Aggressive periodontitis ul

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<ol><li> 1. Aggressive Periodontitis (etiology and pathogenesis) Seminar : Leena Parmar </li><li> 2. Index Introduction Definition Classification Etiology &amp; pathogenesis:- a) microbiologic factor b) immunologic factor c) genetic factor d) environmental factor </li><li> 3. Introduction :- Aggressive periodontitis may be universally distinguished from chronic periodontitis by the age of onset, the rapid rate of disease progression, the nature and composition of the associated subgingival microflora, alterations in the host's immune response, and a familial aggregation of diseased individuals. </li><li> 4. Definition In1971, Baer' defined it as "a disease of the periodontium occurring in an otherwise healthy adolescent which is characterized by a rapid loss of alveolar bone about more than one tooth of the permanent dentition. The amount of destruction manifested is not commensurate with the amount of local irritants." </li><li> 5. Classification and clinical syndromes:- In the absence of an etiologic classification, aggressive forms of periodontal disease have been defined based on the following primary features (Lang et al. 1999): Non-contributory medical history Rapid attachment loss and bone destruction Familial aggregation of cases. </li><li> 6. Secondary features that are considered to be generally but not universally present are: Amounts of microbial deposits inconsistent with the severity of periodontal tissue destruction. Elevated proportions of Actinobacillus actinomycetemcomitans (Aggregatibacter actinomycetemcomitans) and, in some Far East populations, Porphyromonas gingivalis </li><li> 7. Phagocyte abnormalities. Hyper-responsive macrophage phenotype, including elevated production of prostaglandin E2 (PGE2) and interleukin-1 (IL-1) in response to bacterial endotoxins Progression of attachment loss and bone loss may be self-arresting. </li><li> 8. The international classification workshop identified clinical and laboratory features deemed specific enough to allow subclassification of AgP into localized and generalized forms (Lang et al. 1999; Tonetti &amp; Mombelli 1999). The following features were identified: Localized aggressive periodontitis (LAP) Generalized aggressive periodontitis (GAP) </li><li> 9. Localized aggressive periodontitis (LAP): Circumpubertal onset. Localized first molar/incisor presentation with interproximal attachment loss on at least two permanent teeth, one of which is a first molar, and involving no more than two teeth other than first molars and incisors Robust serum antibody response to infecting agents </li><li> 10. Generalized aggressive periodontitis (GAP): Usually affecting persons under 30 years of age, but patients may be older. Generalized interproximal attachment loss affecting at least three permanent teeth other than first molars and incisors. Pronounced episodic nature of the destruction of attachment and alveolar bone. Poor serum antibody response to infecting agents. </li><li> 11. Etiology and Pathogenesis :- Microbiologic Factors Immunologic Factors Genetic Factors Environmental Factors </li><li> 12. A) Microbiologic Factors :- Early studies attempting the identification of the involved bacteria using culture techniques were performed by Newman et al. and by Slots (Newman et al. 1976; Slots 1976; Newman &amp; Socransky 1977). </li><li> 13. Dominant microorganisms in LAP included Actinobacillus actinomycetemcomitans (A.a., now termed Aggregatibacter actinomycetemcomitans), Capnocytophaga sp., Eikenella corrodens, saccharolytic Bacteroides-like organisms now classified as Prevotella sp., and motile anaerobic rods today labeled Campylobacter rectus. Gram-positive isolates were mostly streptococci, actinomycetes, and peptostreptococci. </li><li> 14. A.a., Capnocytophaga sp., and Prevotella sp. were also shown to be the most prominent members of the subgingival microbiota of periodontitis lesions in the primary dentition. One of these organisms, A. actinomycetemcomitans, a short, facultatively anaerobic, non-motile, Gram negative rod, received particular attention and was increasingly viewed as a key microorganism in LAP. </li><li> 15. This view was principally based on four lines of evidence (Socransky &amp; Haffajee 1992): 1. Association studies, linking the organism to the disease: A.a. was isolated in periodontal lesions from more than 90% of LAP patients and was much less frequent in periodontally healthy individuals (Ashley et al. 1988; Van der Velden et al. 1989; Albandar et al. 1990; Gunsolley et al. 1990; Slots et al. 1990; Asikainen et al. 1991; Aass et al. 1992; Ebersole et al. 1994; Listgarten et al. 1995). In some studies it was possible to demonstrate elevated levels of A.a. in sites showing evidence of recent or ongoing periodontal tissue destruction (Haffajee et al. 1984; Mandell 1984; Mandell et al. 1987). </li><li> 16. 