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Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

DOI： 10.1016/j.heliyon.2020.e05531

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Objectives: We evaluated whether the periodontal inflamed surface area (PISA), a measure of the inflammatory burden posed by periodontitis, is associated with the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). Methods: We conducted a retrospective study that collected rheumatologic and periodontal data from 54 patients with RA who had received corticosteroid, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 6 months of bDMARD therapy. After the patients were divided into two groups based on high or low PISA according to the median measurements at baseline, the rheumatologic condition was compared between the groups. Results: The patients with a low PISA showed significantly lower values for the Clinical Disease Activity Index (CDAI) (p = .008), swollen joint count (p = .02), and patient's and evaluator's global assessment (p = .01 and p = .03) and significantly greater decreases in changes in the CDAI from baseline to 6 months than the patients with a high PISA (p = .01), although these values were comparable at baseline. Both univariate and multivariate analyses revealed a significantly positive correlation between the baseline PISA and changes in the CDAI (p = .04 and p < .001). Conclusion: The PISA is associated with the clinical response to bDMARDs in patients with RA.

DOI： 10.1080/14397595.2019.1680100

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Authorship：Lead author,　Corresponding author   Language：Japanese  

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Most studies that have demonstrated an association between number of remaining teeth and cognitive impairment have treated teeth as a continuous variable, although the relationship is nonlinear. The aim of this cross-sectional study was to determine the critical number of remaining teeth in hospital outpatients at which the association with cognitive impairment becomes apparent. Japanese adults living on Sado Island who visited Sado General Hospital were invited to participate in Project in Sado for Total Health. In total, 2,530 adults were interviewed and had their teeth counted; 1,476 of these individuals also completed the Mini-Mental State Examination (MMSE) and underwent measurement of their serum high-sensitivity C-reactive protein (hsCRP) levels. Patients on dialysis and those with hsCRP ≥ 10 mg/L were excluded. The final study group consisted of 565 adults (290 men and 275 women) of mean age 69.8 (range 29-91) years. An MMSE score < 24 was considered to indicate cognitive impairment. The subjects were categorized according to whether they had an edentulous jaw or one to 10, 11-20, 21-27, or ≥28 remaining teeth. One hundred twenty-eight of the 565 study participants were diagnosed to have cognitive impairment. Multiple logistic regression analysis revealed associations of cognitive impairment with older age, ischemic heart disease, smoking, and alcohol consumption. After adjustment for covariates, having one to 10 remaining teeth was significantly associated with cognitive impairment. There is a significant association between having only one to 10 remaining teeth and cognitive impairment in hospital outpatients.

DOI： 10.1002/cre2.147

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BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults.

DOI： 10.1002/JPER.17-0412

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OBJECTIVES: An interrelationship between rheumatoid arthritis (RA) and periodontitis has been suggested due to their common pathogenic mechanisms. Protein carbamylation and neutrophil extracellular traps (NETs) formation have been shown to be related to autoimmune conditions, including RA, but their association with periodontitis has not been elucidated. Therefore, we assessed whether or not circulating levels of carbamylated protein (CarP) and NETs are associated with periodontitis severity and influenced by periodontal treatment. METHODS: We conducted a retrospective case-control study that included 40 patients with RA and periodontitis, 30 patients with periodontitis, and 43 systemically and periodontally healthy controls to assess the circulating levels of CarP and NETs and rheumatologic and periodontal conditions. The same assessments were also performed in 22 patients with RA and periodontitis after 2 months of periodontal treatment, including oral hygiene instruction and full-mouth supragingival scaling. RESULTS: Patients with RA and periodontitis showed significantly higher serum levels of CarP and NETs than the control group (P = 0.04 and P < 0.001, respectively). The serum levels of CarP and NETs were significantly correlated positively with the mean values of probing depth (P = 0.01 and P = 0.007, respectively) and clinical attachment level (P = 0.007 and P = 0.001, respectively) in the 40 patients with RA and periodontitis. Multiple logistic regression analyses also revealed significantly positive associations between the serum levels of CarP and NETs and moderate to severe periodontitis (P = 0.03 and P = 0.001, respectively). Furthermore, periodontal treatment significantly decreased the serum levels of CarP and NETs in patients with RA and periodontitis (P = 0.03 and P = 0.02). CONCLUSION: The circulating levels of CarP and NETs are associated with periodontitis severity and influenced by periodontal treatment in patients with RA.

DOI： 10.1371/journal.pone.0192365

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Background: The interaction of periodontopathic bacteria with host immune system induces the production of inflammatory mediators which leads to alveolar bone loss (ABL), the essential feature of periodontitis. Concurrently, periodontal diseases cause the elevation of blood cytokine levels, the alteration of gut microbiota and the dissemination of enterobacteria to the liver. Owing to these mechanisms, periodontal disease might be a risk for liver dysfunction. Several epidemiological studies have reported associations between periodontal diseases and liver dysfunction, although the association between ABL and liver dysfunction has not been investigated. This cross-sectional study determined if elevated serum liver enzyme levels were associated with ABL in Japanese adults. Material and Methods: Japanese adults living on Sado Island who visited Sado General Hospital were invited to participate in the study. Participants over 40 years of age who underwent dental panoramic radiography and blood tests were included. Drinking and smoking habits were self-administered. After excluding patients with edentulous jaw, diagnosed liver diseases, and those on dialysis, data from 44 men and 66 women with a mean age of 73 years were analyzed. The average percentage of ABL for each participant was calculated for mesial and distal sites of all remaining teeth. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were determined. Univariate analyses were performed to select covariates to be put in multivariate analyses. The association between elevated serum liver enzyme levels and the highest quartile of ABL were assessed by multiple logistic regression analysis. Results: After adjusting for covariates, no significant association was found between elevated serum AST, ALT, or GGT levels as dependent variables and the highest quartile of ABL as an explanatory variable. Conclusions: There was no significant association between the elevation of serum liver enzyme levels and ABL in Japanese adults. Key words:Liver enzymes, dental panoramic radiography, alveolar bone loss, Japanese adults.

DOI： 10.4317/jced.54555

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Conservative Dentistry  

DOI： 10.11471/shikahozon.60.197

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CiNii Article

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Objective: DNA methylation of the cytokine genes may play a role in the pathogenesis of periodontitis. The aim of this study is to evaluate whether the alteration of interleukin-6 (IL-6) gene promoter methylation in the gingival tissue (GT) and peripheral blood (PB) is unique to chronic periodontitis (CP).
Design: DNA isolated from the GT and PB of 25 patients with (CP) and 20 healthy controls (H) was modified with sodium bisulfite and analyzed for IL-6 promoter methylation with direct sequencing. The levels of IL-6 mRNA and serum IL-6 protein were evaluated by a quantitative reverse transcription polymerase chain reaction and an enzyme-linked immunosorbent assay.
Results: The CP group showed that the overall methylation rates of IL-6 promoter that contained 19 cytosine-guanine dinucleotide (CpG) motifs were significantly decreased in GT in comparison to PB (p &lt; 0.001), which was significantly negatively correlated with the probing depth (p = 0.003). The GT and PB of the H group displayed similar overall methylation rates. No significant difference was observed in the methylation rates at each CpG in GT in comparison to the PB in both groups. The levels of IL-6 mRNA in the GT and PB and serum IL-6 of the two groups were comparable. The ratio of IL-6 mRNA in the GT relative to the PB was significantly higher in the CP group than in the H group (p = 0.03).
Conclusion: The increased expression of IL-6 gene transcription may be related to IL-6 promoter hypomethylation in the GT from CP patients. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2016.05.018

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Conservative Dentistry  

Purpose: Much attention has been focused in recent years on a possible relationship between periodontitis and rheumatoid arthritis (RA). The aim of this study was to evaluate whether periodontitis coincidence affects the disease activity of RA and serum antibody response to Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in patients with RA. Methods: This study was approved by the Institutional Review Board of the Niigata University Faculty of Dentistry and Niigata Rheumatic Center. The study participants were 44 patients with RA and periodontitis (test group) and 13 patients with RA and non-periodontitis (control group) who provided informed consent. Assessments of periodontal parameters including plaque control record, gingival index, bleeding on probing, probing depth, and clinical attachment level, as well as evaluations of rheumatologic conditions such as the disease activity score including 28 joints using C-reactive protein (DAS28-CRP) and RA medications were performed. Serum levels of rheumatoid factor, CRP, matrix metalloproteinase-3, interleukin-6, tumor necrosis factor-alpha, and immunoglobulin G (IgG) to cyclic citrullinated peptide (CCP) and PPAD were also determined with an enzyme-linked immunosorbent assay. Significance of differences in the parameter values between the groups was assessed by the Mann-Whitney U test. Results: The test group showed significantly higher levels of periodontal parameter values than the control group. However, similar levels were observed in age, gender, smoking status, number of teeth present, and all rheumatologic and serum biochemical measurements between the groups. A trend toward increase was shown in the serum levels of anti-CCP IgG in the test group. Conclusion: The results of this study suggest that periodontitis coincidence has no effect on the disease activity of RA in patients with RA, although an evaluation of a large cohort is required.

DOI： 10.11471/shikahozon.59.266

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Other Link： http://search.jamas.or.jp/link/ui/2016391615

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Objectives
To determine whether serum immunity to Porphyromonas gingivalis peptidylarginine deiminase (PPAD) affects the clinical response to biological disease-modifying antirheumatic drug (bDMARD) in patients with rheumatoid arthritis (RA).
Methods
In a retrospective study, rheumatologic and periodontal conditions of 60 patients with RA who had been treated with conventional synthetic DMARD were evaluated before (baseline) and after 3 and 6 months of bDMARD therapy. After serum levels of anti-PPAD immunoglobulin G (IgG) were determined at baseline, the patients were respectively divided into two groups for high and low anti-PPAD IgG titers according to the median measurements. Genotypes at 8 functional single nucleotide polymorphisms (SNPs) related to RA were also determined.
Results
After 3 and 6 months of therapy, patients with low anti-PPAD IgG titers showed a significantly greater decrease in changes in the Disease Activity Score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.04 for both) and anti-cyclic citrullinated peptide (CCP) IgG levels (P = 0.03 and P = 0.04) than patients with high anti-PPAD IgG titers, although these parameter values were comparable at baseline. The anti-PPAD IgG titers were significantly positively correlated with changes in the DAS28-CRP (P = 0.01 for both) and the anti-CCP IgG levels (P = 0.02 for both) from baseline to 3 and 6 months later. A multiple regression analysis revealed a significantly positive association between the anti-PPAD IgG titers and changes in the DAS28-CRP after 6 months of bDMARD therapy (P = 0.006), after adjusting for age, gender, smoking, periodontal condition, and RA-related SNPs. Conclusion
The serum IgG levels to PPAD affect the clinical response to bDMARD in patients with RA.

DOI： 10.1371/journal.pone.0154182

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Background and ObjectiveOver-expression of tumor necrosis factor-alpha (TNF-) plays a pathological role in chronic periodontitis (CP) and rheumatoid arthritis (RA), which might be regulated by the epigenetic mechanism. The aim of the present study was to evaluate whether there is a unique methylation profile of the TNF- gene promoter in blood cells of individuals with CP and RA.
Material and MethodsThe study participants consisted of 30 Japanese adults with RA (RA group), 30 race-matched adults with CP only (CP group) and 30 race-matched healthy controls (H group). Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed, by direct sequencing, to investigate DNA methylation of the TNF- gene promoter region. The level of TNF- produced in mononuclear cells stimulated with Porphyromonas gingivalis lipopolysaccharide was determined using ELISA.
ResultsTwelve cytosine-guanine dinucleotide (CpG) motifs were identified in the TNF- promoter fragment from -343 to +57bp. The CP group showed a significantly higher methylation rate and frequency at -72bp than the H group (p&lt;0.01). The RA group exhibited significantly higher methylation rates at seven CpG motifs (-302, -163, -119, -72, -49, -38 and +10bp), and significantly higher methylation frequencies at six CpG motifs (-163, -119, -72, -49, -38 and +10bp), than the H group (p&lt;0.01 for all comparisons). The levels of TNF- produced were significantly different between individuals with and without methylation at -163bp (p=0.03).
ConclusionThese results suggest that the hypermethylated status of CpG motifs in the TNF- gene promoter in blood cells may be unique to Japanese adults with CP and RA.

