Azurophil granule.
Nonoxidative killing:
-In Cytosol: Calprotectin.
-In Specific granules: Lactoferrin, cobalophilin, and lysozyme.
-In the Azurophil granule membrane: Bactericidal/Permeability Increasing protein.
-In the Azurophil granule: Defensins, Lysozyme, and Neutral serine proteases (including P29b, Cathepsin, Elastase, Azurocidin, and Cationic protein).
Neutrophils help control the colonization of oral bacteria. Experimental neutropenia leads to rapid apical extension of the subgingival plaque front into the JE without bacterial invasion of CT.
Neutrophil elastase or cathepsin G decreases the adherence of S. sanguis but increases the adherence of P. gingivalis to saliva coated hydroxyapetite in vitro. Neutrophils are capable of detaching S. mutans from glass, and A. viscosus from saliva-coated hydroxyapatite.
Nonoxidative killing maybe more important in controlling the periodontal microflora, since oxidative disorders in neutrophils are less influential on periodontal disease. (gingival crevice is hypoxic)
In individuals with localized aggressive periodontitis, neutrophils exhibit decreased killing of A.a. despite normal phagocytosis, oxidative burst, and secretion of specific granules components. There is also variable expression of defensin HNP-3 (function of which is unknown).
Bacteria have evolved strategies to evade neutrophils, these include Catalase, which catalyzes the disproportionation of H2O2 -. Mannans are capable of interfering with the microbial activities of Myeloperoxidase. Siderophores may combat the bacteriostatic effects of lactoferrin by competing for iron. Extracelluar polymers may also assist bacteria in evading host defense systems.
Purpose: To describe the acute inflammatory response to infection, and the relationship of phagocyte function to the onset and progression of periodontal diseases.
Discussion: Following initial bacterial invasion, a directed and targeted movement of the neutrophils and monocytes to the site of infection occurs. The most important function of the neutrophils is phagocytosis. The functions of macrophages (which derive from monocytes) include phagocytosis, antigen presentation and cytokine secretion (IL-1B, PGE2). These cytokines amplify inflammation and stimulate tissue breakdown.
Although bacteria produce several proteases (P. gingivalis also produces collagenases), their action is limited by host’s mechanisms:1-a wall of neutrophils between the epithelium and the bacteria limits invasion 2-Significant fluid flow emanates from the widened spaces of the JE. While bacteria produce products that can damage the periodontium, the main destruction of periodontal tissues occurs by the host’s defense.
The net effect of complement activation is to augment opsonization of bacteria by antibodies, to allow some antibodies to kill bacteria, to recruit phagocytes to the site of complement activation and attack the membrane of pathogens. Complement is activated by three different ways: 1) Classical pathway (antigen-antibody complex) 2) Lectin pathway 3) Alternative pathway. While there are 3 different pathways, they ultimately result in the production of a protease called C3 convertase that is bonded to the pathogen surface.
The initial recruitment of circulatory phagocytes is prompted by the expression of selectin (initial adhesion) and Integrin (tight attachment) class adhesion molecules on capillary endothelial cells. Cytokines released in the periodontium in response to bacteria up-regulate the cell adhesion molecules. After traversing the endothelium, neutrophils then follow the increasing level of chemotactic factors to the site of bacterial challenge (chemotaxis). Neutrophils are initially the predominant host defense cells found in periodontal lesions (and in all bacterial infections).
There are five types of receptors for bound complement (4 of which are found on phagocytic cells). Binding of inactivated C3b by the CR3 stimulates phagocytosis and represents the major mechanism for non-immune opsonization. Complement receptors on neutrophils and monocytes can be directly affected by complement components (C5ainc expression of CR1 and CR3Inc adherence to vessel walls, chemotaxis and their ability to ingest particles)
Fc receptors are found on macrophages, neutrophils, eosinophils and mast cells. They are a group of molecules that bind to the Fc portion of the immunoglobulin. The binding cell type depends on the specificity of the antibody. This binding activates a number of different biological processes: 1) Phagocytosis; 2) antibody dependent cellular cytotoxicity; 3) clearance of immune complexes; 4) activation of the respiratory burst; 5) release of inflammatory mediators.
