The studies performed to date aimed mainly at exploring the patomechanisms and factors associated with periodontitis development and natural history. The results of these studies enabled us to systematize the factors influencing host susceptibility to periodontal diseases. They were distinguished into phenomenons one cannot modify, called risk determinants, and the exact risk factors. All of them modulate host immunologic reaction, making oral tissues prone to periodontal diseases. The risk determinants include age, gender, social status and genetic determinants. The other group comprised true risk factors: smoking, stress, diabetes, osteoporosis and diseases characterised by congenital or aquired immune deficiencies. One of the important groups of factors determining the etiopathogenesis of periodontitis is genetic factors. The antigens of periodontal pathogens can modulate host response in different ways. Matsuyama has observed human gingival epithelial cells, colonized by Actinobacillus actinomycetemcomitans strains. In the aftermath of IFN- stimulation these cells exhibited increased expression of MHC class II genes, as well as B cells surface antigens, B7-1 (CD80). These molecules presented antigen to T cells, binding to the specific CD4+ receptor on their surface, thus stimulating humoral immune response. Interestingely, no CD4+ receptors activation was observed in lack of periopathogenic A. actinomycetemcomitans strain in gingival epithelial cells [1]. On the other hand, Schreiner et al. have stated, that the possibility of A. actinomycetemcomitans colonization depends on exact sequence of 14 genes in locus called tad (tight-adherence). According to these authors, rats inoculated with A. actinomycetemcomitans exhibiting mutation within tad locus developed no immune response or alveolar bone loss [2]. The studies performed by Srisatjaluk et al. have proven, that the proteolytic enzymes inside membrane vesicles of Porphyromonas gingivalis can inhibit the IFN--mediated expression of HLA-DR- gene, as well as transcription of CIITA (a transactivator of class II MHC genes). As a result the P. gingivalis bacteria impair cell functions and inhibit host immune response [3]. Both the innate and adaptive immunological reactivity can be modified by genetic factors. It is the particular genotype that determines the susceptibility or resistance to periodontal disease. Many studies have supported the hypothesis of genetic implications in the etiopathogenesis of periodontitis, genetic polymorphism being emphasized as a distinctively important phenomenon. Special attention should be paid to the genes encoding major histocompatibility complex (MHC) antigens; in humans it is referred to as a human leukocyte antigens (HLA) system. The HLA molecules play a significant role in the progress of immunological response by presenting bacterial antigens to the effector cells of the immune system. The MHC genes exhibit marked polymorphism, which means high level of allelic diversity. The DR allele, encoding the polipeptide chain of heterodimer HLA-D, belonging to MHC class II, could determine increased susceptibility to infection [4]. On the surface of many cell types there are specific glycoprotein receptors, which play an important role in the regulation of inflammatory processes in periodontal tissues. Their role was extensively studied in the past years. The expression of these receptors on the cell surface, i.e. on the neutrophiles, is one of the determinants of effective phagocytosis. In the aggressive periodontitis an impaired migration and adhesion functions of neutrophiles was observed. This defect results from point mutations and leads to the lack of Mac-1, LFA-1 and p-150,95 (CD 11/18) receptors expression on the neutrophilic leukocyte surface membrane. It is referred to as a leukocyte adherence deficiency I (LAD I) syndrome [5]. The other important molecules, that are expressed on the neutrophiles and determine the antigen-antibody complex recognition, are the FcR receptors for IgG. There are three distinct kinds of IgG receptors: FcRI (CD64), exhibiting high avidity against immunoglobulin, and low avidity receptors FcRII (CD32) and FcRIII (CD16). There are two structural forms of FcRII: FcRIIA, expressed on the phagocytic cells, and FcRIIB on B cells. The presence of high avidity receptor leads to increased immunoglobulin synthesis and as a consequence to the tissue degradation. Also FcRIII is expressed in two distinct forms, of which FcRIIIA is present mainly on NK cells and FcRIIIB on neutrophils. Both forms of FcRII and FcRIII receptors were proven to exist in two different allotypes of different avidity against IgG, clinically presenting as different susceptibility to infection [6]. The polymorphic FcRIIA (R131 and H131), FcRIIIA (V158 and F158) and FcRIIIB (NA1 and NA2) were subject of many studies. Kobayashi have observed higher avidity of the FcRIIIB-NA1 against IgG1 and IgG3 complexes, as compared to the