DOI： 10.1111/jre.12314

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Background and ObjectiveAutoimmunity against citrullinated proteins through peptidylarginine deiminase (PAD) may be involved in the pathophysiology of rheumatoid arthritis (RA). The present study evaluated the serum levels of antibodies to citrullinated proteins and to Porphyromonas gingivalis PAD (PPAD), and the endogenous expression of PAD-4, in individuals with and without RA, as well as before and after periodontal treatment.
Material and MethodsThe study participants consisted of 52 patients with RA (RA group) and 26 age-, gender- and smoking status-matched healthy controls (non-RA group). Of the 52 patients, 26 were randomly assigned to receive oral hygiene instruction and supragingival scaling (RA subgroup). After periodontal and rheumatologic assessments, the serum levels of anti-cyclic citrullinated peptide (CCP) immunoglobulin G (IgG), anti-PPAD IgG and PAD-4 were determined using ELISA.
ResultsThe serum levels of anti-CCP IgG and anti-PPAD IgG were significantly higher in the RA group than in the non-RA group (p&lt;0.001 and p=0.03). A significant, positive correlation was observed between the serum levels of anti-PPAD IgG and anti-CCP IgG (p=0.04), but not between the serum levels of PAD-4 and anti-CCP IgG. Multiple logistic regression analyses revealed a significant association between anti-PPAD IgG responses and RA after adjustment for age, gender and smoking (p=0.004). Supragingival scaling significantly improved the periodontal condition and disease activity of RA (p&lt;0.05), but failed to decrease the serum levels of anti-CCP IgG, anti-PPAD IgG and PAD-4 after 2mo of treatment.
ConclusionThese results might suggest an association between anti-PPAD IgG and anti-CCP IgG responses, implicating a role for PPAD in protein citrullination in patients with RA and periodontitis.

DOI： 10.1111/jre.12288

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DOI： 10.1007/s40496-014-0039-2

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

Interleukin-6 (IL-6) may play a pathological role in rheumatoid arthritis (RA) and periodontitis. Although the efficacy of medication with IL-6 receptor inhibitor, tocilizumab (TCZ), has been demonstrated in the treatment of RA, very little is known about whether TCZ therapy affects periodontitis. The aim of the present study is to compare periodontal condition in patients with RA and periodontitis before and after TCZ therapy. The study participants consisted of 20 patients with RA and periodontitis who were treated with TCZ and 40 patients with RA and periodontitis who received medication with tumor necrosis factor inhibitor (TNFI). Clinical periodontal and rheumatologic assessments and serum biochemical measurements using enzyme-linked immunosorbent assays were performed at baseline and 3 and 6 months later. TCZ and TNFI therapies significantly reduced periodontal inflammation that was determined by gingival index, bleeding on probing, and probing depth (p &lt
0.017), although plaque levels were comparable before and after the therapies. Both therapies also significantly decreased disease activity score including 28 joints using C-reactive protein (CRP), number of tender and swollen joints, and serum levels of anti-cyclic citrullinated peptide antibodies, rheumatoid factor, CRP, and matrix metalloproteinase-3 (p &lt
0.017). Additionally, a significant decrease was observed in periodontal clinical attachment level after TCZ therapy (p &lt
0.017), but not after TNFI therapy. TCZ therapy significantly decreased serum levels of TNF-α, total immunoglobulin G, and serum amyloid A (p &lt
0.017), although serum levels of IL-6 and soluble IL-6R were significantly increased (p &lt
0.017). These results suggest a beneficial effect of TCZ therapy on levels of periodontal inflammation in patients with RA and periodontitis, which might be related to decrease in serum inflammatory mediators.

DOI： 10.1002/cre2.11

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Authorship：Lead author,　Corresponding author   Language：English  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Tumor necrosis factor (TNF)-alpha inhibitor has been shown to affect the periodontal condition of patients with rheumatoid arthritis (RA). The aim of the present study is to assess the effect of a fully humanized anti-TNF-alpha monoclonal antibody, adalimumab (ADA), on the periodontal condition of patients with RA and to compare serum protein profiles before and after ADA therapy.
Methods: The study participants consisted of 20 patients with RA treated with ADA. Clinical periodontal and rheumatologic parameters and serum cytokine levels were evaluated at baseline and 3 months later. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant difference in abundance before and after ADA therapy were found and identified using mass spectrometry and protein databases.
Results: The patients showed a significant decrease in gingival index (P = 0.002), bleeding on probing (P = 0.003), probing depth (P = 0.002), disease activity score including 28 joints using C-reactive protein (P &lt; 0.001), and serum levels of TNF-alpha (P &lt; 0.001) and interleukin-6 (P &lt; 0.001) after ADA medication, although plaque levels were comparable. Among a total of 495 protein spots obtained, nine spots were significantly decreased in abundance at reassessment, corresponding to complement factor H, phospholipase D, serum amyloid A, complement component 4, and alpha-1-acid glycoprotein (P &lt; 0.01).
Conclusion: These results suggest a beneficial effect of ADA therapy on the periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

DOI： 10.1902/jop.2014.140194

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Background: Rheumatoid arthritis (RA) and chronic periodontitis (CP) are chronic inflammatory conditions and share many pathologic features. The common molecular pathogenesis of the two inflammatory diseases is unclear. The aim of the present study is to evaluate serum protein profiles specific for patients with RA and CP by a comprehensive proteomic analysis.
Methods: The study participants were: 10 patients with RA, 10 patients with CP, 10 patients with RA and CP, and 10 healthy controls. All groups were balanced for age, sex, and smoking status. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant differences in abundance among the four groups were determined with computer image analysis and identified with mass spectrometry and protein databases.
Results: A total of 1,694 protein spots were obtained in sera of the four groups. Seven spots were significantly different in abundance among the four groups. Of these, three spots (complement component 3, complement factor H, and ceruloplasmin) were significantly different in the RA+ CP group compared with the other three groups (P &lt; 0.05). The similar profiles of complement component 3, complement factor H, and ceruloplasmin were observed by enzyme-linked immunosorbent assay.
Conclusion: These results suggest that patients with RA and CP may exhibit three serum proteins with different abundance compared with healthy controls and patients with RA only or CP only.

DOI： 10.1902/jop.2013.120741

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Background: Overproduction of interleukin (IL)-6 may play a pathologic role in rheumatoid arthritis (RA) and chronic periodontitis (CP). The present study assesses IL-6 receptor (IL-6R) inhibition therapy on the periodontal condition of patients with RA and CP.
Methods: The study participants were 28 patients with RA and CP during treatment with IL-6R inhibitor, and 27 patients with RA and CP during treatment without IL-6R inhibitor. Periodontal and rheumatologic parameters and serum levels of cytokine and inflammatory markers and immunoglobulin G against periodontopathic bacteria were examined after medication with IL-6R inhibitor for 20.3 months on average (T1) and again 8 weeks later (T2).
Results: No differences were observed between the groups in any parameter values at T1, except for serum IL-6 levels. The anti-IL-6R group showed a significantly greater decrease in gingival index, bleeding on probing (BOP), probing depth (PD), clinical attachment level (CAL), and serum levels of IL-6 and matrix metalloproteinase (MMP)-3 from T1 to T2 than the control group (P &lt; 0.05). A significant correlation was found between changes in serum anticyclic citrullinated peptide levels and those in PD and CAL in the anti-IL-6R group (P &lt; 0.05), whereas both groups exhibited a significant association between changes in serum MMP-3 levels and those in BOP (P &lt; 0.05).
Conclusion: Changes in periodontal and serum parameter values were different between the patients with RA and CP during treatment with and without IL-6R inhibitor.

DOI： 10.1902/jop.2013.120696

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Background: Porphyromonas gingivalis has been implicated as an etiologic agent of rheumatoid arthritis (RA) because of the expression of peptidylarginine deiminase. The present study evaluates whether periodontal treatment may affect serum antibodies to P. gingivalis and citrulline levels in relation to disease activity of RA.
Methods: Fifty-five patients with RA were randomly assigned to receive oral hygiene instruction and supragingival scaling (treatment group, n = 26) or no periodontal treatment (control group, n = 29). Periodontal and rheumatologic parameters and serum levels of cytokine and inflammatory markers citrulline and immunoglobulin (Ig)G to P. gingivalis were examined at baseline and 8 weeks later.
Results: Both groups did not differ statistically in any parameters except percentage of sites with probing depth and clinical attachment level &gt;= 4 mm at baseline. The treatment group exhibited a significantly greater decrease in disease activity score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.02), serum levels of IgG to P. gingivalis hemin binding protein (HBP) 35 (P = 0.04), and citrulline (P = 0.02) than the control group. Serum levels of IgG to P. gingivalis HBP35 were significantly correlated positively with those of anti-cyclic citrullinated peptide antibodies (P = 0.0002). The same correlation was obtained between serum levels of IgG to P. gingivalis-sonicated extracts and those of rheumatoid factor (P = 0.02).
Conclusions: These results suggest that supragingival scaling decreases DAS28-CRP and serum levels of IgG to P. gingivalis HBP35 and citrulline in patients with RA. These observations may reflect a role of P. gingivalis in the protein citrullination, which is related to the pathogenesis of RA.

DOI： 10.1902/jop.2013.130079

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Background: Methylation status of the cytokine genes may play a role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA) and chronic periodontitis (CP). This study was undertaken to evaluate whether the DNA methylation profile of the interleukin-6 (IL-6) gene promoter was unique to individuals with RA and CP.
Methods: The study participants consisted of 30 patients with RA, 30 patients with CP, and 30 age-, sex-, and smoking status-balanced healthy controls. Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed for DNA methylation levels of IL-6 gene with direct sequencing. Levels of IL-6 were determined by an enzyme-linked immunosorbent assay.
Results: The region of IL-6 gene promoter from -1200 to +27 bp was shown to contain 19 CpG motifs. The methylation levels of the CpG motif at -74 bp were significantly lower in patients with RA and CP than those in controls (P = 0.0001). Both levels of serum IL-6 and IL-6 production by mononuclear cells were significantly different between individuals with and without the methylation at -74 bp (P = 0.03). The +19 bp motif exhibited differential levels of the methylation among the groups, which was not associated with serum levels of IL-6. The other 17 CpG motifs exhibited comparable levels of the methylation between the groups.
Conclusion: These results suggest that hypomethylated status of a single CpG in the IL-6 promoter region may lead to increased levels of serum IL-6, implicating a role in the pathogenesis of RA and CP. J Periodontol 2012;83:917-925.