Phagocytosis is enhanced by coating the bacteria with antibody or complement (opsonins). There are 2 mechanisms by which the pathogen can be destroyed:
1) Intracellular killing: granules within the neutrophil are responsible for killing
2) Extracellular killing: release of granules into infected tissues, which can also destroy adjacent normal tissues.
H2O2 produced by neutrophils’ metabolism can be used by peroxidases and also is bactericidal in high concentrations.
A significant level of redundancy exists in the mechanisms used by phagocytic cells and this ensures that most bacteria are killed, since some of them could be resistant to some mechanisms but sensitive to others. The agents used by the neutrophils in killing have been divided to oxidative and non-oxidative groups. Neutrophils have two main types of granules that function in killing the ingested microorganisms, the primary (azurophilic) and the secondary (specific). When activated, neutrophils generate reactive oxygen intermediates (respiratory burst), which is essential in destroying pathogens.
Bacteria can avoid phagocytosis in several ways (polysaccharide capsule, sialic acid). The lipopolysaccharide of P. gingivalis has been found to be able to block E-selectin stimulation, which minimizes the initial neutrophil colonization to the site of infection. A.a. produces Leukotoxin, which creates small pores in the host immune cells, ultimately destroying them. Some microorganisms can enter the host cells evading this way antibodies and complement.
The greatest concentration of chemotactic agents is associated with the supragingival and subgingival plaque, and the connective tissue has the lowest concentration. Neutrophils use this gradient and form a “wall” separating the advancing front of plaque from the epithelium. As the level of inflammation increases connective tissue becomes exposed to neutrophils and the cytokines produced by them. While neutrophils are primarily involved in phagocytosis, macrophages within the periodontal apparatus function primarily as antigen presenting cells.
Abnormal phagocyte function (especially neutrophils) is related with early onset periodontal disease. Localized juvenile periodontitis has been reported to be associated with decreased neutrophil chemotaxis in 75% of patients clinically diagnosed with LAP.
Alterations in monocyte response would probably result in abnormal disease patterns. Recent studies have shown that in Adult periodontitis lesions there is an absence of IL-4 producing T Cells. IL-4 has been shown to inhibit monocyte secretion of cytokines and prostaglandin E2. The depletion of IL-4 has been hypothesized as a mechanism for tissue destruction in the progression of periodontal disease.
Immunoglobulin function can be evaluated, including assays measuring either complement – mediated killing, phagocytosis or both. In vitro studies have shown that B cells from black patients with localized juvenile periodontitis produced elevated levels of IgG2.
Studies about the role of FcγRII-A polymorphism in infectious diseases have indicated the importance of the FCγRII-A allotype in preventing infections; however, there has been no such study done looking at periodontitis.
PURPOSE: To review recent developments in PMN function and dysfunction in periodontal disease.
DISCUSSION:
Neutrophil structure: Neutrophils are the predominant leukocytes found in the oral cavity. PMNs contain cytoplasmic granules, which perform different functions. There are 3 categories:
1) primary (or azurophil) functions: microbial killing, histamine release, enhance phagocytosis, antibacterial, exacerbation and mediation of inflammatory reaction
2) secondary (or specific) functions: hydrolysis of cell wall proteoglycan, collagen destruction, bactericidal.
3) tertiary (or secretory) functions: cell surface receptor expression
Neutrophil function: Neutrophils respond to microbial invasion as follows:
Adherence: involves margination and attachment of the PMNs to vascular endothelium via specific molecules present on the surface of the PMN and endothelial cell.
Chemotaxis: neutrophils travel to the site of microbial injury in response to specific chemical agents (chemoattractants such as C5a, FLMP and arachidonic acid metabolite LTB4). Chemotactic response is initiated when binding of a ligand to its specific receptor on the PMN surface.
Recognition and phagocytosis (opsonization): the invading organism is coated with opsonins such as IgG and C3b, which enhances adhesions and renders the organism more susceptible to phagocytosis.
Microbial killing: fusion of phagosome and neutrophil granule. Intra or extracellular release, which could damage nearby structures.