FcRIIIB-NA2. It determines the capability of phagocytosis of the P. gingivalis bacteria cells opsonised by immunoglobulins, as well as the local release of free oxygen radicals by the neutrophils. In a study on patients suffering from chronic periodontitis the clinical attachment loss was found to progress faster in those exhibiting FcRIIIB-NA2 allele (both homozygotes and heterozygotes) than in patients with FcRIIIB-NA1 allele [7]. In another study a polymorphic FcR-FcRIIIB-NA2 receptor was found to be significantly more prevalent in patients with aggressive periodontitis, as compared to chronic periodontitis and healthy control. Moreover the coincidence of FcRIIIB-NA2 and FcRIIIA-158F genotypes was found more frequently in aggressive periodontitis [8]. The results obtained by Kobayashi were further supported by Sugity study. The FcRIIIB-NA1 form was more effective towards IgG1/IgG3 as compared to the FcRIIIB-NA2. Moreover in patients with no signs of periodontal disease the more prevalent form is FcRIIIB-NA1, suggesting that FcRIIIB-NA2 could predispose to periodontitis [9]. In another study on Caucasian population the FcRIIIA-V158 and FcRIIA-H131 were found to present more frequently in the periodontitis group than in the control group [10]. Another receptor exhibiting genetic polymorphism that can be of importance in the etiopathogenesis of periodontal disease is vitamin D receptor (VDR). Vitamin D is responsible for the proper bone metabolism. The active form of vitamin, 1,25-dihydroxycholecalciferol, stimulates synthesis of bone matrix proteins and its’ mineralization, as well as monocytes and macrophages production. The biological activity of vitamin D results from binding to the VDR. Vitamin D receptor exhibits genetic polymorphism. Some of the alleles lack the specific DNA sequences, recognized by Apa I, Bms I, Taq I and Fok I restriction endonucleases. In a study on Japanese patients with chronic periodontitis and Taq I polymorphism a more frequent presence of the allele lacking the sequence digested by restriction endonuclease as compared to the healthy control was observed [11]. Some other authors, investigating the effect of VDR polymorphism on periodontitis, have found the higher prevalence of periodontal tissue inflammation in patients presenting 27823*CC allele [12]. Yet another cellular receptor with genetic polymorphism of biological significance is N-formyl peptide (fMLP) receptor. The fMLP receptor has structural similarity with bacterial products stimulating the chemotaxis of neutrophils. There are two known polymorphisms in the fMLP receptors at base 329 T to C and base 378 C to G [13]. Another receptor studied for the correlation between genetic polymorphism and periodontitis is receptor for advanced glycation end products (RAGE). The interaction between RAGE and monocytes leads to an increased cytokine production, while the interaction between RAGE and fibroblasts decreases collagen synthesis. In patients with periodontitis a polymorphic allele with a single base change at base 1704 (G to T) was more prevalent then in a healthy control group [14]. In another study a correlation between CD14 encoding gene and periodontitis was assessed. CD14 is a glycoprotein receptor, present on the cell surface neutrophiles, monocytes, macrophages, fibroblasts etc. It recognises the bacterial lypopolysaccharides bound to a specific protein binding LPS, present in the circulation. Gene encoding the CD14 molecule can be present in one of two polymorphic forms: at base 159 (C to T) and at 1359 (G to T). More frequent 159*C allele presence was stated in Caucasians suffering from periodontal disease as compared to the healthy controls [15]. Other studies have assessed the polymorphism of metaloproteinases (MMP) genes. Metaloproteinases are enzymes directly responsible for collagen deterioration as a result of inflammatory processes in periodontal tissues. One of the objects of the studies was polymorphism of MMP-1-encoding gene, distinguished by deletion or addition of G at base 1607. The alleles were defined as 1G and 2G, respectively. Allele 2G was found to be more frequent in Caucasians with chronic periodontitis then in a healthy control group [16]. Keles et al. have been investigating the single nucleotide polymorphism of the metalloproteinase 9 (MMP-9) encoding gene at base 1562. They have observed the correlation between this allele and prevalence of periodontal disease [17]. On the basis of many studies a genetic test was developed, embracing the polymorphism of genes encoding cytokines and their receptors. Patients carrying the allele 2 of IL-1 gene are six times more prone to periodontal diseases as compared to the allele 1 of IL-1 gene [18]. The subsequent studies have shown a significantly higher prevalence of IL-1+3953 allele in aggressive periodontitis then in healthy control group [19]. Other reports have shown that allele 2 IL-1+3953 is over-represented in chronic periodontitis. Moreover there is a