DOI： 10.1902/jop.2011.110356

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Many studies have reported an association between periodontal disease and preterm birth, although this remains controversial. Cytokines and antibodies produced to give resistance to infection can enter the bloodstream and cause preterm labor. We analyzed maternal genetic polymorphisms in various immunoregulatory genes that could affect both preterm birth and periodontitis. A total of 1099 women referred to the Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital were candidates for participation, 424 of whom refused, and 553 were excluded. The final number of subjects was 122 (51 with preterm birth, 71 with term birth). Genomic DNA was isolated from venous blood, and 22 polymorphisms were determined: IL-1A, IL-1B, IL-1RN, IL-2, IL-4, IL-6, IL-10, TNFA, TNFRI, TNFRII, Fc gamma RIIA, Fc gamma RIIB, Fc gamma RIIIA, Fc gamma RIIIB and Fc alpha R. Within five days of labor, periodontal parameters were evaluated, and bacteria from subgingival plaque were detected using real-time PCR. There was no difference in the prevalence and degree of periodontitis between term and preterm births. Chi-squared tests showed that an age &lt;33 years and Fc alpha R(+56)T/C alleles were associated with preterm birth. Multiple logistic regression analysis represented a model with significant fitness in which four variables were associated with preterm birth: maternal age, number of Aggregatibacter actinomycetemcomitans. IL-6(-572)G/C, and Fc alpha R(+56)T/C. In conclusion, there was no association between preterm birth and periodontitis in this study. A. actinomycetemcomitans, IL-6, and Fc alpha R were suggested to be associated with preterm birth. Multiple logistic regression models with both genetic and environmental factors would be useful for evaluating susceptibility to preterm birth. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jri.2012.01.005

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Sugita N, Iwanaga R, Kobayashi T, Yoshie H. Association of the Fc RIIB-nt645+25A/G polymorphism with the expression level of the Fc RIIb receptor, the antibody response to Porphyromonas gingivalis and the severity of periodontitis. J Periodont Res 2012; 47: 105113. (C) 2011 John Wiley & Sons A/S

DOI： 10.1111/j.1600-0765.2011.01411.x

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Background and Objective: The gram-negative anaerobe Porphyromonas gingivalis has been implicated as an important pathogen in the development of adult periodontitis, and its colonization of subgingival sites is critical in the pathogenic process. We previously identified a 35 kDa surface protein (hemin binding protein 35; HBP35) from P. gingivalis that exhibited coaggregation activity, while additional analysis suggested that this protein possessed an ability to bind heme molecules. For development of passive immunotherapy for periodontal diseases, human-type monoclonal antibodies have been prepared using HBP35 as an antigen in TransChromo mice. In the present study, we focused on a single antibody, TCmAb-h13, which is known to inhibit heme binding to recombinant HBP35. The aim of our investigation was to clarify the redox-related function of HBP35 and consider the benefits of human-type monoclonal antibodies.
Material and Methods: To examine the antigen recognition capability of TCmAbs with immunoblotting and Biacore techniques, we used the native form as well as several Cys-to-Ser variants of recombinant HBP35.
Results: We found that the redox state of recombinant HBP35 was dependent on two Cys residues, (48)C and (51)C, in the thioredoxin active center (WCGxCx). Furthermore, TCmAb-h13 recognized the reduced forms of recombinant HBP35, indicating its inhibitory effect on P. gingivalis growth.
Conclusion: Hemin binding protein 35 appears to be an important molecule involved in recognition of the redox state of environmental conditions. In addition, TCmAb-h13 had an inhibitory effect on heme binding to recombinant HBP35, thereby interfering with P. gingivalis growth.

DOI： 10.1111/j.1600-0765.2011.01389.x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Periodontopathic bacteria have been implicated as contributory to the etiology of rheumatoid arthritis (RA). Anticyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF) were shown to be associated with RA. This study examines whether serum levels of antibodies to periodontopathic bacteria may affect clinical and laboratory profiles of RA.
Methods: The study participants consisted of 80 patients with RA, and 38 age-, sex-, smoking status-, and periodontal condition-balanced healthy controls. After periodontal and rheumatologic examination, serum levels of immunoglobulin G(IgG) antibodies to Porphyromonas gingivalis (Pg), Prevotella intermedia, Aggregatibacter actinomycetemcomitans (Aa) (previously Actinobacillus actinomycetemcomitans), and Eikenella corrodens (Ec) and those of anti-CCP antibodies and RF were determined by an enzyme-linked immunosorbent assay.
Results: Patients with RA showed significantly higher levels of anti-Pg and anti-CCP antibodies than controls (P = 0.04 and P &lt; 0.0001). In contrast, IgG responses to Aa and Ec in patients with RA were significantly lower than those in controls (P &lt; 0.0001 and P = 0.0001). Multiple logistic regression analysis revealed a significant association of anti-Pg and anti-Aa IgG responses with RA, after adjustment for age, sex, and smoking (P = 0.005 and P = 0.02). Anti-Pg titer displayed a significant correlation with RF levels, probing depth, and clinical attachment level (P = 0.03, P = 0.03, and P = 0.02).
Conclusion: These results suggest that serum levels of anti-Pg IgG antibodies were associated with RA, and might affect serum levels of RF and periodontal condition in patients with RA. J Periodontol 2011; 82: 1433-1441.

DOI： 10.1902/jop.2011.110020

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Language：Japanese  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

This study was undertaken to evaluate the effect of oral administration of lactoferrin (LF) and lactoperoxidase-(LPO-)containing tablet on periodontal condition. Seventy-two individuals with chronic periodontitis were randomly assigned to take either bovine LF and LPO-containing tablets (test group, n=37) or control tablets (control group, n=35) every day for 12 weeks. Periodontal parameters and levels of subgingival plaque bacteria, human and bovine LF, and endotoxin in gingival crevicular fluid (GCF) were evaluated at baseline, 1 week, 4 weeks, and 12 weeks. Significant differences were observed in GCF levels of bovine LF between the test and control groups throughout the study (P&lt
.05). However, clinical and bacteriological parameter values proved comparable between the two groups at 1 week to 12 weeks. Therefore, the effect of oral administration of LF and LPO-containing tablets might be weak on periodontal and bacteriological profile in this study. Copyright © 2011 Eiju Shimizu et al.

DOI： 10.1155/2011/405139

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Background and Objective:
Neutrophils are essential in host defense against periodontopathic bacteria. Immunoglobulin G Fc receptor IIIb (Fc gamma RIIIb) is a neutrophil-specific receptor for immunoglobulin G and bears the functional NA1-NA2 polymorphism. Accumulating evidence suggests a significant association between Fc gamma RIIIb gene polymorphism and periodontitis. In this study, we employed a proteomic approach to evaluate the relevance of Fc gamma RIIIb polymorphism to protein expression profiles of neutrophils.
Material and Methods:ensp;
Neutrophils were collected from ten healthy subjects whose Fc gamma RIIIb genotypes were determined by allele-specific PCRs. Expressions of proteins induced by interaction via Fc gamma RIIIb were examined between the Fc gamma RIIIb genotypes with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins that were significantly different in expression levels between the Fc gamma RIIIb genotypes were determined with computer image analysis, and identified with mass spectrometry and protein databases.
Results:
A total of 757 protein spots were observed in the two-dimensional electrophoretograms of neutrophils from five Fc gamma RIIIb-NA1/NA1 and five Fc gamma RIIIb-NA2/NA2 donors. A statistical analysis revealed that the expression levels of five proteins were significantly different between the Fc gamma RIIIb genotypes (p &lt; 0.05). The Fc gamma RIIIb-NA1/NA1 neutrophils exhibited two spots that were significantly underexpressed (protein-arginine deiminase type-4 and annexin VI) and three spots that were significantly overexpressed (Cdc42hs-Gdp complex, myosin light chain 12A and coactosin-like 1) when compared with Fc gamma RIIIb-NA2/NA2 neutrophils. The same expression profiles of protein-arginine deiminase type-4 were obtained by ELISA.
Conclusion:
Differential protein expression profiles were observed in neutrophils between Fc gamma RIIIb genotypes.

DOI： 10.1111/j.1600-0765.2010.01300.x

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Lactoferrin (LF) is a component of saliva and is suspected to be a defense factor against oral pathogens including Streptococcus mutans and Candida albicans. Periodontitis is a very common oral disease caused by periodontopathic bacteria. Antimicrobial activities and other biological effects of LF against representative periodontopathic bacteria, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia, have been widely studied. Association of polymorphisms in LF with incidence of aggressive periodontitis and the role of LF in the gingival crevicular fluid as a marker of periodontitis severity have also been reported. Periodontopathic bacteria reside as a biofilm in supragingival and subgingival plaque. Our recent study indicated that LF exhibits antibacterial activity against planktonic forms of P. gingivalis and P. intermedia at higher concentrations, and furthermore, LF effectively inhibits biofilm formation and reduces the established biofilm of these bacteria at physiological concentrations. A small-scale clinical study indicated that oral administration of bovine LF reduces P. gingivalis and P. intermedia in the subgingival plaque of chronic periodontitis patients. LF seems to be a biofilm inhibitor of periodontopathic bacteria in vitro and in vivo.

DOI： 10.1007/s10534-010-9304-6

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Rheumatoid arthritis (RA) and periodontitis are common chronic inflammatory conditions and share many pathologic features. A similar profile of cytokines is involved in the pathogenesis of the two diseases. The relationship between the disease activity of RA and the periodontal condition remains unclear. This study examines whether the disease activity of RA affects serum cytokine and periodontal profiles.
Methods: The study subjects consisted of 84 Japanese adults with RA and 22 race-matched control individuals. After periodontal and rheumatologic examination, the disease activity of RA was determined with the Disease Activity Score including 28 joints using C-reactive protein (DAS28-CRP). Serum levels of cytokines including interleukin (IL)-1 beta, IL-6, IL-12, IL-12 p40, IL-18, and tumor necrosis factor-alpha (TNF-alpha) were determined by an enzyme-linked immunosorbent assay. High-sensitive CRP was also measured with a latex particle-enhanced nephelometric method.
Results: Of 84 patients with RA, 28 and 56 patients exhibited low and moderate to high disease activity, respectively. Serum levels of IL-6, TNF-alpha, and CRP were significantly different between the two groups (P&lt;0.05). Additionally, a significant correlation was observed between DAS28-CRP and percentage of sites with bleeding on probing (BOP) (P = 0.008) and between serum TNF-alpha levels and percentage of sites with BOP (P = 0.01) in 56 patients with RA with moderate to high activity.
Conclusion: These results suggest that the disease activity of RA correlated with serum levels of IL-6, TNF-alpha, and CRP, and it might influence BOP in the patients with moderate to high disease activity. J Periodontol 2010;81:650-657.

DOI： 10.1902/jop.2010.090688

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Genetic variants at multiple loci have been shown to be associated with susceptibility to periodontitis. To better assess the genetic risk factors for periodontitis, we performed a case-control study in 319 Japanese individuals with periodontitis (172 aggressive and 147 chronic disease) and 303 race-matched healthy control individuals. Thirty-five functional gene polymorphisms that had been previously associated with immune responses were genotyped. For all gene polymorphisms tested, no significant differences were observed in the allele frequencies of persons with aggressive, chronic, and combined ( aggressive and chronic) periodontitis, compared with control individuals. Multiple logistic regression analysis revealed a significant association of the vitamin D receptor + 1056 T/C polymorphism with susceptibility to chronic periodontitis, after adjustment for age, gender, and smoking status (P = 0.002). These results suggest that none of the polymorphisms tested was strongly associated with periodontitis in a Japanese population. However, the vitamin D receptor + 1056 polymorphism may be related to chronic periodontitis.

DOI： 10.1177/0022034509350037

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Oral lichen planus (OLP) is a refractory mucosal disease. Its pathogenesis is thought to involve immunologic and genetic alterations. To gain a better understanding of the genetic risk factors, the authors evaluated associations between 14 functional gene polymorphisms and OLP. 32 Japanese patients with OLP and 99 unrelated healthy Japanese controls were genotyped for 14 single nucleotide polymorphisms (SNPs) of genes that regulate host immune responses. Genotyping was performed with a modified version of the serial invasive signal amplification reaction. A trend towards over-representation of tumor necrosis factor receptor 2 (TNFR2) +587 G allele was found in the patients compared with the controls (allele frequency: P = 0.049). The other 13 SNPs were unassociated with OLP. These results suggest that TNFR2 +587 gene polymorphism may be associated with susceptibility to OLP. © 2009 International Association of Oral and Maxillofacial Surgeons.

DOI： 10.1016/j.ijom.2009.05.001

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Lactoferrin (LF) is an iron-binding antimicrobial protein present in saliva and gingival crevicular fluids, and it is possibly associated with host defense against oral pathogens, including periodontopathic bacteria. In the present study, we evaluated the in vitro effects of LF-related agents on the growth and biofilm formation of two periodontopathic bacteria, Porphyromonas gingivalis and Prevotella intermedia, which reside as biofilms in the subgingival plaque. The planktonic growth of P. gingivalis and P. intermedia was suppressed for up to 5 h by incubation with &gt;= 130 mu g/ml of human LF (hLF), iron-free and iron-saturated bovine LF (apo-bLF and holo-bLF, respectively), and &gt;= 6 mu g/ml of bLF-derived antimicrobial peptide lactoferricin B (LFcin B); but those effects were weak after 8 h. The biofilm formation of P. gingivalis and P. intermedia over 24 h was effectively inhibited by lower concentrations (&gt;= 8 mu g/ml) of various iron-bound forms (the apo, native, and holo forms) of bLF and hLF but not LFcin B. A preformed biofilm of P. gingivalis and P. intermedia was also reduced by incubation with various iron-bound bLFs, hLF, and LFcin B for 5 h. In an examination of the effectiveness of native bLF when it was used in combination with four antibiotics, it was found that treatment with ciprofloxacin, clarithromycin, and minocycline in combination with native bLF for 24 h reduced the amount of a preformed biofilm of P. gingivalis compared with the level of reduction achieved with each agent alone. These results demonstrate the antibiofilm activity of LF with lower iron dependency against P. gingivalis and P. intermedia and the potential usefulness of LF for the prevention and treatment of periodontal diseases and as adjunct therapy for periodontal diseases.