Neutrophil function and periodontal disease: Neutrophil function is central to maintaining the integrity of the PDL. Neutrophils in LAP patients exhibit many dysfunctions including decreased chemotaxis, phagocytosis, and bactericidal activity. Superoxide generation may be elevated.
Neutrophil-bacteria interaction: Neutrophils in the gingival crevice are the first line of defense against periodontophathic organisms. A. a. produces a protein that inhibits chemotaxis and H2O2 production in neutrophils. P. gingivalis LPS can enhance superoxide production in RPP (rapidly progressive periodontitis) patients and can also inhibit PMN chemotaxis. Fusobacterium has the ability to depress PMN adherence.
Neutrophil-mediated killing of pathogens and tissue destruction: Neutrophils can kill bacteria via oxidative (O2- and H2O2) and nonoxidative mechanisms (granule secretion, phagocytosis, cytolysis). Secretory and secondary granules are released extracellularly and have the potential to cause localized tissue destruction. Patients with active periodontal disease often have elevated levels of beta-glucuronidase. Increased levels/activity of this enzyme could play a potentially destructive role in periodontal disease progression. Elastase also has been shown to be elevated in disease. Superoxide production is also contributory to tissue destruction.
CONCLUSION/BL: PMNs are capable of causing periodontal tissue destruction by both 1) production of superoxide anion, H2O2, hydroxyl radical, and the potentially lethal hypochlorous acid and 2) PMN granule secretion and lysosomal enzymes. Patients with impaired neutrophil function are at an increased risk for periodontal breakdown.
What is the role of lymphocytes as part of the cell-mediated adaptive immune system in periodontal disease?
The adaptive immune system consists of humoral and cell-mediated immunity.
T-lymphocytes are the key components of cell-mediated immunity.
CD4+ helper T-lymphocytes facilitate B-cells to differentiate and produce specific antibodies, whereas CD8+ cytotoxic T-lymphocytes kill virally infected cells.
Periodontal disease have been associated with a variety of imbalances in the regulation of immune responses.
Proliferative responses:
SLR (spontaneous lymphocyte response) a measure of AMLR(autologous mixed lymphocyte reaction) is generally depressed in patient with early-onset and chronic forms of periodontitis.
These patients have fewer CD4+CD45RA+(naïve) T-cells and depressed interlukin 2 production.
CD4:CD8 ratios in periodontal disease
Overall the CD4:CD8 ratio does not appear to altered in patients with early –onset or chronic forms of the disease, but research is conflicting and it might be due to a large variability of the within patient groups.
Specificity of peripheral blood lymphocyte response
Antigen which stimulates specific T-cell subsets may be bacterial species-specific therefore cells exist in peripheral blood that respond to specific periodontal bacteria.
Both disease activity and the types of bacteria might be involved in the conflicting proportions of CD4:CD8 cells.
Tissue-born Immune Cells
When compared with peripheral blood the CD4:CD8 ratio in disease tissues tends to be decreased, due to both a reduction in number of CD4 cells and a sight increase in the number of CD8 cells.
This implies that any dysfunction in immunoregulation is confined locally to the affected periodontal tissue and may not manifest in peripheral blood.
Superantigen activity in periodontal disease
Superantigens can activate T-cell by binding to only the V region of the beta chain of the major hitocompatibility complex and do not require binding to the alpha chain, therefore the response generated is extreamly potent.
Several bacterial antigens have been shown to express such superantigens
Gamma Delta T-cells in Perio
At present the role of gamma cells in the pathogenesis of periodontal disease is not well understood. It has been suggested that they defend against bacterial invasion in the gingiva by destroying stressed or infected epithelial cells.
Natural Killer Cells
NK cells may play a role in the pathogenesis of periodontal disease through their cytotoxic activity against host cells.
Purpose: To characterize the CD4+ T cell subsets in lymphocytes extracted from human periodontal disease lesions in terms of their expression of CD45RA and CD29, and to compare the phenotype ratios with those found in normal periodontal tissue and in peripheral blood.
Methods: A. Peripheral blood mononuclear cells were obtained from a total of 38 pts: 16 w/ adult periodontitis, 6 w/ LJP, and 16 normal or gingivitis subjects.