higher prevalence of allele 1 TNF--308 in periodontitis patients as compared to those suffering from gingivitis [20]. The risk of exacerbation of periodontitis is over 12 times higher in the patients with chronic periodontitis presenting specific IL-1+4845/ IL-1+3953 genotype [21]. Another group has compared two groups of patients: the first one exhibiting IL-1-889, IL-1+3953 genotype (referred to as PST(+) (periodontitis susceptibility trait), that was believed to be more susceptible to periodontitis, and the other designated as PST(–). The peripheral monocytes isolated from both PST(+) and PST(+) group secreted comparable amount of IL-1 upon stimulation with bacterial lipopolysaccharides [22]. On the other hand, the analysis performed by means of polymerase chain reaction (PCR) has not revealed any significant difference between periodontitis and healthy controls as to the prevalence of polymorphic IL-1-889, IL-1+3953 genes [23]; other studies did not support the differences between specific TNF- genotype (referred to as A+ genotype), comprising the polymorphic alleles TNF--376, TNF--308, TNF--238 and TNF-+489, in patients with periodontitis and control group. Moreover there was no significant difference of alveolar bone loss between patients with A+ genotype and those without these particular polymorphic forms of TNF- gene [24]. Similarly, Endo et al. have not observed the correlations mentioned above, neither for the same genetic alleles, nor for the polymorphic forms of tumor necrosis factor gene: TNF--1031, -863, -857 [25]. According to the subsequent studies, the monocytes isolated from peripheral blood of patients suffering from aggressive periodontitis and possessing the TNF--308 allele secrete significantly higher levels of TNF- then the control group [26]. The genetic diversity of IL-1 may influence the course of periodontal disease by means of its linkage to other genes. The IL-1-encoding gene is located within chromosome 2, in close proximity to IL-1 and IL-1Ra genes. Thus some specific haplotypes can be associated with the etiopathogenesis of periodontitis. The correlation between IL-1Ra level and distinct IL-1 alleles (i.e. IL-1+3953 and IL-1-511) was a subject of a recent study. Seventy-five out of 200 healthy subjects presenting with IL-1-511 genotype have also exhibited allele 2 of IL-1Ra gene. This percentage was significantly increased as compared to the control group. Also the IL-1 receptor antagonist level in the peripheral blood was significantly higher in those possessing the allele 2 of IL-1Ra gene. On the other hand, the IL-1+3953 genotype coexisted twice less often with allele 2 IL-1Ra gene [27]. Tai et al. have shown that the patients with aggressive periodontitis carry the polymorphic IL-1RN (VNTR) gene significantly more often than the control group. Still in these patients no correlation was found between IL-1+4845, IL-1-511 or IL-1+3953 genotype and aggressive periodontitis prevalence [28]. Another study has also not supported the correlation between IL-1-889, IL-1+3953, IL-1-511, TNF--308 or IL-1RN and aggressive periodontitis [29]. On the basis of evidence presented above, one can expect the emergence of new, customized therapeutic protocols, based on the genetics of periodontal disease. Much hope is being placed on the potential of genetic therapy, i.e. modified techniques of gene transfer and genetic reprogramming of the target cells [30].
References
1. Matsuyama T, Kawai T, Izumi Y, Taubman MA (2005): Expression of major histocompatibility-complex class II and CD80 by gingival epithelial cells induced activation of CD4+ T cells in response to bacterial challenge. Infect Immun 73: 1044-1051.
2. Schreiner HC, Sinatra K, Kaplan JB, et al. (2003): Tight-adherence genes of Actinobacillus actinomycetemcomitans are required for virulence in a rat model. Proc Natl Acad Sci USA 100: 7295-7300.
3. Srisatjaluk R, Kotwal GJ, Hunt LA, Justus DE (2002): Modulation of gamma interferon-induced major histocompatibility complex class II gene expression by Porphyromonas gingivalis membrane vesicles. Infect Immun 70: 1185-1192.
4. McDevitt HO (2000): Discovering the role of the major histocompatibility complex in the immune response. Annu Rev Immunol 18: 1-17.
5. Dixon DR, Bainbridge BW, Darveau RP (2004): Modulation of the innate immune response within the periodontium. Periodontol 2000 35: 53-74.
6. Fu Y, Korostoff JM, Fine DH, Wilson ME (2002): Fc gamma receptor genes as risk markers for localized aggressive periodontitis in African-Americans. J Periodontol 73: 517-523.
7. Kobayashi T, van der Pol WL, van de Winkel JG, et al. (2000): Relevance of IgG receptor IIIb (CD16) polymorphism to handling of Porphyromonas gingivalis: implications for the pathogenesis of adult periodontitis. J Periodontal Res 35: 65-73.
8. Kobayashi T, Sugita N, van der Pol WL, et al. (2000): The Fc receptor genotype as a risk factor generalized early-onset periodontitis in Japanese patients. J Periodontol 71: 1425-1432.