DOI： 10.1128/AAC.01688-08

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Cytokines play a major role in the pathogenesis of rheumatoid arthritis (RA) and periodontitis. Both diseases were previously shown to be partly influenced by cytokine gene polymorphisms. Therefore, we evaluated whether the distributions of the cytokine genotypes were unique to subjects with both diseases.
Methods: The study subjects consisted of Japanese adults with RA (RA group; n = 153), periodontitis only (P group; n = 117), and healthy individuals (H group; n = 108). Clinical periodontal condition was defined by measurements of probing depth, clinical attachment level, and bleeding on probing. Genomic DNA was isolated from peripheral blood and analyzed for the determination of 16 gene polymorphisms encoding interleukin (IL)-1, -2, -4, -6, and -10, tumor necrosis factor-alpha, and transforming growth factor-beta 1.
Results: The frequency of patients with RA who exhibited periodontitis was 89.5% (RA + P group; n = 137). No significant differences were observed in any of the frequencies of cytokine genotypes and alleles among the subject groups. After adjustment for age, gender, and smoking status, multiple logistic regression analysis revealed a significant difference in the distribution of IL-IB +3954 genotypes between RA + P and P groups (P=0.006) and between RA + P and H groups (P = 0.008).
Conclusion: Japanese individuals with RA and periodontitis may exhibit different distributions of IL-IB +3954 genotypes than healthy controls and subjects with periodontitis only. J Periodontol 2009;80:792-799.

DOI： 10.1902/jop.2009.080573

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Background: A genome-association study is a powerful toot for analyzing small gene effects in complex diseases such as chronic periodontitis (CP), although the cost of analysis is prohibitive. We designed a study using the DNA pooling method, which could be a breakthrough in lowering such costs. This study was conducted to assess the genetic association in severe CP in a Japanese population.
Methods: We adopted a DNA pooling method by genotyping 454 densely spaced microsatellite (MS) markers in chromosome 19 as a pilot study, with the possibility of future use in a whole-genome study. This can reduce the high cost and technical burden, which is generally unavoidable in a genomic association study. Pooled DNA samples from 300 case subjects, 300 control subjects, and 200 systemically healthy subjects were screened by genotyping MS markers. The case-control association in the candidate region was analyzed by individual typing of MS and single nucleotide polymorphisms (SNPs).
Results: The single MS marker allele 17 of 1902G31 was isolated in association with severe CP (P = 0.0012 for 2 x 2; P&lt;0.046 for 2 x m, where m refers to the number of polymorphic alleles observed in a population). No other SNP or MS polymorphism hypothesized to affect biologic functions in the critical region was found in the linkage disequilibrium block analysis.
Conclusions: We efficiently isolated the susceptible locus for severe CP in chromosome 19 and identified a useful marker to evaluate the risk for disease. This approach can be applied to a whole-genome study in severe CP. J Periodontol 2009;80:663-671.

DOI： 10.1902/jop.2009.080516

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Objective: Mannose binding lectin (MBL) is a key molecule in first line defense against variou's microorganisms. Polymorphism of the MBL gene greatly affects serum MBL concentration, and is known to be associated with occurrence of infectious diseases. We aimed to determine whether there is a relationship between occurrence or severity of chronic periodontitis (CP) and polymorphism of the MBL gene. Patients and methods: Ninety-eight CP patients and 63 healthy subjects with no periodontitis were typed for the codon 54 polymorphism of the MBL gene by PCR-restriction fragment length polymorphism method. Results: Genotype frequencies of the codon 54 polymorphism were similar between patients and control subjects. When patients were categorized to mild, moderate and severe periodontits groups, possession of the low serum MBL concentration allele was a risk factor for having severe CP, as assessed by logistic regression analysis. Conclusion: Patients with MBL genotypes that cause lower serum MBL concentration may be at risk of having severe periodontitis. MBL gene typing may become useful to predict the prognosis of CP. © 2009 The Japan Society for Clinical Immunology.

DOI： 10.2177/jsci.32.48

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Human Fc gamma RIIB is one of the receptors for immunoglobulin G (IgG) and suppresses the activation of B lymphocytes through cross-linking with the B cell receptor via immune complexes. This function of Fc gamma RIIB is essential for the negative regulation of antibody production. Our previous study has demonstrated the gene polymorphism Fc gamma RIIB-I232T to be associated with periodontitis. The polymorphism Fc gamma RIIB-232T has been reported to inhibit B-cell antigen receptor signaling more effectively compared to Fc gamma RIIB-232I, while other groups concluded that Fc gamma RIIB-232T had no ability to inhibit activatory receptors. In this study, we examined whether Fc gamma RIIB-I232T polymorphism would change the IgG antibody response to the periodontopathic bacteria Porphyromonas gingivalis.
Forty-seven patients with periodontitis were genotyped with the direct sequencing of genome DNA. Serum IgG and specific IgG subclass levels for the sonicate of P. gingivalis and the recombinant 40 kDa outer membrane protein (OMP) were determined.
No significant difference in the total IgG level and IgG response to P. gingivalis sonicate were observed between sera from Fc gamma RIIB-232T carriers and non-carriers. The Fc gamma RIIB-232T carriers revealed a significantly lower IgG(2) response to P. gingivalis 40 kDa OMP compared to non-carriers (p = 0.04, Mann-Whitney U-test). Lower responses of Fc gamma RIIB-232T carriers were also observed in specific IgG and IgG(1) levels. The Fc gamma RIIB-232T carriers revealed a low level of IgG(2) response to P. gingivalis 40 kDa OMP, even with a high average probing pocket depth.
These results suggest that association of the Fc gamma RIIB-232T allele with periodontitis might be related to the lower levels of antibody response to P. gingivalis.

DOI： 10.1111/j.1600-0765.2007.01078.x

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Genetic variants at multiple loci have been shown to be associated with periodontitis risk. In this study, we have focused on nine functional gene polymorphisms encoding immunoregulation-related molecules such as cytokines (interleukin-1 (IL-1), transforming growth factor-beta 1 (TGF-beta 1)) and cell surface receptors (immunoglobulin G and A Fc receptors (Fc gamma R and Fc alpha R)). In total, 113 Japanese patients with chronic periodontitis (CP) and 108 race-matched healthy controls were genotyped with the modified serial invasive signal amplification reaction. There was a significant difference in the distribution of IL-1 receptor antagonist (RN) +2018 T/C allele between the patient and control groups, with enrichment of the +2018 C in controls (P = 0.021, odds ratio = 0.38). An increased frequency of the IL-1 haplotype comprising IL-1A +4845 G, IL-1B -31 C, and IL-1RN +2018 C was observed in controls (P = 0.004). Moreover, a multivariate logistic regression analysis revealed that subjects with IL-1RN +2018 C allele were less likely to have CP (P = 0.016, odds ratio = 0.29). These findings document the association of IL-1RN +2018 C with reduced susceptibility to CP in the Japanese.

DOI： 10.1111/j.1744-313X.2008.00757.x

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Background: The balance between the degradation and synthesis of extracellular matrix determines periodontal attachment levels and alveolar bone matrix concentration in periodontal diseases. Matrix metalloproteinases (MMPs) are known to degrade periodontal ligamental attachment and bone matrix proteins. The purpose of this study was to examine the effect of different expression levels of MMPs and their inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), in periodontitis.
Methods: Sixteen inflamed gingival tissue samples from subjects with generalized chronic periodontitis and 14 control tissue samples from systemically and periodontally healthy subjects were evaluated. The total RNA was extracted, and the transcript levels for MMP-1, -3, -9, and -13 and TIMP-1, -2, -3, and -4 relative to P-actin were determined by quantitative real-time reverse transcription - polymerase chain reaction.
Results: Gene transcript levels for MMP-1 and TIMP-4 were significantly higher in periodontitis-affected gingival tissues (P &lt;0.05). MMP-3, -9, and - 13 and TIMP-1 mRNAs also were elevated in periodontitis; however, the difference was not statistically significant. TIMP-2 and -3 mRNA levels were similar in healthy and diseased gingivae. The ratios of MMP-1 /TIMP-2 (P &lt;0.01), MMP-3/TlMP-2 (P&lt;0.05), MMP-9/TIMP-2 (P&lt;0.05), and MMP-1/TIMP-3 (P&lt;0.01) from periodontitis lesions were significantly higher than those in the control tissues.
Conclusions: Upregulated MMP expression and an increased MMP/TIMP ratio indicate that a potential imbalance between degradation and synthesis of extracellular matrix persists in periodontitis-affected gingival tissues. This process may be responsible for increased tissue breakdown in periodontitis.

DOI： 10.1902/jop.2008.070159

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: The pathobiology of rheumatoid arthritis (RA) is similar to that of periodontitis in that proinflammatory cytokines and immunoglobulin G Fc receptor (Fc gamma R) play an important role. Functional polymorphisms of interleukin (IL)-1 and Fc gamma R were shown to be associated with susceptibility to both diseases. Therefore, we evaluated whether the IL-1 and Fc gamma R gene polymorphisms represent a common risk factor for RA and periodontitis.
Methods: The study population consisted of Japanese adults with RA (RA group; N = 100), periodontitis only (P group; N = 100), and healthy individuals with no systemic or oral disease (H group; N = 100). Clinical periodontal condition was defined by measurements of probing depth, clinical attachment level, and bleeding on probing. Genomic DNA was isolated from peripheral blood and analyzed for determination of IL-1 genotypes (IL-1A+4845, IL-1B+3954, and IL-1RN+2028) and Fc gamma R genotypes (Fc gamma RIIA, Fc gamma RIIIA, and Fc gamma RIIIB) by allele-specific polymerase chain reactions.
Results: Among 100 patients with RA, 86% showed periodontal tissue destruction. However, the RA group exhibited milder levels of periodontal tissue destruction than the P group (P &lt; 0.01). There was a significant difference in the distribution of IL-1B+3954 C/T genotypes between the RA and P groups and between the RA and H groups (P= 0.03 for both comparisons), with enrichment of the T allele in the RA group (P= 0.04; odds ratio, 2.9 for both comparisons). The combination of IL-1A+4845 T and IL-1+3954 T alleles yielded a strong association with RA and periodontitis (RA versus P group: P= 0.00001; RA versus H group: P= 0.00001).
Conclusions: These results failed to show that IL-1 and Fc gamma R gene polymorphisms constitute a common risk factor for RA and periodontitis. However, it was suggested that the distributions of IL-1B+3954 genotypes and IL-1A+4845 and IL-1B+3954 haplotypes were unique to the patients with RA and periodontitis.

DOI： 10.1902/jop.2007.070136

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The functional bi-allelic polymorphism of immunoglobulin G (IgG) Fc receptor (Fc gamma R) IIa influences the efficiency of human IgG2 binding. Our previous study showed that the high affinity Fc gamma RIIa genotype (-H/H131) was associated with periodontitis risk. As interleukin-1 (IL-1) is one of the major causes of periodontal tissue destruction, it is hypothesized that the Fc gamma RIIa-H/H131cross-linking could induce an increased IL-1 release by mononuclear cells. In this study, we evaluated the intracellular expressions of IL-1 beta in CD14 positive cells upon stimulation with human IgG2 by flow cytometry. Fc gamma RIIa-H/H131 subjects exhibited a higher percentage of IL-1 beta-producing cells than Fc gamma RIIa-R/H131 and -R/R131 subjects (P &lt; 0.05). These results support the concept that Fc gamma RIIa genotype may affect IL-1 beta production, possibly leading to interindividual differences in periodontitis risk.