B. Tissue was obtained from a total of 22 patients who were undergoing periodontal surgery (11 adult periodontitis, 6 LJP, 5 normal).
Double and triple staining immunofluorescence was carried out.
Results: In peripheral blood lymphocytes: NSSD in the CD4/CD8 ratio and NSSD in the CD4 subsets between normal and periodontally diseased subjects.
In cells extracted from diseased periodontal tissues: all the CD4+CD29+ cells were expressing high density CD29. Both diseased groups showed SS increase in CD29+ and CD45RA+ populations. Both diseased groups contained SS higher percentages of CD4+CD45RA+ cells than normal.
Conclusion: CD4+ T lymphocytes in periodontal disease not only demonstrate varying levels of maturity but also that the accumulation of CD4+ T cells within periodontal tissues may be a result of increased adhesion and transendothelial migration.
P: To quantitate lymphocyte subsets in infiltrates from periodontal biopsies associated with disease activity compared to those from similar stable or healthy sites.
M&M: 20 adult patients with recurrent periodontitis. 88 gingival biopsies including 37 active sites (increase in of total CALoss of at least 2mm from the last 3-month visit), 28 stable sites and 23 healthy sites evaluated for cell populations. Lymphocyte density was enumerated and PMNs and plasma cells identified in the sulcular, middle, and apical 1/3 of each section. Blood samples also evaluated using direct immunofluorescence.
R: Infiltrate of plasma cells or PMNs could not be detected in healthy sites.
Active sites demonstrated significant prevalence of B cells compared to healthy and stable.
A decreased ratio of T/B cells in active sites as compared to stable sites and blood
A trend towards decreased numbers of T helper cells in the sulcular infiltrates. There was no significant difference between groups when the entire specimen was taken into account, however, there was a greater density of T cells in the sulcular third of diseased sites.
BL: Active periodontal disease displays elevated B cell populations and lower relative numbers of T-helper cells. Abnormal immune regulation may be occurring and may involve T helper cells.
Purpose: To evaluate bacterial and immunological changes during conversion of a chronic gingivitis to a progressing periodontitis in cynomolgus monkeys, and the effect of an immunoregulating drug on the lymphocyte profile.
Materials and methods: 12 adult female monkey lymphocyte profiles were used. All teeth in lower left posterior sextant were ligated. Peripheral blood and sub-g plaque samples were taken six weeks prior to ligation and at the time of ligation (T=0) and at 6 and 8 weeks after ligation. At 10 weeks animals were randomly assigned to receive Thymopentin (TP5) (a pentapeptide corresponding to amino acids 32-36 of the thymic hormone-thymopoietin) or placebo for 6 weeks. Bacterial and blood samples were repeated at 12, 15 and 16 weeks. Each week measurements of plaque, PD and gingivitis were also recorded. T- and B- cells populations were evaluated.
Results/BL: The two baseline readings taken 6 weeks apart were stable for all cell types. Proportions of T-cell reduced from 6 to 8 weeks significantly. Animals treated with TP5 demonstrated a significant increase in helper T-cells comparing to placebo. Proportions of B-cells increased significantly after ligation. During treatment period both groups of animals exhibited a decrease in Ig-positive cells. Total numbers of lymphocytes increased significantly.
5/12 animals started with significantly higher proportion of B-cells than the other animals and exhibited rapid bone loss. From the rest of the remaining animals, 5 showed bone loss ultimately and at that point B-cells were increased and 2 animals never developed clear clinical or radiographic evidence of disease and B-cells in these animals showed no increase.
Conclusion: The conversion of a stable gingivitis to a progressing periodontitis was associated with a decrease in peripheral blood helper T-cells and an increase in peripheral B-cells.
Keywords: Natural killer cells; gingiva; gingivitis; periodontitis
Purpose: To locate and identify Natural Killer cells in healthy and diseased gingival tissue.
Materials and methods:
46 healthy patients, divided into 3 groups.
Group 1- Experimental gingivitis (EG): 20 patients; prophy 1x per week for 4 weeks prior, then no OH for remainder of study. Biopsy of gingival tissue of MB #3 taken at day 0, 4, 8 or 21.