9. Sugita N, Kobayashi T, Ando Y, et al. (2001): Increased frequency of FcRIIIb-NA1 allele in periodontitis-resistant subjects in an elderly Japanese population. J Dent Res 80: 914-918.
10. Loos BG, Leppers-Van de Straat FG, Van de Winkel JG, Van der Velden U (2003): Fc receptor polymorphisms in relation to periodontitis. J Clin Periodontol 30: 595-602.
11. Tachi Y, Shimpuku H, Nosaka Y, et al. (2003): Vitamin D receptor gene polymorphism is associated with chronic periodontitis. Life Sci 73: 3313-3321.
12. Park KS, Nam JH, Choi J (2006): The short vitamin D receptor is associated with increased risk for generalized aggressive periodontitis. J Clin Periodontol 33: 524-528.
13. Gwinn MR, Sharma A, De Nardin E (1999): Single nucleotide polymorphisms of the N-formyl peptide receptor in localized juvenile periodontitis. J Periodontol 70: 1194-1201.
14. Hollá LI, Kanková K, Fassmann A, et al. (2001): Distribution of the receptor for advanced glycation end products gene polymorphisms in patients with chronic periodontitis: a preliminary study. J Periodontol 72: 1742-1746.
15. Donati M, Berglundh T, Hytönen AM, et al. (2005): Association of the -159 CD14 gene polymorphism and lack of association of the -308 TNFA and Q551R IL-4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians. J Clin Periodontol 32: 474-479.
16. de Souza AP, Trevilatto PC, Scarel-Caminaga RM, et al. (2003): MMP-1 promoter polymorphism: association with chronic periodontitis severity in Brazilian population. J Clin Periodontol 30: 154-158.
17. Keles GC, Gunes S, Sumer AP, et al. (2006): Association of matrix metalloproteinase-9 promoter gene polymorphism with chronic periodontitis. J Periodontol 77: 1510-1514.
18. Kornman KS, Crane A, Wang HY, et al. (1997): The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 24: 72-77.
19. Parkhill JM, Hennig BJ, Chapple IL, et al. (2000): Association of interleukin-1 gene polymorphisms with early-onset periodontitis. J Clin Periodontol 27: 682-689.
20. Galbraith GM, Hendley TM, Sanders JJ, et al. (1999): Polymorphic cytokine genotypes as markers of disease severity in adult periodontitis. J Clin Periodontol 26: 705-709.
21. Thomson WM, Edwards SJ, Dobson-Le DP, et al. (2001): IL-1 genotype and adult periodontitis among young New Zealanders. J Dent Res 80: 1700-1703.
22. Mark LL, Haffajee AD, Socransky SS, et al. (2000): Effect of the interleukin-1 genotype on monocyte IL-1beta expression in subject with adult periodontitis. J Periodontal Res 35: 172-177.
23. Hodge PJ, Riggio MP, Kinane DF (2001): Failure to detect an association with IL1 genotypes in European Caucasians with generalized early onset periodontitis. J Clin Periodontol 28: 430-436.
24. Craandijk J, van Krugten MV, Verweij CL, et al. (2002): Tumor necrosis factor-alpha gene polymorphisms in relation to periodontitis. J Clin Periodontol 29: 28-34.
25. Endo M, Tai H, Tabeta K, et al. (2001): Analysis of single nucleotide polymorphisms in the 5’-flanking region of tumor necrosis factor-alpha gene in Japanese patients with early-onset periodontitis. J Periodontol 72: 1554-1559.
26. Shapira L, Stabholz A, Rieckmann P, Kruse N (2001): Genetic polymorphism of the tumor necrosis factor (TNF)-alpha promoter region in families with localized early-onset periodontitis. J Periodontal Res 36: 183-186.
27. Hurme M, Santtila S (1998): IL-receptor antagonist (IL-1Ra) plasma levels are coordinately regulated by both IL-1Ra and IL-1 genes. Eur J Immunol 28: 2598-2602.
28. Tai H, Endo M, Shimada Y, et al. (2002): Association of interleukin-1 receptor antagonist gene polymorphisms with early onset periodontitis in Japanese. J Clin Periodontol 29: 882-888.
29. Trevilatto PC, Tramontina VA, Machado MA, et al. (2002): Clinical, genetic and microbiological findings in a Brazilian family with aggressive periodontitis. J Clin Periodontol 29: 233-239.
30. Tarner IH, Fathman CG (2001): Gene therapy in autoimmune disease. Curr Opin Immunol 13: 676-682.