DOI： 10.1111/j.1744-313X.2007.00701.x

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Background: Porphyrornonas gingivalis has been implicated as an important pathogen in the development of adult periodontitis, and its colonization of subgingival sites is critical in the pathogenic process. We recently reported the construction and characterization of human immunoglobulin G isotype clones, which were specifically reactive with recombinant (r) 40-kDa outer membrane protein (OMP) of P. gingivalis. The aim of this study was to investigate the efficacy of human monoclonal antibody (hMAb) against r40-kDa OMP of P. gingiualisto the protection alveolar bone loss by P. gingivalis in rats.
Methods: The role of 40-kDa OMP in the adherence of P. gingivalis to human gingival epithelial cells (HGECs) was examined by preincubating with r40-kDa OMP hMAb before adding the HGECs. Moreover, we used a rat model to examine the effect of the anti-r40-kDa OMP hMAb in alveolar bone loss by oral infection. Forty-six days after the last infection, the periodontal bone level was assessed morphometrically on defleshed rat jaws.
Results: The adherence to HGECs was reduced by 84% compared to adherence levels without the antibody. P. gingivalis could not be detected from rats in a P. gingiva lis-non -infected group and a group that was administered the anti-r40-kDa OMP hMAb. The bone loss in P. gingiualis-infected animals that were administered the anti-r40-kDa OMP hMAb was significantly lower than that of P. gingiva lis-infected rats.
Conclusions: Our results suggest that transchromosomic mouse-derived hMAb against r40-kDa OMP of P. gingivalis protects against periodontal bone loss. This newly constructed anti-r40-kDa OMP hMAb was used to protect against periodontal diseases caused by P. gingivalis infection.

DOI： 10.1902/jop.2007.060245

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Background: Saliva has been used as a diagnostic fluid in medicine and dentistry. It is easy to collect using non-invasive methods. The intracellular enzymes present in saliva have been studied as markers of periodontal disease. The purpose of this study was to determine the salivary enzyme levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) after scaling and to clarify the influence of interleukin (IL)-1 genotypes on these enzyme levels.
Methods: Forty-nine Japanese patients with chronic periodontitis (24 men and 25 women; mean age: 55.1 years) were enrolled in this study. Measurements of clinical parameters including probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) and collections of stimulated whole mixed saliva were performed at baseline and 4 weeks after scaling. After evaluation of salivary AST, ALT, and LDH levels, DNA was extracted from various cells in whole saliva. IL-1A+4845 G/T genotype was determined by polymerase chain reaction amplification, followed by enzyme digestion and electrophoresis. Statistical analysis was performed by the Wilcoxon signed-rank and Mann-Whitney U tests. A significant difference was set at P &lt; 0.05.
Results: Mean PD, CAL, and BOP values significantly decreased after scaling (mean +/- SE: 3.2 +/- 0.1 mm to 2.6 +/- 0.1 mm in PD; 3.9 +/- 0.2 mm to 3.3 +/- 0.2 mm in CAL; and 41% 4% to 18% 3% in BOP) (P &lt; 0.001). The values of AST, ALT, and LDH were 77.0 +/- 7.5, 43.9 +/- 5.5, and 753.4 +/- 96.5 (units per liter [U/l]) at baseline, and significantly decreased to 55.5 +/- 6.5, 30.0 +/- 5.5, and 394.7 +/- 34.0 (U/l) after scaling, respectively (P = 0.01, P = 0.006, and P &lt; 0.001). The carriage rate of the IL-1A+4845 allele 2 was 24.5%. No difference was noted in the decrease in PD, CAL, and BOP after scaling between the carriers (N = 12) and non-carriers (N = 37) of IL-1A+4845 allele 2. However, the IL-1A allele 2 non-carriers displayed a significant decrease in salivary AST and ALT levels (P &lt; 0.001), in contrast to the carriers who did not show any changes in the salivary levels of the enzymes after scaling.
Conclusions: These results documented that salivary AST, ALT, and LDH levels reflect inflammation and destruction of periodontal tissue, suggesting clinically useful markers following periodontal therapy. In addition, although IL-1A+4845 alleles may not influence clinical parameters, they may influence post-scaling values of salivary AST and ALT.

DOI： 10.1902/jop.2007.060216

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: The pathobiology of systemic lupus erythematosus (SLE) is similar to that of periodontitis in that the immunoglobulin G Fc receptor (Fc gamma R) and proinflammatory cytokines play an important role. Genetic variations of Fc gamma R and interleukin (IL)-1 are associated with susceptibility to both diseases. Therefore, we evaluated whether the combination of Fc gamma R or IL-1 polymorphic genes represents a common risk factor for SLE and periodontitis.
Methods: The study population consisted of Japanese adults with SLE and periodontitis (SLE+P group; n = 46), SLE only (SLE group; n = 25), periodontitis only (P group; n = 58), and healthy individuals with no systemic or oral disease (H group; n = 44). Clinical periodontal condition was evaluated by measurement of probing depth, clinical attachment level, and alveolar bone loss. Genomic DNA was isolated from peripheral blood and analyzed for determination of Fc gamma R genotypes (Fc gamma RIIA, Fc gamma RlIB, Fc gamma RIIIA, and Fc gamma RIIIB) and IL-1 genotypes (IL-1A +4845 and IL-1B +3954) by allele-specific polymerase chain reactions or DNA sequencing.
Results: A significant overrepresentation of the R 131 allele of stimulatory Fc gamma RIIA and the 232T allele of inhibitory Fc gamma RIIB was found in the SLE+P group compared to the H group (P=0.01 and P=0.0009, respectively). The combination of Fc gamma RIIA-R131 and Fc gamma RIIB-232T alleles yielded a strong association with SLE and periodontitis (SLE+P group versus P group: P=0.01, odds ratio: 3.3; SLE+P group versus H group: P = 0.0009, odds ratio: 11.2). Furthermore, SLE patients with the combined Fc gamma R risk alleles exhibited more severe periodontal tissue destruction compared to other SLE patients. The frequencies of IL-1 polymorphic alleles were too low to assess the association with SLE or periodontitis.
Conclusion: The combination of stimulatory Fc gamma RIIA and inhibitory Fc gamma RIIB genotypes may increase susceptibility to SLE and periodontitis in the Japanese population.

DOI： 10.1902/jop.2007.060194

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DOI： 10.1111/j.1600-0757.2006.00164.x

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Authorship：Lead author   Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Hemagglutinin and outer membrane protein (OMP) are major virulence factors associated with colonization of Porphyromonas gingivalis in the gingival crevice. The genes for the 200-kDa antigenic protein (200-kDa AP) and 40-kDa OMP of P. gingivalis have been successfully cloned. Additionally, the 200-kDa AP gene has been shown to constitute the hemagglutinin A (hagA) gene of P. gingivalis. Therefore, this study was constructed to evaluate the distributions and serum levels of immnoglobulin G (IgG) antibodies specific for 200-kDa AP and 40-kDa OMP in periodontitis patients.
Methods: Fifty patients with chronic periodontitis and 59 controls without periodontal destruction were enrolled in this study. We cloned the genes for 200-kDa AP and 40-kDa OMP from P. gingivalis and constructed the purified recombinant proteins. Serum levels of IgG subclass antibodies specific for both recombinant 200-kDa and 40-kDa OMP were determined in patients and controls by an enzyme-linked immunosorbent assay (ELISA).
Results: The serum IgG subclass distribution for patients and controls was IgG1 &gt; IgG4 &gt; IgG2 &gt; IgG3 in the anti-200-kDa AP response, which was almost identical to that in the anti-40-kDa OMP response. The patient group showed significantly higher serum IgG responses to the 40-kDa OMP than the control group (P &lt; 0.01). In contrast, IgG subclass responses to the 200-kDa AP were not different between the patients and controls. Serum levels of antibodies reactive with both 200-kDa and 40-kDa proteins did not have a significant association with mean probing depth.
Conclusion: These results suggested that serum IgG responses against P. gingivalis OMP rather than the hagA may be more active in chronic periodontitis.

DOI： 10.1902/jop.2006.050138

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Authorship：Lead author,　Corresponding author   Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)  

Genetically complex diseases like periodontitis have been extensively studied over the past decade. With the pooled knowledge about genetic polymorphisms that were claimed to play a role in the predisposition to and the progression of aggressive and chronic periodontitis, it is now possible to identify candidate genes that could act as potential risk or protective factors for the disease. Genetic researches in periodontitis were generally focused on 1) inflammatory cytokines, 2) cell surface receptors and 3) enzymes and related factors. Our reports have indicated the positive relationship between IgG Fc receptor (Fcγ R) IIIB, Fcγ RIIB, interleukin-1 receptor antagonist (IL-1RN), IgA Fc receptor (Fcα RI) gene polymorphisms and aggressive periodontitis in Japanese. Moreover, variations in the Fcγ RIIIA, Fcγ RIIA, tumor necrosis factor (TNF) receptor 2 and IL-6 gene correlated with the severity of chronic periodontitis. Periodontitis may be explained not only by the presence of specific bacteria and environmental factors, but also by the several relatively common polymorphisms with cumulative high-susceptibility profiles. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ics.2005.06.063

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Background: As a safe immunotherapeutic approach, human monoclonal antibody (hMAb) may be effective in clearing periodontopathic bacteria. The trans-chromosomic (TC) technology has recently been applied to construction of the TC mouse, which enables us to incorporate entire human chromosome fragments containing immunoglobulin (Ig) gene cluster. The aim of this study is to establish TC mouse-derived hMAb, and to test the in vitro opsonophagocytic activity.
Methods: Human Ig-producing TC mouse was immunized by recombinant 40-kDa outer membrane protein (r40-kDa OMP) of Porphyromonas gingivalis 381, and the spleen cells were fused with the mouse myeloma cell line. The specificity of anti-r40-kDa OMP hMAb was evaluated with the enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance assays. Flow cytometric analyses were performed to assess the opsonophagocytic activity.
Results: We successfully constructed 99 IgG isotype clones (IgG 1: 84; IgG2: 11; IgG4: four clones), which were specifically reactive with r4O-kDa OMP. The anti-r40-kDa OMP IgG1 hMAbs promoted phagocytosis of P. gingivalis by neutrophils. Futhermore, an increased opsonophagocytic activitity of anti-r40-kDa OMP IgG1 hMAbs was observed not only in P gingivalis 381, but also in the W50, W83, and Su63 strains.
Conclusion: Our results document the TC mouse-derived hMAb to promote neutrophil phagocytosis of P. gingivalis, suggesting an immunotherapeutic option for clearance of P. gingivalis.

DOI： 10.1902/jop.2005.76.5.680

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Background: Fc gamma RIIIb genotypes and smoking are risk factors for periodontal disease. However, the interaction of Fc gamma RIIIb-NA1-NA2 polymorphism with smoking remains unclear. The purpose of this study was to determine if Fc gamma RIIIb-NA1-NA2 polymorphism and smoking are associated with periodontal disease progression among elderly people.
Methods: Among 70-year-old subjects, 164 with neither diabetes mellitus nor blood sugar &gt;= 140 mg/dl, who had more than 20 teeth and who could participate in both the baseline and the follow-up examinations were included in the study. The NA1 group comprised subjects with Fc gamma RIllb-NA1NA1 genotype (N = 53), while the NA2 group included subjects with Fc gamma RIIIb-NA1NA2 or NA2NA2 genotype (N = 111). We examined the progression of periodontitis by measuring attachment loss during 3 years.
Results: The frequency of subjects who showed &gt;= 4 mm additional attachment loss at one or more sites was 55.6% for smokers and 37.2% for non-smokers. The odds ratio (OR) was 2.13 (confidence interval [CI]: 0.92 to 4.76). We found a better association between periodontal progression and smoking in the NA2 group. The OR for smokers was 3.03 (CI: 1.12 to 8.33, P = 0.028). Additionally, the mean number of sites with &gt;= 4 mm additional attachment loss per person between smokers and non-smokers in the NA2 group or between smokers and non-smokers in the NA1 group was 2.90 +/- 3.42 and 0.74 +/- 1.53 or 0.57 +/- 0.79 and 0.68 +/- 1.03, respectively (P &lt; 0.001; analysis of variance [ANOVA]).
Conclusion: Our results may suggest an association between smoking and periodontal disease progression in elderly people with Fc gamma RIIIb-NA2 polymorphism.