Group 2- Children’s Gingivitis (CG): 10 patients <8 years old needing extraction of deciduous molars for orthodontic treatment. Biopsy from sites with GI> 1 and PD 2mm or less.
Group 3- Chronic inflammatory periodontal disease (CIPD): 16 patients after SRP, biopsy taken during Modified widman flap surgery from sites with GI> 2 and PD> 6mm. Tissue samples examined under Kohler illumination using monoclonal antibodies
Reagents:
anti-leu 4 = panperipheral T cells
anti-leu 7 = NK/ lymphocyte cells
anti-leu 11 = NK cell/K lymphocyte cells LGL Fc receptor
Results:
EG group:
Day 0: considered gingival health; Day 4: no change from day 0. Days 8 and 21 had increasing #’s of NK cells.
CG group:
NK cell #/distribution resembled 21 day EG.
CIPD group:
subdivided based on major lymph. Lesions were classified as "T cell" if >90% of the lymphocytes reacted with the Leu 4 monoclonal antibodies. Lesions containing MGP+ (Methyl Green Pyronin- identifying plasma cells) and <60% Leu 4+ lymphocytes were classified as "B cells". “T cell” + leu-4 areas with few NK cells. “B cell” areas had several leu 7+ (NK cells) closely associated. No NK cells were found in fibrous tissue zone bordering these lesions, and no association with fibroblasts.
BL: NK cells are absent in gingival health but present in inflammation. Lesions of gingivitis consist predominantly of T cells with occasional NK cells. The number of NK cells increased as plaque induced inflammation increased. The greatest number of NK cells were found in established chronic lesions (“B cell” lesions). This refutes previous assumption that NK cells are involved in cellular cytotoxicity than against plaque-affected fibroblasts in chronic lesions. It is possible that NK cells might be an important factor in conversion of a stable “T cell” lesion to a progressive “B cell” lesion.
What is the role of the humoral immunity as part of the adaptive immune system and the role of complement in periodontal disease?
B: The host's immune response to bacteria also has been implicated as a mediator of destruction by both direct and indirect means. Plasma cell infiltrate have been shown to increase in number with disease severity.
In non-inflamed tissues albumin is present in extravascular sites at a concentration substantially lower than that of serum and IgG should also be proportionally lower in extravascular concentration. In inflamed tissue, permeability changes and albumin and IgG are found at higher concentrations in extravascular sites. Thus any variation in IgG/albumin ratio in the gingival when compared to the corresponding serum ratio would therefore result from local changes in IgG production or accumulation.
Albumin (synthesized in liver)
Intravascular
Extrasulcular (interstitial fluid)
IgG (synthesized by lymphocytes/plasma cells)
Intravascular
Extravascular
Interstitial fluid
Locally produced
P: To determine serum and gingival IgG concentrations relative to reference albumin levels in an attempt to find out if gingival IgGs are produced locally or systemically.
M&M: Blood and tissue samples were obtained from 16 patients with pockets at least 5mm deep. Efforts were made to obtain tissue samples consisting of sulcular epithelium and inflamed sub adjacent CT. Electro-immunoassay for IgG and albumin was performed.
R: The mean IgG/albumin obtained for serum was 0.875, while that obtained for gingiva was 4.244. This comparison was proven significant and indicated that an average of 74.56% of the IgG in the gingival extracts was of local origin.
BL: Definite local origin of the immunoglobulins is found in the gingiva in periodontitis. 74.6% of gingival IgG was of local origin.
Cr: Tissue sample not standardized, so extracts contained varying protein conc. Author made conservative assumption on the extravascular site wrt to IgG/ albumin ratio since albumin is normally found in lower concentrations and IgG is a larger molecule so it has low permeability.
Purpose:
1) To identify active forms of periodontal disease and its immune response characteristics
2) To examine host reactivity to representative organisms of the complex microflora in periodontal lesions.
Method:
Serum, Static Crevicular Fluid (SCF) & microbiological samples collected from pts classified as:
LJP (localized juvenile periodontitis)
ADP (advanced destructive periodontitis)
AP (adult periodontitis)
Serum from healthy subjects for comparison -ELISA procedure.
