Interleukin Gene Variability and Periodontal Bacteria in Patients with Generalized Aggressive Form of Periodontitis

Petra Borilova Linhartova, Zdenek Danek, Tereza Deissova, Filip Hromcik, Bretislav Lipovy, David Szaraz, Julius Janos, Antonin Fassmann, Jirina Bartova, Ivo Drizhal, Lydie Izakovicova Holla, Petra Borilova Linhartova, Zdenek Danek, Tereza Deissova, Filip Hromcik, Bretislav Lipovy, David Szaraz, Julius Janos, Antonin Fassmann, Jirina Bartova, Ivo Drizhal, Lydie Izakovicova Holla

Abstract

Host genetic predispositions to dysregulated immune response can influence the development of the aggressive form of periodontitis (AgP) through susceptibility to oral dysbiosis and subsequent host-microbe interaction. This case-control study aimed to perform a multilocus analysis of functional variants in selected interleukin (IL) genes in patients with the generalized form of AgP in a homogenous population. Twelve polymorphisms in IL-1 gene cluster, IL-6 and its receptor, IL-10, IL-17A, and IL-18 were determined in 91 AgP patients and 210 controls. Analysis of seven selected periodontal bacteria in subgingival sulci/pockets was performed with a commercial DNA-microarray kit in a subgroup of 76 individuals. The pilot in vitro study included stimulation of peripheral blood monocytes (PBMC) from 20 individuals with periodontal bacteria and measurement of IL-10 levels using the Luminex method. Only the unctional polymorphism IL‑10-1087 A/G (rs1800896) and specific IL-10 haplotypes were associated with the development of the disease (P < 0.05, Pcorr > 0.05). Four bacterial species occurred more frequently in AgP than in controls (P < 0.01, Pcorr < 0.05). Elevated IL-10 levels were found in AgP patients, carriers of IL‑10-1087GG genotype, and PBMCs stimulated by periodontal bacteria (P < 0.05, Pcorr > 0.05). We therefore conclude that a combination of genetic predisposition to the altered expression of IL-10 and the presence of specific periodontal bacteria may contribute to Th1/Th2 balance disruption and AgP development.

Keywords: aggressive periodontitis; genetic predisposition; inflammation; interleukin; oral bacteria; polymorphism.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in writing the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Linkage disequilibrium (LD) plots indicating the D coefficient in the interleukin-1 (IL-1), IL-10, and IL-18, respectively, in controls. Strong LDs are highlighted in red. LD blocks (bold black line), were generated using the solid spine of the LD method.
Figure 2
Figure 2
Concentrations of interleukin-10 (IL-10) in unstimulated peripheral blood monocytes (PBMCs) isolated from 4 patients with the aggressive form of periodontitis (AgP) and 16 healthy controls (p = 0.014, calculated by Kruskal–Wallis test). IQR, interquartile range.
Figure 3
Figure 3
Concentrations of interleukin-10 (IL-10) in unstimulated peripheral blood monocytes (PBMCs) isolated from 20 individuals according to their IL-10 −1087 A/G (rs1800896) profile (p = 0.038, calculated by Kruskal–Wallis test). IQR, interquartile range.
Figure 4
Figure 4
Possible role of interleukin-10 (IL-10) gene variants in the etiopathogenesis of aggressive periodontitis (AgP)—model based on the literature review and results of the current study. Concentrations of IL-10 reflect the host genetic predisposition to up/downregulated IL-10 gene expression and the presence of external stimuli, such as lipopolysaccharides (LPS) released from the outer membrane of Gram-negative bacteria. (A,B) represent the condition without external stimulation of the immune system cells. (C,D) show inflammatory status after stimulation of the immune system cells by LPS of periodontal bacteria via toll-like receptor 4 (TLR4) and nuclear factor kappa B (NFκB) leading to the upregulated IL-10 gene expression and thus massively increased IL-10 production. Genetic predisposition is determined by IL-10 haplogenotypes, which are composed of three functional promotor gene polymorphisms: IL-10 −1087 A/G (rs1800896), IL-10 −824 C/T (rs1800871), and IL-10 −597 C/A (rs1800872). Carriers of IL-10 GCC/GCC haplogenotype (A,C) have −1087G alleles in both strands; therefore, the binding sites for the Sp1 transcription factors are also present in both strands. Under comparable conditions, the IL-10 gene expression in these individuals is higher than in carriers of the ATA/ATA haplogenotype (B,D). While the transcription factors PU.1 and Spi-B bind to both −1087G and −1087A alleles, the activator of transcription Sp1 is not bound to IL-10 −1087A allele. Individuals with the GCC/GCC haplogenotype of the IL-10 gene and certain periodontal bacteria in periodontal sulci/pockets are more susceptible to the AgP development (Figure 4C) than carriers of other IL-10 haplogenotypes. The disease development may be caused by dysregulation of the cytokine network via IL-10 overexpression.

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