DOI： 10.1902/jop.2005.76.2.250

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Phagocytosis and killing of pathogens by polymorphonuclear neutrophils (PMN) from gingival crevicular fluid (GCF) is diminished in chronic periodontitis patients. As an approach to improve tar of PMN toward a periodontopathogen. Porphyromonas gingivalis, the efficacy of a bispecific antibody (BsAb) directed against both recombinant 130 kDa hemagglutinin domain (r130k-HMGD) of P. gingivalis, and PMN Fc receptor (FcR) was evaluated. GCF PMN exhibited higher IgA FcR (FcalphaRI) levels. and lower IgG FcR (FegammaRIIa and FcgammaRIIIb) levels than PB PMN. Functional studies revealed that GCF PMN exhibited a higher capacity to phagocytose and kill P gingivalis opsonized with a BsAb targeting P. gingivalis r130k-HMGD to FcalphaRI as compared to an anti-r130k-HMGD antibody. However. phagocytosis and killing activity of PB PMN that were incubated with the two antibodies proved comparable. These data support targeting of pathogens toward FcalphaRI as an option to improve antibacterial immunity in chronic periodontitis patients. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.vaccine.2004.07.015

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Background: Genetic polymorphisms for cytokines and their receptors have been proposed as potential markers for periodontal disease. Tumor necrosis factor receptor 2 (TNFR2) is one of the cell surface receptors for TNF-alpha. Recent studies have suggested that TNFR2 gene polymorphism is involved in autoimmune and other diseases.
Objectives: The aim of the present study is to evaluate whether TNFR2(+587T/G) gene polymorphism is associated with chronic periodontitis (CP).
Methods: One hundred and ninety-six unrelated subjects (age 40-65 years) with different levels of CP were identified according to established criteria, including measurements of probing pocket depth (PPD), clinical attachment level (CAL), and alveolar bone loss (BL). All subjects were of Japanese descent and non-smokers. Single nucleotide polymorphism at position +587(T/G) in the TNFR2 gene was detected by a polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method.
Results: The frequency and the positivity of the +587G allele were significantly higher in severe CP patients than in controls (p=0.0097; odds ratio=2.61, p=0.0075; odds ratio=3.06). In addition, mean values of PPD, CAL, and BL were significantly higher in the +587G allele positive than in the negative subjects (p=0.035, 0.022, and 0.018, respectively).
Conclusions: These findings suggest that the TNFR2(+587G) polymorphic allele could be associated with severe CP in Japanese.

DOI： 10.1111/j.1600-051X.2004.00513.x

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Immunoglobulin A Fc receptor (FcalphaRI) has been implicated in the pathogenesis of periodontitis, because increased IgA responses and FcalphaRI-bearing neutrophils are observed in the disease lesions. Inter-individual differences in susceptibility to periodontitis may be attributable to genetic variability in FcalphaRI-mediated immunity. We here identified an FcalphaRI novel polymorphism (nt 324 A-to-G transition) in the membrane-distal extracellular domain encompassing the ligand-binding site, not resulting in an amino acid change. We compared the FcalphaRI genotype distributions among 46 Japanese aggressive periodontitis (AGP) patients, 80 race-matched healthy controls (HCs), and 59 Caucasian HCs. No ethnic differences were observed in the FcalphaRI genotype distributions between Japanese and Caucasian HC. Notably, we observed a difference in the genotype distribution between the AGP and HC groups. Carriage rate of the nt 324 A allele was higher in the AGP (65.2%) than that in the HC group (42.5%) (odds ratio 2.54). Polymorphonuclear neutrophils from peripheral blood and gingival crevicular fluid exhibited a decreased phagocytosis of periodontopathic bacteria (Porphyromonas gingivalis) in the nt 324 A/A patients as compared with the nt 324 G/G patients. These results document a genetic polymorphism at the FcalphaRI ligand-binding site to be associated with susceptibility to AGP.

DOI： 10.1111/j.0001-2815.2004.0228.x

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Objectives: Recently, interleukin (IL) 4 gene polymorphisms have been analyzed in association with periodontitis. Genetic differences between Caucasian and Japanese patients with periodontitis have previously been detected. The aim of the present study was to analyze IL-4 genotypes in Caucasian and Japanese patients with aggressive periodontitis (AgP).
Material and Methods: One hundred and twenty-four subjects were included in the study, 31 Japanese and 30 Caucasian patients with generalized AgP, plus 30 Japanese and 33 Caucasian healthy controls. IL-4 polymorphisms were determined by polymerase chain reaction. A logistic regression was used to investigate the possible association of the genotypes with the disease in both populations. Odds ratio (OR) estimates were analyzed for allele frequencies.
Results: No significant association of IL-4 polymorphisms with the risk of AgP was determined in either population. However, the allele frequencies showed different results between populations. The carriage of the polymorphism in intron 2 was higher in Caucasian patients compared with controls (OR: 2.0, 95% confidence interval: [1.0;4.2]. Furthermore, the frequency of the IL-4 promoter/intron 2 composite genotype (PP+/IP+) in patients and controls, respectively, was found to be approximately 25% and 60% higher in the Japanese population than in the Caucasian population.
Conclusion: There was no evidence of an association of IL-4 genotypes and AgP in either population, although the frequencies of the IL-4 genotypes in the Japanese and the Caucasians were different.

DOI： 10.1111/j.1600-051X.2004.00492.x

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Background: Functional polymorphisms of immunoglobulin G (IgG) Fc receptors IIIa and IIIb (FcgammaRIIIa and FcgammaRIIIb) have been shown as risk factors for periodontitis. The aim of this study is to examine whether FcgammaRIIa polymorphism is associated with a disease risk as well.
Methods: Baseline periodontal and general health examinations were carried out on 1,221 Caucasian adults. From these, 422 subjects with moderate to severe, or little or no periodontal disease were assigned to two groups according to their mean clinical attachment loss (CAL). Subjects with mean CAL greater than or equal to2.94 mm were diagnosed with chronic periodontitis (n = 213, 62 never-smokers and 151 smokers). Subjects with mean CAL less than or equal to1.77 mm were considered as having little or no periodontal disease and designated as controls (n = 209, 125 never-smokers and 84 smokers). The FcgammaRIIa genotype for three bi-allelic polymorphisms (FcgammaRIIa-R/ R131, R/H131, and H/H131) was determined by means of allele-specific polymerase chain reactions.
Results: The distribution of FcgammaRIIa genotype between the patient and control groups was significantly different, with enrichment of the high ligand-binding genotype FcgammaRIIa-H/H131 in the patients (patients versus controls: 36.6% versus 25.4%; P= 0.04). Multivariate logistic regression model demonstrated that subject age and gender, smoking, and the FcgammaIIa genotype were significantly associated with severity of chronic periodontitis. For smokers, a significant over-representation of FcgammaRIIa-H/H131 in the patient group compared to the control group (patients versus controls: 35.1% versus 19.0%; P= 0.03). Additionally, smokers with FcgammaRIIa-H/H131 exhibited significantly greater mean CAL (mean +/- SE: 3.44 +/- 0.16 mm) than those with FcgammaRIIa-R/H131 (2.91 +/- 0.14 mm) and R/R131 (2.82 +/- 0.16 mm) (P = 0.04). There was no association between FcgammaRIIa genotype and the disease susceptibility or severity in subjects who had never smoked.
Conclusions: Our results suggest that the Fc7RIIa-H/H131 genotype may be associated with chronic periodontitis risk (and disease severity) in Caucasian smokers. Further studies with families and studies of mechanisms are necessary to help establish the extent to which this is a genetic determinant of periodontal diseases.

DOI： 10.1902/jop.2004.75.4.517

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Human type II low-affinity receptor for immunoglobulin G (FcgammaRII) constitutes a clustered gene family consisting of FcgammaRIIA, IIB and IIC genes. FcgammaRIIB is unique in its ability to transmit inhibitory signals in B cells via immunoreceptor tyrosine-based inhibitory motif (ITIM). B-cell activation and subsequent elevated production of IgG are the immunopathological features of inflammatory disease such as periodontitis. To determine whether an association with periodontitis susceptibility exists, genetic polymorphisms of FcgammaRIIB were examined in Japanese patients with aggressive periodontitis (AGP) and chronic periodontitis (CP), and in the race-matched healthy controls (HCs). A significant difference was observed in the distribution of FcgammaRIIB - 232I/T allele (exon 5) between the AGP and HC groups, with enrichment of the 232T in the AGP group (P = 0.006). In addition, the FcgammaRIIB- nt 646 - 184A/G allele (intron 4) distribution was significantly different between the CP and HC groups, with enrichment of the nt 646 - 184A in the CP group (P = 0.011). These results document the association of FcgRIIB gene polymorphisms with susceptibility to periodontitis in the Japanese.

DOI： 10.1038/sj.gene.6364021

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Language：Japanese   Publisher：JAPANESE SOCIETY OF PERIODONTOLOGY  

Periodontitis is considered to be a polygenic disease. Susceptibility to aggressive periodontitis (AgP), formerly known as early-onset periodontitis, might be associated with genetic polymorphisms. Tumor necrosis factor receptor (TNFR) 1 and 2 are cell surface receptors for TNF-α. Recent studies have suggested that TNFRs may modulate TNF-α-mediated inflammatory responses in periodontal disease. The aim of the present study was to evaluate whether TNFR1 and TNFR2 gene polymorphisms are associated with AgP in Japanese patients.<BR>Forty-five generalized AgP (G-AgP) patients and 100 age-matched healthy Japanese subjects were selected according to established clinical criteria. Single nucleotide polymorphisms at positions -383 (A/C) and +36 (A/G) in the TNFR1 gene, at positions +587 (T/G) and +694 (G/A) in the TNFR2 gene, and the variable number of tandem repeats (VNTR) promoter polymorphism in the TNFR 2 gene were detected using polymerase chain reactions, restriction fragment length polymorphisms, single-strand conformation polymorphisms, and direct sequencing methods. Statistically significant differences between the AgP and healthy groups were determined using chi-square and Fisher exact tests, equivalent results were assessed using the equivalence-delta test and further adjusted using the Mantel-Haenszel method.<BR>The frequency of the -383C allele was significantly lower in the G-AgP patients group than in the healthy group (p=0.04). On the other hand, equivalent allele frequencies between the two groups were found at three positions (+587 (T/G), +694 (G/A) and VNTR) in the TNFR2 gene. After adjusting for a confounding factor, the +587 (T/G) and VNTR allele frequencies of the two groups were found to be significantly equivalent (p<0.01).<BR>These findings suggest that the TNFR1 (-383A/C) gene polymorphism might be associated with G-AgP, whereas the TNFR2 +587 (T/G) and VNTR gene polymorphisms are not likely to result in a susceptibility to G-AgP. J Jpn Soc Periodontol, 45: 267-278, 2003.

DOI： 10.2329/perio.45.267

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Other Link： http://search.jamas.or.jp/link/ui/2004084380

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

Human IgG receptors (FcgammaR) display considerable heterogeneity, and are crucial immune response modulating molecules. FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB display functional biallelic polymorphisms. FcgammaR polymorphisms have been found associated with susceptibility to infectious and autoimmune diseases. Linked transmission of FcgammaR alleles was studied by determining the distribution of FcgammaRIIA-FcgammaRIIIA-FcgammaRIIIB genotype combinations in 514 Dutch Caucasian, and 149 Japanese blood donors. The structure of the FcgammaR locus was studied by radiation hybrid mapping of FcgammaRIA, FcgammaRIIA, FcgammaRIIB, FcgammaRIIIA, FcgammaRIIIB, and adjacent genes from the pentraxin family. In addition, crossing-over frequencies within the FcgammaR locus were determined in 63 Dutch Caucasian families, encompassing 183 individuals. FcgammaRII and FcgammaRIII subclasses were mapped in close proximity (0.47-3.14 cR). Accordingly, crossing-over frequencies within the FcgammaRII-III locus in Dutch families were low. Analysis of combined FcgammaR genotypes strongly suggested non-random distribution of FcgammaRIIA-FcgammaRIIIA-, and FcgammaRIIIA-FcgammaRIIIB genotypes in Dutch donors (P&lt;0.001 and P&lt;0.00001, respectively), and of FcgammaRIIA-FcgammaRIIIb genotypes in Japanese blood donors (P&lt;0.02). Frequencies of FcgammaRII-FcgammaRIII haplotypes differed significantly between Dutch and Japanese (P&lt;0.00001). This study provides important information for the interpretation of studies reporting associations of FcgammaR alleles with disease, and underscores the apparent differences in FcgammaR heterogeneity between ethnic groups.