Results:
LJP pts: 90% had high Ab levels to A.a.
ADP & AP pts: 37-48% had normal response to all organisms except P.gingivalis.
Controls: 85% showed extreme responses to none of the microorganisms.
There was no sig diff in Ab synthesis in SCF between individual teeth. When local SCF Ab & microorganisms were observed together, 84% of teeth exhibited active disease during clinical monitoring, while if only one of these was observed, disease activity was found in <50% teeth, either local antibody synthesis or the microorganism.
|
Distribution of clinical disease types among antibody response categories |
||||
|
Clinical disease type (%) |
||||
|
Characteristic Response |
LJP |
ADP |
AP |
N |
|
High Aa |
28.4 |
12.9 |
0 |
0 |
|
High Aa, Low Cs |
41.8 |
4.8 |
1.2 |
0 |
|
High Aa, High Bg |
16.4 |
12.9 |
9.4 |
1.2 |
|
High Bg |
3.0 |
37.1 |
48.2 |
4.9 |
|
High 1 Gm |
4.5 |
11.3 |
9.4 |
8.5 |
|
High ≥ 3 Gm |
4.5 |
19.4 |
14.1 |
0 |
|
None high |
3.0 |
1.6 |
17.6 |
85.4 |
|
n = |
67 |
62 |
85 |
82 |
Discussion: The existence of such differences in Ab levels provides evidence for major variations in systemic responses among periodontal disease types. The observed systemic host responses may indicate association of specific bacterial infections with different types of periodontal disease. The combination of potentially pathogenic microorganisms & an accompanying local immune response may be an indication of a tooth with a high risk of disease.
BL: Teeth at high risk for disease may be detected by combination of the presence of potentially pathogenic microorganisms and local immune response in SCF.
Purpose: To determine if the elevated serum reactivities are reflective of a homologous bacterial colonization of periodontal sites.
Method: 116 total subjects (ages 18-63y) were divided into 4 groups: Localized juvenile periodontitis (n=5 pts), Advanced destructive periodontitis (n=7) and 22 adult perio patients (n=22). Subjects with no bone loss and mild gingivitis as control group (n=82). Disease activity was recorded by a minimum of 2mm attachment loss. Antigens for detection of systemic antibody levels for various periodontal pathogens were prepared. Microorganisms in subgingival plaque were identifies using the serological ELISA test. Serum IgG antibody levels for each microorganism were assessed in all groups.
Results: IgG levels were significantly higher for at least one of the microorganisms in all of the patient groups, and substantial heterogeneity in the bacterial specificity for the elevation was found for all groups. Some species were primarily isolated from the diseased sites: A.a exhibited a high frequency in LJP pts, but was also seen in some AP patients. B. gingivalis was generally associated with the AP and ADP subjects. W. recta was detected solely in AP patients.
Discussion: Elevated systemic antibody levels to subgingival plaque-associated bacteria appear to relate to the oral microflora. Microorganisms, to which elevated systemic antibody levels are detected, are often represented in the flora of disease-active site. In 85% of the patients examined, there was agreement between the specificity of elevated antibody levels and the isolation of the organism.
PURPOSE: To report on the presence of IgG, IgM, and C3 in the human inflamed gingiva, as IgG and IgM can bind complement when complexed to antigen, making their presence in gingiva essential.
METHODS: 20 patients were selected with a history of gingivitis or chronic perio and had >4mm pockets. 0.5mm x 0.5mm gingivectomy performed and gingiva was frozen/sectioned. Presence of immunoglobulin and C3 was shown by means of direct immunofluorescence technique. One specimen of tissue from the maxillary tuberosity was used as a control.
RESULTS: All 20 patients were found to have IgG present, 10 had IgM, and C3 in 7 patients. Fluorescence was mainly localized in the lamina propria. Tissue samples from the tuberosity were negative for IgG, IgM, and C3. Histologic examination showed the presence of edema, loss of collagen fibers, dilated capillaries, perivascular plasma cell infiltration, lymphocytes, and polymorphonuclear leukocytes localized mainly in the lamina propria.
