Kouji Yamamoto

The Fcγ Receptor Genotype as a Risk Factor for Generalized Early-Onset Periodontitis in Japanese Patients

BACKGROUND Genetic polymorphisms of immunoglobulin G (IgG) Fc receptors (FcγR) were recently shown to be associated with recurrence rates of adult periodontitis (AP). The purpose of this study was to evaluate whether FcγR 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. FcγR 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 FcγRIIIb genotypes between G-EOP patients and healthy controls (P = 0.02). Additionally, a significant over-representation of FcγRIIIb-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 GEOP and the composite genotype comprising FcγRIIIb-NA2 and FcγRIIIa-158F (G-EOP versus controls: odds ratio 2.4, 95% CI 1.0-6.0, X2 = 4.13, P = 0.04). CONCLUSIONS This study indicates that the FcγRIIIb-NA2 allele and possibly FcγRIIIa-158F could be associated with susceptibility to G-EOP in Japanese patients. J Periodontol 2000;71:1425-1432.

The Fcγ Receptor Genotype as a Severity Factor for Chronic Periodontitis in Japanese Patients

BACKGROUND Functional polymorphisms of immunoglobulin G (IgG) Fc receptors (FcγR) 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 FcγR 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). FcγR genotypes for 3 bi-allelic polymorphisms (FcγRIIa-R/H131, FcγRIIIa-158V/F, FcγRIIIb-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 FcγRIIIa-158V allele in severe CP patients compared to moderate CP patients (odds ratio 2.03, 95% confidence interval [CI] 1.03-4.01, χ 2 = 4.86, P = 0.028). In addition, we found a strong association between CP severity and FcγR composite genotype comprising FcγRIIIa-158V plus FcγRIIIb-NA2 (severe CP versus moderate CP: odds ratio 4.69, 95% CI 1.52-15.10, χ 2 = 9.35, P = 0.002; severe CP versus healthy controls: odds ratio 4.10, 95% CI 1.62-10.59, χ 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 FcγRIIIa-158V allele and possibly FcγRIIIb-NA2 to be associated with severity of CP in Japanese patients. J Periodontol 2001;72:1324-1331.

Analysis of Vitamin D and Fcγ Receptor Polymorphisms in Japanese Patients with Generalized Early-onset Periodontitis

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-Fcγ receptor IIIb (FcγRIIIb-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 FcγRIIIb 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 FcγRIIIb genotypes were determined by allele-specific polymerase chain-reactions. Our results indicated that frequencies of the VDR-B non-carrier and the FcγRIIIb-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-FcγRIIIb 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 FcγRIIIb genotype combination may be associated with susceptibility to G-EOP.

Serum Cytokine and Periodontal Profiles in Relation to Disease Activity of Rheumatoid Arthritis in Japanese Adults

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)-1beta, 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 <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.

Cytokine Gene Polymorphisms Associated With Rheumatoid Arthritis and Periodontitis in Japanese Adults

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-1B +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-1B +3954 genotypes than healthy controls and subjects with periodontitis only.

Increased Frequency of FcγRIIIb-NA1 Allele in Periodontitis-resistant Subjects in an Elderly Japanese Population

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 FcγRIIIb-NA1 displays a more efficient interaction with IgGl- and IgG3-opsonized bacteria, compared with the FcγRIIIb-NA2. We investigated a 70-year-old Japanese population (n = 599) to determine whether the FcγRIIIb polymorphism was associated with resistance to periodontitis. Among subjects with≥ 20 teeth present, periodontitis-resistant (n = 46) and periodontitis-susceptible groups (n = 73) were selected based on the percentage of sites with ≥ 4 mm probing attachment loss in the entire dentition. The FcγRIIIb-NA1 allotype was overrepresented in the periodontitis-resistant group, compared with the periodontitis-susceptible group (χ2 = 4.89, p = 0.03, odds ratio = 1.87, 95% CI, 1.07 to 3.28). This suggests that FcγRIIIb-NA1 may be associated with resistance to periodontitis.

Effective in vitro clearance of Porphyromonas gingivalis by Fcα receptor I (CD89) on gingival crevicular neutrophils

ABSTRACT 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-Fc receptor (FcR) interactions play a role in the effector functions of polymorphonuclear neutrophils (PMN), we evaluated which FcR 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 (FcγR and FcαR, respectively) expression and function by studying IgG- and IgA-mediated elimination of P. gingivalis. GCF PMN exhibited higher FcαRI and FcγRI levels and lower FcγRIIa and FcγRIIIb levels than PB PMN. Functional studies revealed that GCF PMN exhibited less of a capacity to phagocytose and kill IgG1-opsonized P. gingivalisthan 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 FcαRI represents a candidate target for FcR-directed immunotherapy for the clearance of P. gingivalis.

Proteomic profiling of human neutrophils in relation to immunoglobulin G Fc receptor IIIb polymorphism.

BACKGROUND AND OBJECTIVE Neutrophils are essential in host defense against periodontopathic bacteria. Immunoglobulin G Fc receptor IIIb (FcγRIIIb) is a neutrophil-specific receptor for immunoglobulin G and bears the functional NA1-NA2 polymorphism. Accumulating evidence suggests a significant association between FcγRIIIb gene polymorphism and periodontitis. In this study, we employed a proteomic approach to evaluate the relevance of FcγRIIIb polymorphism to protein expression profiles of neutrophils. MATERIAL AND METHODS Neutrophils were collected from ten healthy subjects whose FcγRIIIb genotypes were determined by allele-specific PCRs. Expressions of proteins induced by interaction via FcγRIIIb were examined between the FcγRIIIb genotypes with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins that were significantly different in expression levels between the FcγRIIIb 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 FcγRIIIb-NA1/NA1 and five FcγRIIIb-NA2/NA2 donors. A statistical analysis revealed that the expression levels of five proteins were significantly different between the FcγRIIIb genotypes (p < 0.05). The FcγRIIIb-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 FcγRIIIb-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 FcγRIIIb genotypes.

The FcγRIIa polymorphism influences production of interleukin-1 by mononuclear cells

The functional bi‐allelic polymorphism of immunoglobulin G (IgG) Fc receptor (FcγR) IIa influences the efficiency of human IgG2 binding. Our previous study showed that the high affinity FcγRIIa 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 FcγRIIa‐H/H131cross‐linking could induce an increased IL‐1 release by mononuclear cells. In this study, we evaluated the intracellular expressions of IL‐1β in CD14 positive cells upon stimulation with human IgG2 by flow cytometry. FcγRIIa‐H/H131 subjects exhibited a higher percentage of IL‐1β‐producing cells than FcγRIIa‐R/H131 and ‐R/R131 subjects (P < 0.05). These results support the concept that FcγRIIa genotype may affect IL‐1β production, possibly leading to interindividual differences in periodontitis risk.