2. Demonstration of virulence factors: A.a. was shown to produce several potentially pathogenic substances, including a leukotoxin, was capable of translocating across epithelial membranes, and could induce disease in experimental animals and non-oral sites ( Zambon et al. 1988; Slots &amp; Schonfeld 1991). </li><li> 17. 3. Findings of immune responses towards this bacterium: Investigators repeatedly reported significantly elevated levels of serum antibodies to A.a. in LAP patients (Listgarten et al. 1981; Tsai et al. 1981; Altman et al. 1982; Ebersole et al. 1982, 1983; Genco et al. 1985; Vincent et al. 1985; Mandell et al. 1987; Sandholm et al. 1987). Such patients were furthermore shown to produce antibodies locally against this organism at diseased sites (Schonfeld &amp; Kagan 1982; Ebersole et al. 1985b; Tew et al. 1985). </li><li> 18. 4. Clinical studies showing a correlation between treatment outcomes and levels of A.a. after therapy: unsuccessful treatment outcomes were linked to a failure in reducing the subgingival load of A.a. (Slots &amp; Rosling 1983; Haffajee et al. 1984; Christersson et al. 1985; Kornman &amp; Robertson 1985; Mandell et al. 1986, 1987; Preus 1988). </li><li> 19. Recently six serotypes ( a,b,c,d,e and f ) of A.a have been described based on the composition of structurally and antigenically distinct O-polysaccharides of their lipopolysaccharides. In addition, a novel serotype g has recently been proposed. </li><li> 20. (Zambon et al. 1983, 1996). In the United States, A serotype-dependent pattern of association with LAP was found . Serotype b strains were more often isolated from patients with localized juvenile periodontitis. (Asikainen et al. 1991, 1995) A higher frequency of serotype b strains was also reported from Finnish subjects with periodontitis </li><li> 21. Leukotoxin production A major virulence factor of A. actinomycetemcomitans and all strains. Which makes the bacterium capable of evading the host response by killing leukocytes. A highly leukotoxic clonal type of A. actinomycetemcomitans serotype b was first isolated , in the early 1980s, from an 8 year old male child with localized aggressive periodontitis. </li><li> 22. Gram-negative bacteria It enveloped by two membranes, of which the outer is rich in endotoxin. This identifying feature of Gram negative bacteria consists of </li><li> 23. Lipid + polysaccharide = lipopolysaccharide (LPS) LPS is set free when bacterial cells die or multiply. </li><li> 24. Mechanism of LPS LPS of A.a Host cells (macrophages) Inflammatory mediators ( prostaglandins, interleukin-1, TNF) Activate secrete </li><li> 25. Fives-Taylor et al. (1996) Properties of A.a Immunosuppressive properties, Collagenolytic activity &amp; Inhibition of neutrophil chemotaxis </li><li> 26. Leukotoxin Destroys human polymorphonuclear leukocytes Macrophages </li><li> 27. Lally et al. (1996). Leukotox in family of RTX (Repeats in ToXin) Pore- forming toxins </li><li> 28. Haraszthy et al. (2000); Tan et al. (2001); Cortelli et al.(2005) JP2 clone Commonly found Aggressive periodontitis patients (North and West African) </li><li> 29. Among potential virulence factors, cytolethal distending toxin, which seems to be characteristic for A.a, but not for other periodontal organisms, has gained considerable research interest. Outer membrane vesicles of A.a Cytolethal distending toxin &amp; Bacterium Other virulence agents Host tissue Transfer of </li><li> 30. Determinants of virulence and pathogenic potential of A. actinomycetemcomitans SignificanceFactor Destroys human polymorphonuclear leukocytes and macrophages Leukotoxin Activates host cells to secrete infammatory mediators (prostaglandins, interleukin-1, tumor necrosis factor-) Endotoxin </li><li> 31. May inhibit growth of beneficial species Bacteriocin May inhibit IgG and IgM production Immunosuppressi ve Factors Cause degradation of collagenCollagenases </li><li> 32. May inhibit neutrophil chemotaxis Chemotactic inhibition factors </li><li> 33. Bacterial damage to the periodontium :- Disease-associated bacteria are thought to cause destruction of the marginal periodontium via two related mechanisms: (Tonetti 1993). Disease-associated bacteria (Direct) Action of the microorganisms or their products on the host tissues (Indirect) Eliciting tissue-damaging inflammatory responses </li><li> 34. The relative importance of these two mechanisms in AgP remains speculative. (Saglie et al. 1988) Aggregatibacter Actinomycetemcomitans Across the junctional epithelium Connective tissue translocate invade </li><li> 35. Apical spread of bacteria Controlled through High turnover of junctional epithelium keratinocytes Directed migration of polymorphonuclear leukocytes through the junctional epithelium Outward flow of crevicular fluid </li><li> 36. B) Immunologic Factors :- Both local and systemic host responses to AgP associated microflora have been described. Local inflammatory responses An intense recruitment of polymorphonuclear leukocytes (PMNs) Tissues Periodontal pocket </li><li> 37. Presence of PMNs underlines the importance of these cells in the local defense against bacterial aggression and their potential role in host-mediated tissue destruction. B cells and antibody-producing