DISCUSSION: The presence of IgG, IgM, and c3 suggests that antigen antibody complexes form in gingivitis, which bond and activate complement. The presence of complement fragment in the basement membrane suggests that complement is activated by the classical route. IgG, IgM, and C3 bound to the basement membrane suggests that injury to the gingiva in perio may be a function of complement through its phospholipase activity, which could destroy cell membranes.
CONCLUSION/BL: It is probably that antigen-antibody complexes binding complement is a significant mechanism in the pathogenesis of gingivitis and periodontitis.
P: To investigate the biosynthesis of complement proteins in chronically inflamed human gingiva.
M&M: Normal & diseased gingival tissues biopsies were taken from patients undergoing extractions for orthodontic purposes and perio patients, respectively. Samples were assayed for C3 and C5 biosynthesis using autoradiographs of immunoprecipitates. An immunochemical detection of 14C-labeled amino acid incorporated protein from gingival explant cultures.
R: C3 and C5 were demonstrated in 8 of 10 patients with periodontal disease and in none of the controls. C3 and C5 biosynthesis appears to occur locally by cells in chronically inflamed gingiva.
D: Although it has been assumed that the serum was the source of complement components, the present study demonstrated that there was a local contribution to complement in the GCF. The complement presence could play a role in inflammatory response modulation.
BL: Bacterial plaque and their products could contribute to the induction of complement synthesis in chronically inflamed gingiva.
Purpose: Summary of research designs and results, to provide a profile of antibody in health, gingivitis, and periodontitis.
Discussion: The recognition of both local and humoral responses in periodontal disease prompted studies to evaluate the mechanism of protection and destruction of the host tissue. Inflammation and tissue destruction in the periodontium are related to the affinity, avidity, quality, quantity and specificity of the antibody.
Affinity: the strength of a single interaction
Avidity: refers to the accumulated strength of multiple affinities of individual non-covalent binding interactions, such as between a protein receptor and its ligand, and is commonly referred to as functional affinity.
Antibody avidity has been correlated to acute stages of systemic bacterial infections, diagnosing, differentiating and determination of duration and onset of infection. The maturation of host response via antibody avidity could determine the active and recent infection versus quiescent state of the disease process.
Studies have been proven that the increase level and a maturation of the immune response towards antibody population with increase avidity in both acute infection and active immunization.
Enough evidence is available for the ability of the antibody to augment the host immune system to control oral pathogen.
There is little information about the factors controlling individual variation in the ability of antibody to affect antibacterial host resistance, resulting in control but not elimination of the pathogen.
As in other bacteria related infectious disease, infection in periodontitis would be expected to elicit a specific host immune response. However most bacterial disease are acute infection, the relationship b/w pathogen and the host in periodontal disease is appear to chronic interaction with unknown factors triggering a progressing disease limiting the use of antibody testing to predict or provide the risk evaluation for disease episode or recurring periodontitis
Response to A. actinomycetemcomitans
Antibody response characteristics suggest that A. actinomycetemcomitans should not be perceived to be limited as a pathogen to only young individuals but may have the capacity to initiate disease in an at-risk adult group.
Response to P. gingivalis
The host responses to P. gingivalis provides evidence for the etiological contribution of this microorganism to periodontitis. Recent studies have supported the capacity of P. gingivalis to express variations in virulence between subjects in a population and across patient populations, potentially contributing to its distribution and pathogenicity.
Conclusion: The recognition of antibody characteristics in periodontitis and changes association in disease progression and treatment appear to be dependent on patient selection, the antibody specificity examined, and the design of the study.
How does immune dysfunction affect the manifestation of periodontal disease?
P: Taking current information to present a model for the contribution of the immune system to the pathogenesis of perio dz in order to better understand immune dysfunction and its link to perio dz.
D: Basic mechanisms of the immune response in perio dz: The immune system is beneficial in protecting/limiting bacterial infection in the gingival region, but can contribute to the dz process.
Evidence of immune dysfunction in pts with perio dz: host response could be suppressed, defective lymphocyte response, abnormal immune regulation, or impairment in specific aspects of host immunity (such as neutrophil chemotaxis)
Immunosuppressive properties of suspected oral pathogens: enhanced susceptibility to infectious dz. (includes immune dysfunction as a sequelae of microbial infections in an otherwise healthy pt).