DOI： 10.1007/s00251-003-0574-9

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Background: Leukocyte Fc receptors for immunoglobulin G (FcgammaR) play a major role in the handling of immune complexes and pathogens in systemic lupus erythematosus (SLE) and periodontitis. Both diseases have been shown to be partly influenced by genetic components including FcgammaR genotype. The aim of this study was therefore to evaluate whether FcgammaR gene polymorphisms are associated with periodontitis risk in SLE patients.
Methods: The study subjects consisted of 42 SLE patients with periodontitis (SLE/P), 18 SLE patients without periodontitis (SLE/H), 42 healthy subjects with periodontitis (H/P), and 42 healthy subjects without periodontitis (H/H), who were all unrelated Japanese non-smokers. Genomic DNA was isolated from peripheral blood, and FcgammaR genotypes for 3 biallelic polymorphisms (FcgammaRIIa-R131/H131, FcgammaRIIIa-158V/158F, FcgammaRIIIb-NA1/NA2) were determined by allele-specific polymerase chain reactions.
Results: The SLE/P group was found to have more mild levels of periodontal destruction than the H/P group (P &lt; 0.01). There was a significant difference in the distribution of FcgammaRIIa genotypes between SLE/P and H/H groups (P = 0.004). A significant overrepresentation of the FcgammaRIIa-R131 allele was found in the SLE/P group compared to the H/H group (SLE/P versus H/H: odds ratio [OR] 3.13, 95% confidence interval [CI] 1.46-6.77, P = 0.0013). Furthermore, the prevalence of periodontitis was found to be 70% in SLE patients. The FcgammaRIIa-R131 allele was also found to be overrepresented in the SLE/P group compared to the SLE/H group (SLE/P versus SLE/H: OR 3.40, 95% CI 1.18-10.25, P = 0.011).
Conclusion: These results show the FcgammaRIIa-R131 allele to be associated with periodontitis risk in SLE patients.

DOI： 10.1902/jop.2003.74.3.378

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Background: The aim of the present study was to compare the effectiveness of Nd:YAG and CO2 laser treatment to that of ultrasonic scaling used as monotherapies by examining clinical parameters, subgingival microflora, and interleukin-1 beta (IL-1beta) in gingival crevicular fluid (GCF).
Methods: Eighteen patients, each of whom had 2 or more sites with probing depth measuring &gt;5 mm, were included this clinical trial. The 41 sites were randomly assigned treatment with either Nd:YAG laser alone (n = 14, 100 mj, 20 pps, 2.0 W, 120 seconds), CO2 laser alone (n = 13, 2.0 W, 120 seconds), or ultrasonic scaling alone (n = 14, maximum power, 120 seconds). At baseline and at 1, 4, and 12 weeks, clinical measurements (plaque index, PI; gingival index, GI; probing depth, PD; clinical attachment level, CAL; and bleeding on probing, BOP) were performed and subgingival plaque and GCF sampled. A quantitative analysis of Porphyromonas gingivalis was carried out using real-time polymerase chain reaction (PCR) procedures. The amounts of lL-1beta were estimated by an enzyme-linked immunosorbent assay (ELISA).
Results: Decreased inflammation and PD were observed in all 3 groups after treatment. A microbiological analysis indicated significant decreases in P gingivalis in the Nd:YAG and scaling groups at 1, 4, and 12 weeks compared to baseline (P&lt;0.05). The amount of GCF significantly decreased in the Nd:YAG and scaling groups at 12 weeks. The amount of IL-1beta increased in the CO2 group from baseline to 1 week (P &lt;0.05). The Nd:YAG group tended to show a decrease in IL-1beta from 1 to 12 weeks, although these data were not statistically significant.
Conclusions: Our data suggest that Nd:YAG laser and ultrasonic scaling treatments showed significant improvements regarding the clinical parameters and subgingival microflora compared to the baseline, but no significant difference was observed between the 3 groups.

DOI： 10.1902/jop.2003.74.2.175

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Background/Aims: Early onset periodontitis (EOP), newly 'aggressive periodontitis', is considered to have genetic basis, which have not been clearly defined. The interleukin-1 (IL-1) gene cluster polymorphism as one of genetic factors may influence the expression of several chronic inflammatory diseases. The aim of this study is to investigate the frequency of single nucleotide polymorphisms (SNPs) in the genes encoding IL-1alpha, IL-1beta and a variable number of tandem repeat (VNTR) polymorphisms in the IL-1 receptor antagonist gene (IL-1RN) in 47 generalized EOP (G-EOP) patients and 97 periodontally healthy controls.
Material and methods: All subjects were of Japanese descent and systemically healthy. They were identified according to established clinical criteria. SNPs in the IL-1alpha (+4845) and IL-1beta (-511, +3954) genes were analyzed by amplifying the polymorphic region using polymerase chain reaction (PCR), followed by restriction-enzyme digestion and agarose gel electrophoresis. IL-1RN (VNTR) polymorphisms were then detected by PCR amplification and fragment size analysis.
Results: There was no significant difference in the IL-alpha (+4845) and IL-1beta (-511, +3954) genotypes and allele frequencies between G-EOP patients and healthy controls. However, the frequency of IL-1RN (VNTR) polymorphic alleles was found to be significantly increased in G-EOP patients (chi(2) test, P=0.007; odds ratio=3.40). Additionally, the carriage rate of IL-1RN (VNTR) polymorphisms was significantly higher in G-EOP patients than in healthy controls (chi(2) test, P=0.005; odds ratio=3.81).
Conclusion: These findings suggest that IL-1RN (VNTR) polymorphisms are associated with G-EOP in Japanese.

DOI： 10.1034/j.1600-051X.2002.291002.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

Early-onset periodontitis (EOP) is considered to have a genetic basis which has not been clearly defined. Genetic polymorphisms of the vitamin D receptor (VDR-B-b) and the immunoglobulin-Fcgamma receptor IIIb (FcgammaRIIIb-NA1-NA2) are associated with bone metabolism and infectious diseases, respectively. The purpose of this study was to investigate the associations of EOP with VDR and FcgammaRIIIb polymorphisms. Subjects were comprised of those with generalized EOP (G-EOP, n = 42), adult periodontitis (AP, n = 52), and healthy control (HC, n = 55). VDR and FcgammaRIIIb genotypes were determined by allele-specific polymerase chain-reactions. Our results indicated that frequencies of the VDR-B non-carrier and the FcgammaRIIIb-NA2 carrier were lower in the G-EOP compared with the AP and HC groups. Furthermore, we found a strong association between G-EOP and the VDR-FcgammaRIIIb composite genotype (G-EOP vs. AP - OR = 5.09, p = 0.009; G-EOP vs. HC - OR = 5.93, p = 0.004). In conclusion, no correlation was found between the VDR genotype and G-EOP. However, the VDR and FcgammaRIIIb genotype combination may be associated with susceptibility to G-EOP.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1034/j.1600-0765.2001.360607.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Variation screening for the immunoglobulin G Fc receptor IIB (FcgammaRIIB) gene was performed with the genomic DNA from 100 healthy Japanese subjects. We identified 3 non-synonymous and 2 synonymous substitutions and 2 single-nucleotide polymorphisms in an intron region. These substitutions were found to be located in the ligand-binding domain and the intron, which might alter the function of FcgammaRIIb.

DOI： 10.1034/j.1399-0039.2001.580509.x

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Background: Early-onset periodontitis (EOP) is considered to have a genetic basis, which has not been clearly defined. The tumor necrosis factor-alpha (TNF-alpha) gene polymorphism as one of the genetic factors may influence the expression of several chronic inflammatory diseases. The aim of the present study was to evaluate whether the polymorphisms in the 5'-flanking region of the TNF-alpha gene are associated with Japanese EOP patients.
Methods: Forty-six Japanese, generalized EOP (G-EOP) patients and 104 Japanese healthy subjects were identified according to established clinical criteria. Twenty healthy subjects were analyzed by nucleotide sequence to screen polymorphisms of the 5'-flanking region of the TNF-alpha gene. Then, all subjects were analyzed by polymerase chain reaction and sequencespecific oligonucleotide probe (SSOP) methods.
Results: We determined 5 single nucleotide polymorphisms at positions - 1031 (T/C), -863 (C/A), -857 (C/T), -308 (G/A), and -238 (G/A) in the 5'-flanking region of the TNF-alpha gene. There were no significant differences in the genotype and allele frequency when we compared G-EOP patients to healthy subjects. Because the frequency of polymorphic alleles at positions -308 and -238 was very low in this study population, we demonstrated the existence of 4 detected haplotypes and 6 detected genotypes concerning 3 single nucleotide polymorphisms (-1031, -863, and -857). The frequency of the H1/H3 (TCC/TCT)-detected genotype tended to decrease in G-EOP patients compared to healthy subjects, but was not statistically significant.
Conclusion: These findings suggest there is no significant association between polymorphisms in the 5'-flanking region of the TNF-alpha gene and susceptibility to G-EOP in Japanese patients.

DOI： 10.1902/jop.2001.72.11.1554

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Functional polymorphisms of immunoglobulin G (IgG) Fc receptors (Fc gammaR) have been shown to be associated with generalized aggressive periodontitis (GAgP) or recurrence of chronic periodontitis (CP) in Japanese patients. The purpose of this study was to evaluate whether Fc gammaR polymorphisms are also associated with severity of CP.
Methods: Fifty Japanese non-smoking patients with severe CP and 39 Japanese non-smoking patients with moderate CP were identified according to established clinical criteria, including measurements of probing depth (PD), clinical attachment level (CAL), and alveolar bone loss (BL). Fc gammaR genotypes for 3 bi-allelic polymorphisms (Fc gamma RIIa-R/H131, Fc gamma RIIIa-158V/F, Fc gamma RIIIb-NA1/NA2) were determined in these CP patients and 64 race-matched, non-smoking healthy controls by means of allele-specific polymerase chain reactions.
Results: There was a significant over-representation of Fc gamma RIIIa-158V allele in severe CP patients compared to moderate CP patients (odds ratio 2.03, 95% confidence interval [CI] 1.03-4.01, chi (2) = 4.86, P = 0.028). In addition, we found a strong association between CP severity and Fc gammaR composite genotype comprising Fc gamma RIIIa-158V plus Fc gamma RIIIb-NA2 (severe CP versus moderate CP: odds ratio 4.69, 95% Cl 1.52-15.10, chi (2) = 9.35, P = 0.002; severe CP versus healthy controls: odds ratio 4.10, 95% Cl 1.62-10.59, chi (2) = 11.13, P = 0.0009). Moreover, CP patients positive for the composite genotype exhibited more severe signs of periodontitis than composite genotype-negative individuals (positive versus negative; mean PD: 3.8 mm versus 3.2 mm, P = 0.005; mean CAL: 4.5 mm versus 3.7 mm, P = 0.005; mean % BL: 37.6% versus 29.9%, P = 0.008).
Conclusion: Our results document the Fc gamma RIIIa-158V allele and possibly Fc gamma RIIIb-NA2 to be associated with severity of CP in Japanese patients.

DOI： 10.1902/jop.2001.72.10.1324

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Porphyromonas gingivalis has been implicated as a causative pathogen in periodontitis. Immunotherapeutic approaches have recently been suggested to aid in the clearance of P, gingivalis from disease sites. Because antibody-Fe receptor (FeR) interactions play a role in the effector functions of polymorphonuclear neutrophils (PMN), we evaluated which FeR on PMN from gingival crevicular fluid (GCF) serves as an optimal target molecule for FcR-directed immunotherapy. GCF PMN and peripheral blood (PB) PMN from adult periodontitis patients were analyzed for their immunoglobulin G (IgG) and IgA FcR (Fc gammaR and Fc alphaR, respectively) expression and function by studying IgG- and IgA-mediated elimination of P. gingivalis. GCF PMN exhibited higher Fc alpha RI and Fc gamma RI levels and lower Fc gamma RIIa and Fc gamma RIIIb levels than PB PMN. Functional studies revealed that GCF PMN exhibited less of a capacity to phagocytose and kill IgG1-opsonized P. gingivalis than PB PMN. IgA1-mediated phagocytosis and killing capacity was, however, comparable between GCF PMN and PB PMN. In summary, these in vitro results document that Fc alpha RI represents a candidate target for FcR-directed immunotherapy for the clearance of P. gingivalis.