plasma cells also represent a significant component (Liljenberg &amp; Lindhe 1980). </li><li> 38. Mackler et al. (1977, 1978); Waldrop et al. (1981); Ogawa et al. (1989). Plasma cells IgG-producing cells &amp; IgA-producing cells </li><li> 39. Taubman et al. (1988, 1991). Important component of the local inflammatory infiltrate are T cells. Subset analysis of local T cells has indicated a depressed T-helper to T suppressor ratio as compared to both healthy gingival and peripheral blood. These findings have been interpreted to suggest the possibility of altered local immune regulation </li><li> 40. Masada et al. (1990); Offenbacher et al. (1993). Local inflammatory responses PGE2, IL-1 IL-1 Crevicular fluid Tissue Characterized by </li><li> 41. Schenkein &amp; Genco (1977); Patters et al. (1989) Specific antibodies against AgP-associated microorganisms Crevicular fluid from AgP lesions. Detected in </li><li> 42. Steubing et al. (1982); Hall et al. (1990, 1991, 1994) Substantial amount of antibodies against A.a. and P. gingivalis serum of AgP patients Detected in </li><li> 43. Genco et al. (1980, 1986); Van Dyke et al. (1982, 1986, 1988). PMNs of some LAP and GAP Decreased migration Decreased antibacterial functions </li><li> 44. This evidence has been interpreted as a suggestion that the LAP-associated PMN defect may be inherited. Other recent reports have indicated. (Shapira et al. 1994; Agarwal et al. 1996). PMN abnormalities in LAP patients serum of some AgP Hyper-inflammatory state pro-inflammatory cytokines Result of Presence of In </li><li> 45. C) Genetic Factors:- Periodontitis is a multifactorial disease for which several risk and susceptibility factors are proposed. The striking familial aggregation of trait in Aggressive Periodontitis is consistent with a significant genetic etiology. A gene of major effect in Aggressive Periodontitis appears to be etiologically complex and heterogenous. </li><li> 46. In 1986, Boughman et al reported that a major gene located on chromosome 4q was responsible for autosomal dominant transmission of Localised Aggressive Periodontitis in an extended family that also exhibited Dentinogenesis Imperfecta. </li><li> 47. It is now established that genetic factors regulate the innate immune system and that certain genetic polymorphism may render the immune system defective. Genetic factors may play a more significant role in the pathogenesis of AgP. </li><li> 48. Formyl Peptide receptors on the cell surface of leukocytes are involved in mediating immune cell responses to infection. The bacteria derived N-formly-methionyl peptides have high affinity to the N-formly- methionyl peptide cell receptor and after binding to neutrophil receptor the neutrophils get activated. Thus triggering them to migrate to the site of infection. </li><li> 49. Some reports suggest that the abnormal neutrophil chemotactic response to N-formly-methionyl peptides is limited to some cases of AgP. Early studies suggested that neutrophils from the serum of patients with AgP show impaired chemotaxis to these antigens. An in-vitro experiment showed that phosphoionositide dependent kinase-1 regulates neutrophil chemotaxis. This suggests that the expression &amp; activation levels of phosphoionositide dependent kinase-1 which are significantly reduced in AgP may explain the impaired neutrophil chemotaxis in such patients. </li><li> 50. Albandar et al reported that the serum levels of IgA reactive to periodontal pathogens were significantly higher in AgP. Furthermore neutrophils from AgP patients show increased levels of expression of the FcRI receptor. Cross-linking of IgA with the Fc receptor on phagocytes triggers the following host cellular responses such as phagocytosis, antibody-dependent cell mediated cytotoxicity and release of inflammatory mediators. Hence it concluded that individuals with increased expression levels of FcRI receptor on phagocytes and elevated levels of IgA reactive to periodontal pathogen, may be at higher risk for AgP. </li><li> 51. Papillon-Lefevre syndrome there is a loss of function mutation affecting the cathepsin C gene on chromosome 11q14.2 and this influences a key enzyme essential in activation of certain immune cells and in regulation of epitheial cells. In Chediak-Higashi syndrome, mutations have been identified in Lysosomal trafficking regulator ( CHS1/ LYST) gene on chromosome 1q42.3. </li><li> 52. D) Environmental Factors:- In a large study, cigarette smoking was shown to be a risk factor for patients with generalized forms of AgP (Schenkein et al. 1995). Smokers with GAP had more affected teeth and greater mean levels of attachment loss than patients with GAP who did not smoke. IgG2 serum levels as well as antibody levels against A.a. are significantly depressed in subjects with GAP who smoke. </li><li> 53. References: Clinical periodontology and implant dentistry -5th edition, Volume-1, Jan Lindhe. Clinical periodontology - 10thedition,Carranza,Neuman,Takei,Klokkevold. Periodontology 2000,vol-65, 2014. Assessment of peripheral neutrophil functions in p...</li></ol>