Mechanisms to evade immune response include antigenic drift (an accumulation of mutations that lead to alterations of AB binding sites a weaker effect of AB’s on pathogens.) causing an immunosuppressed state in the host to facilitate microbial invasion and proliferation, immune response modulation, and production of toxins, enzymes, and metabolites.
Organisms may affect the immune response via several different mechanisms that interfere with either the induction or the expression of immunity. Some factors have been shown to: activate suppressor monocytes, activate T-suppressor cells (eg. Aa), inhibit T-helper cells, directly affect either precursor or mature effector cells, alter lymphocyte recirculation (an important element in the recognition of antigen and initiation of an immune response).
Model of immunosuppression in the etiology/pathogenesis of perio dz: proposal by authors that the development of dz depends heavily on the outcome of the initial interaction of oral pathogens with the host defense system. Failure to produce an “appropriate” immune response allows for the pathogen to colonize by either: 1. an inability to respond/recognize the pathogen as a result of genetic and/or environmental factors, and/or 2. subversion/evasion of the immune response by the organism itself.
BL: Immunosuppression is possibly transient, and the host can overcome it through different mechanisms. This theory, “immune recovery,” explains how the host defense, after a delayed initial response, can respond to pathogens. Relates to perio dz in that the original pathogen exposure can cause direct tissue injury prior to the immune response recovering, and that after recovery, can have immune mediated tissue injury, pathogen mediated tissue injury (lack of host response), or elimination of pathogen with resolution of dz.
Purpose: To discuss periodontal disease mechanisms in immunocompromised patients.
Discussion: The incidence of primary immune deficiency is low. 1/10,000 individuals is born with immune deficiency and 72% occurs in males. Secondary immune deficiencies occur at 2.3% of hospitalized patients (they had less than 4mg/ml of serum gamma globulin while the normal range is 9-25mg/ml). Control of bacterial infection depends on phagocytes acting in cooperation with humoral factors such as antibodies and complement components. Interaction with membrane receptors of leukocytes is a key phenomenon in the defense mechanisms, Mobilization of granulocytes is critical in reducing bacterial capacity but this mobilization is reduced in patients with immune deficiency. Leukocytes adherence to tissue structures is mediated by membrane expression of specific glycoproteins (Mac-1, LFA-1 and pI50,95). Mac-1 or CR3 is also the receptor for C3b and is important for phagocytosis too as well as the production of H2O2. These molecules are stored in the secondary granules and transferred to the membrane as a response to chemotactic factors. Severe hereditary deficiency of these factors causes the death of the patients before the age of 3 and moderate causes recurrent infections and delayed wound healing. These patients frequently suffer from gingivitis or periodontitis without pus formation. Total deficiency of these factors is rare. Although in patients with juvenile periodontitis, defective neutrophil chemotaxis was observed in 70-80% of the cases, they do not show increased susceptibility to extra-oral infections and this indicates that the bacteria colonizing the gingival area interfere with defense mechanisms. H2O2 production is decreased in deficient granulocytes and have a seriously decreased microbicidal activity. Patients with NAPDH oxidase (promotes H2O2 generation) deficient granulocytes develop chronic granulomatous disease but do not have periodontal problems. Monocytes from patients with AIDS are defective in their ability to promote responses of T-cells to soluble antigens and mitogenic stimuli. Release of IL-1 is normal, but the chemotactic responses are impaired. Tolo & Jorkjend 1990, found that patients with rheumatoid arthritis had reduced number of teeth and increased bone loss compared to controls. Serum IgG accounted for about 6% of the variation in periodontal bone loss. Antibody disorders account for 50% of all primary immune deficiencies and IgA-deficiency is the most frequent. Studies in cases of advanced periodontitis showed that there a substantially increased number of plasma cells producing IgG1 and IgG3. These subclasses are considered to be most effective in activation of C3. In conclusion a disturbed immunological homeostasis remains an attractive hypothesis in the etiology of periodontal disease.
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