DOI： 10.1128/IAI.69.5.2935-2942.2001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Immunoglobulin G Fc receptor mb (Fc gamma RIIIb) is constitutively expressed on neutrophils, and has three allelic forms: Fc gamma RIIIb-NA1, Fc gamma RIIIb-NA2, and Fc gamma RIIIb-SH. We identified two Japanese subjects in whom an A to G substitution at nt 221 changes asparagine (N) to serine (S) at amino acid position 45 in the Fc gamma RIIIb-NA2 gene. Fc gamma RIIIb-NA2-specific mono-clonal antibodies (GRM1 and PEN1) did not bind to mutant neutrophils, which lack an N-linked glycosylation site. Furthermore, IgG3-mediated neutrophil phagocytosis by mutant was slightly increased as compared to wildtype donors.

DOI： 10.1034/j.1399-0039.2001.057004363.x

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Many elderly people show minimum periodontal tissue destruction, which might be partly due to genetic advantages in host immune response against periodontopathic bacteria. The human IgG Fc receptor IIIb on neutrophils bears a NA1-NA2 polymorphism. The Fc gamma RIIIb-NA1 displays a more efficient interaction with IgG1- and IgG3-opsonized bacteria, compared with the Fc gamma RIIIb-NA2. We investigated a 70-year-old Japanese population (n = 599) to determine whether the Fc gamma RIIIb polymorphism was associated with resistance to periodontitis. Among subjects with greater than or equal to 20 teeth present, periodontitis-resistant (n = 46) and periodontitis-susceptible groups (n = 73) were selected based on the percentage of sites with greater than or equal to 4 nim probing attachment loss in the entire dentition. The Fc gamma RIIIb-NA1 allotype was overrepresented in the periodontitis-resistant group, compared with the periodontitis-susceptible group (chi (2) = 4.89, p = 0.03, odds ratio = 1.87, 95% CI, 1.07 to 3.28). This suggests that Fc gamma RIIIb-NA1 may be associated with resistance to periodontitis.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Genetic polymorphisms of immunoglobulin G (IBG) Fc receptors (Fc gammaR) were recently shown to be associated with recurrence rates of adult periodontitis (AP). The purpose of this study was to evaluate whether Fc gammaR polymorphisms are also associated with generalized early-onset periodontitis (G-EOP) in Japanese patients.
Methods: Thirty-eight Japanese patients with G-EOP and 83 Japanese patients with AP were identified according to established clinical criteria, including measurements of probing depth, clinical attachment level, and alveolar bone level. Fc gammaR genotypes for 3 bi-allelic polymorphisms were determined in these G-EOP and AP patients and 104 race-matched healthy controls by means of allele-specific polymerase chain reactions.
Results: There was a significant difference in the distribution of Fc gamma RIIIb genotypes between G-EOP patients and healthy controls (P = 0.02), Additionally, a significant over-representation of Fc gamma RIIIb-NA2 allele was observed in G-EOP patients as compared to AP patients and controls (P = 0.02, P = 0.009, respectively). Moreover, we found a strong association between G-EOP and the composite genotype comprising Fc gamma RIIIb-NA2 and Fc gamma RIIIa-158F (G-EOP versus controls: odds ratio 2.4, 95% CI 1.0-6.0, chi (2) = 4.13, P = 0.04).
Conclusions: This study indicates that the Fc gamma RIIIb-NA2 allele and possibly Fc gamma RIIIa-158F could be associated with susceptibility to G-EOP in Japanese patients.

DOI： 10.1902/jop.2000.71.9.1425

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Leukocyte IgG receptors (FcγR) are important immune-response modulating molecules. FcγRIIIa is expressed on macrophages, NK-cells and γδ-T cells and exhibits a genetically determined, functional polymorphism at nucleotide 559. This allelic difference predicts either a phenylalanine (F158) or valine (V158) at amino acid 158 in the membrane-proximal extracellular domain, and has been shown to be associated with autoimmune and infectious diseases. Published methods to determine FcγRIIIa genotypes are cumbersome. Therefore, we developed a novel, rapid and reliable PCR-based method to determine FcγRIIIa genotypes. Comparison of genotyping results with direct FcγRIIIa sequencing of 60 blood donors showed 100% accuracy of this new method. Since genotype frequencies of FcγR polymorphisms depend strongly on race and ethnicity, we compared FcγRIIIa genotype frequencies of 176 Caucasian Dutch and 104 Japanese blood donors. Interestingly, these frequencies were not significantly different (P&gt
0.1), in contrast to the FcγRIIa and FcγRIIIb genotype frequencies (P&lt
0.001). (C) 2000 Elsevier Science B.V.

DOI： 10.1016/S0022-1759(00)00240-4

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Polymorphonuclear neutrophils (PMNs) are essential in host defense against periodontopathic bacteria such as Porphyromonas gingivalis. The uptake of immunoglobulin G (IgG)-opsonized bacteria via IgG Fc receptors (Fc gamma R) on PMN constitutes a central defense mechanism in periodontium. Fc gamma RIIIb is the most abundantly expressed Fc gamma R on PMN and is functionally polymorphic. The Fc gamma RIIIb-NA1 and IIIb-NA2 allotypes interact differently with IgG1- and IgG3-opsonized particles. We recently showed recurrence rates of adult periodontitis (AP) to be higher in patients carrying at least 1 Fc gamma RIIIb-NA2 allele. In this study we evaluated the functional relevance of the Fc gamma RIIIb polymorphism to anti-P. gingivalis PMN effector functions. Our results showed Fc gamma RIIIb-NA2-carrying PMN from both patients with AP and healthy controls to be less efficient in phagocytosis and induction of oxidative burst upon interaction with IgG1- and IgG3-opsonized P. gingivalis. These functional differences between Fc gamma RIIIb-NA1 and IIIb-NA2 were observed in the presence of CD32-blocking antibody fragments, but not upon blocking CD16. Moreover, PMNs from AP patients exhibited increased Fc gamma RIIIb-allelic differences in IgG3-induced oxidative burst compared to control PMNs. These results support the concept that Fc gamma RIIIb heterogeneity may influence the clinical course of AP.

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The immunoglobulin receptor Fc gamma RIIIa (CD16) is distributed on natural killer (NK) cells, macrophages, and gamma delta T cells, and is polymorphic. Fc gamma RIIIa-158V has a higher affinity for both monomeric and immune complexed IgG1, IgG3, and IgG4 than IIIa-158F. We determined Fc gamma RIIIa-158V/F genotypes of Japanese patients with adult periodontitis. A significant over-representation of Fc gamma RIIIa-158F was found in patients with recurrence, compared with patients without recurrence, making Fc gamma RIIIA a candidate gene for recurrence risk of adult periodontitis.

DOI： 10.1046/j.1365-2249.1999.00984.x

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Polymorphonuclear neutrophil (PMN) phagocytic function has been shown to be impaired in some patients with periodontitis. PMN constitutively express members of two immunoglobulin G receptor (Fc gamma R) classes: Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16), Both receptors exhibit genetically determined structural and functional biallelic polymorphisms, which have been shown to influence PMN phagocytic function, In this study, we assessed the relevance of these Fc gamma R polymorphisms to susceptibility to adult periodontitis and recurrence rate, The distribution of Fc gamma RIIa and Fc gamma RIIIb genotypes of 100 Japanese patients with adult periodontitis during follow-up was compared to the distribution of genotypes in 105 race-matched healthy controls, No significant skewing of distributions of Fc gamma RIIa and Fc gamma RIIIb genotypes was observed between patients and controls, Notably, however, a significant overrepresentation of the Fc gamma RIIIb-NA2 allotype was found in patients with disease recurrence (P &lt; 0.05; odds ratio, 4.29; 95% confidence interval, 1.19 to 16.24), Moreover, the annual rate of recurrence was significantly higher in patients with the Fc gamma RIIIb-NA2/NA2 and Fc gamma RIIIb-NA1/NA2 genotypes than in Fc gamma RIIIb-NA1/NA1 individuals (P &lt; 0.05), Fc gamma RIla-R/R131 individuals also exhibited higher recurrence rates, though the difference was not statistically significant (P = 0.06), These results suggest that the Fc gamma RIIIb-NA2 allotype represents a risk factor for recurrence of adult periodontitis.

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Immunoglobulin G type II and III receptors (Fc gamma RII and Fc gamma RIII) are essential for polymorphonuclear leukocytic (PMNs) phagocytosis. Our previous study demonstrated a downregulation of Fc gamma RIII on PMNs in gingival crevicular fluid (GCF). To determine whether this receptor downregulation may contribute to the periodontal host defence borne by PMNs, we examined the correlation between Fc gamma RII and Fc gamma RIII expressions and the phagocytic capacity of GCF-PMNs. In order to verify at which level of cellular events the loss of Fc gamma R occurs, we quantified mRNA levels to assess a de novo synthesis of these receptors. GCF was collected from 21 patients with adult periodontitis by gingival crevicular washing. Autologous peripheral blood (PB) PMNs served as control. Surface expressions of Fc gamma Rs and phagocytic capacity via Fc gamma Rs were analysed by flow cytometry. The difference in Fc gamma R mRNA levels between GCF- and PB-PMNs was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The amplified products were visualized by agarose gel electrophoresis and the endproduct yields were quantified by computerized image-analysis. Both Fc gamma RII and Fc gamma RIII expressions and phagocytic capacity on GCF-PMNs were significantly lower than those on PB-PMNs (p&lt;0.001). The downregulation of Fc gamma Rs on GCF-PMNs significantly correlated with the phagocytic capacity (r = 0.66 for Fc gamma RIII, p &lt; 0.01; r = 0.50 for Fc gamma RII, p &lt; 0.05). The mRNA level of Fc gamma RIII of GCF-PMNs was significantly lower than that of PB-PMNs (p &lt; 0.05). Thus, GCF-PMNs are characterized by the decreased surface expressions and mRNA levels of Fc gamma Rs, and the impaired phagocytosis.

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Authorship：Lead author   Language：Japanese   Publisher：Niigata University  

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We examined the phagocytic capacity and receptor expression on neutrophils stimulated with Porphyromonas gingivalis soluble products. Stimulated neutrophils had decreased phagocytic capacities and altered expression of CR1, CR3, FcgammaRII, and FcgammaRIII. For cases in which TLCK (N-alpha-p-tosyl-L-lysine chloromethyl ketone) neutralized the effects of the stimuli, the P. gingivalis-derived factors causing the phenomena seem to be trypsin-like proteases.

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DOI： 10.1111/j.1365-2591.1990.tb00847.x

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Differential gene expression was investigated in neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine using RNA fingerprinting by arbitrarily primed polymerase chain reaction (RAP-PCR). The cells were isolated from 3 groups of subjects: patients with generalized aggressive periodontitis (Aggressive-P, n = 6), generalized chronic periodontitis (Chronic-P. n = 6) and healthy controls (H, n = 8). Our results show that 37 genes were upregulated, while 27 genes were down-regulated in all Aggressive-P neutrophils by using RAP-PCR with 45 primer pairs. Reverse transcription-PCR analyses revealed that mRNA levels were significantly different (p &lt
0.05) lor heat shock transcription factor 4b (HSF4b) gene, Kruppel-like zinc finger transcription factor 9 (Zf9) and muskelin genes. HSF4b was greater in neutrophils from Aggressive-P compared to groups H and Chronic-P. Zf9 and muskelin genes were lower in Aggressive-P compared to the H groups, but no significant difference was noted compared to the Chronic-P group. The control genes, IL-1β and VEGF genes, were expressed at a significantly higher level in Aggressive-P and Chronic-P than H (p &lt
0.01, p &lt
0.05). In conclusion, the RAP-PCR technique used in this study enabled us to identify 3 Aggressive-P related genes, which had not been reported previously. Neutrophil functions in Aggressive-P patients are suggested to be altered by regulatory factors of the immune system including HSF4b (transcription factor), Zf9 (activator of TGF-β) and muskelin (cellular adhesion).

DOI： 10.1034/j.1600-0765.2001.360607.x

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