| 1. |
- Engström, Marianne, et al.
(author)
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Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis
- 2018
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In: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 16
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Journal article (peer-reviewed)abstract
- BACKGROUND: A relationship between rheumatoid arthritis (RA) and periodontitis has been suggested from findings that individuals with RA are prone to have advanced periodontitis and vice versa. In search of possible common pathogenetic features of these two diseases, we investigated the presence of citrullinated proteins and expression of endogenous peptidylarginine deiminases (PAD2 and PAD4), in periodontal tissue of individuals with periodontitis and healthy controls, in relation to the periodontal pathogens Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), producing leukotoxin as virulence factor. These two oral bacteria have been suggested to be linked to anti-citrullinated protein antibodies in patients with RA.METHODS: Gingival tissue biopsies were obtained from 15 patients with periodontitis and 15 individuals without periodontal disease. Presence of CD3-positive lymphocytes, citrullinated proteins, PAD2, PAD4, P. gingivalis as well as A. actinomycetemcomitans and Mannheimia haemolytica produced leukotoxins were analysed by immunohistochemistry, followed by triple-blind semi-quantitative analysis. Mann-Whitney and Fisher's exact tests were used to analyse differences between groups. PADI2 and PADI4 mRNA levels were assessed by RT-qPCR and analysed using Wilcoxon signed rank test.RESULTS: Increased staining of citrullinated proteins was observed in gingival connective tissue from subjects with periodontitis (80%, 12/15) compared to healthy gingival tissue (27%, 4/15), whereas no differences were observed in gingival epithelium. There was also an increased staining of the citrullinating enzymes PAD2 and PAD4 in gingival connective tissue of patients with periodontitis whereas similar levels of PAD2 and PAD4 were observed in the gingival epithelium of the two groups. Similarly, the mRNA levels of PADI2 and PADI4 were also increased in the gingival tissue of patients with periodontitis compared to healthy controls. Furthermore, presence of P. gingivalis and leukotoxins was comparable in both epithelium and connective tissue, from the different investigated individuals with and without periodontitis, and there were no correlations between the presence of periodontal pathogens and the expression of citrullinated proteins or PAD enzymes.CONCLUSION: Chronic gingival inflammation is associated with increased local citrullination and PAD2 and PAD4 expression in periodontitis. The increased citrullination and PAD2 and PAD4 expression in periodontitis were, however, independent of the presence of periodontal pathogen P. gingivalis and A. actinomycetemcomitans leukotoxin.
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| 2. |
- Eriksson, Kaja, et al.
(author)
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Periodontal Health and Oral Microbiota in Patients with Rheumatoid Arthritis
- 2019
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In: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 8:5
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Journal article (peer-reviewed)abstract
- This study aimed to investigate the periodontal health of patients with established rheumatoid arthritis (RA) in relation to oral microbiota, systemic and oral inflammatory mediators, and RA disease activity. Forty patients underwent full-mouth dental/periodontal and rheumatological examination, including collection of blood, saliva, gingival crevicular fluid (GCF) and subgingival plaque. Composition of plaque and saliva microbiota were analysed using 16S rRNA sequencing and levels of inflammatory mediators by multiplex-immunoassay. The majority of the patients (75%) had moderate or severe periodontitis and the rest had no/mild periodontitis. Anti-citrullinated protein antibody (ACPA) positivity was significantly more frequent in the moderate/severe periodontitis (86%) compared to the no/mild group (50%). No significance between groups was observed for RA disease duration or activity, or type of medication. Levels of sCD30/TNFRSF8, IFN-2, IL-19, IL-26, MMP-1, gp130/sIL-6R ss, and sTNF-R1 were significantly higher in serum or GCF, and April/TNFSF13 was significantly higher in serum and saliva samples in moderate/severe periodontitis. The microbial composition in plaque also differed significantly between the two groups. In conclusion, the majority of RA patients had moderate/severe periodontitis and that this severe form of the disease was significantly associated with ACPA positivity, an altered subgingival microbial profile, and increased levels of systemic and oral inflammatory mediators.
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| 3. |
- Eriksson, Kaja, et al.
(author)
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Salivary Microbiota and Host-Inflammatory Responses in Periodontitis Affected Individuals With and Without Rheumatoid Arthritis
- 2022
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In: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media SA. - 2235-2988. ; 12
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Journal article (peer-reviewed)abstract
- ObjectivesPeriodontitis and rheumatoid arthritis (RA) are two widespread chronic inflammatory diseases with a previously suggested association. The objective of the current study was to compare the oral microbial composition and host ' s inflammatory mediator profile of saliva samples obtained from subjects with periodontitis, with and without RA, as well as to predict biomarkers, of bacterial pathogens and/or inflammatory mediators, for classification of samples associated with periodontitis and RA. MethodsSalivary samples were obtained from 53 patients with periodontitis and RA and 48 non-RA with chronic periodontitis. The microbial composition was identified using 16S rRNA gene sequencing and compared across periodontitis patients with and without RA. Levels of inflammatory mediators were determined using a multiplex bead assay, compared between the groups and correlated to the microbial profile. The achieved data was analysed using PCoA, DESeq2 and two machine learning algorithms, OPLS-DA and sPLS-DA. ResultsDifferential abundance DESeq2 analyses showed that the four most highly enriched (log2 FC >20) amplicon sequence variants (ASVs) in the non-RA periodontitis group included Alloprevotella sp., Prevotella sp., Haemophilus sp., and Actinomyces sp. whereas Granulicatella sp., Veillonella sp., Megasphaera sp., and Fusobacterium nucleatum were the most highly enriched ASVs (log2 FC >20) in the RA group. OPLS-DA with log2 FC analyses demonstrated that the top ASVs with the highest importance included Vampirovibrio sp. having a positive correlation with non-RA group, and seven ASVs belonging to Sphingomonas insulae, Sphingobium sp., Novosphingobium aromaticivorans, Delftia acidovorans, Aquabacterium spp. and Sphingomonas echinoides with a positive correlation with RA group. Among the detected inflammatory mediators in saliva samples, TWEAK/TNFSF12, IL-35, IFN-alpha 2, pentraxin-3, gp130/sIL6Rb, sIL-6Ra, IL-19 and sTNF-R1 were found to be significantly increased in patients with periodontitis and RA compared to non-RA group with periodontitis. Moreover, correlations between ASVs and inflammatory mediators using sPLS-DA analysis revealed that TWEAK/TNFSF12, pentraxin-3 and IL-19 were positively correlated with the ASVs Sphingobium sp., Acidovorax delafieldii, Novosphingobium sp., and Aquabacterium sp. ConclusionOur results suggest that the combination of microbes and host inflammatory mediators could be more efficient to be used as a predictable biomarker associated with periodontitis and RA, as compared to microbes and inflammatory mediators alone.
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| 4. |
- Eriksson, Kaja
(author)
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Studies on the relationship between periodontitis and rheumatoid arthritis
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Periodontitis and rheumatoid arthritis (RA) are both widespread multifactorial diseases, characterized by chronic inflammation leading to tissue and bone destruction around teeth or joints, respectively. An association between periodontitis and RA has been proposed, suggesting that the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) may be involved in the generation of anti-citrullinated protein antibodies (ACPAs) in RA. Previous findings indicate that patients with RA may have increased prevalence/incidence and severity of periodontitis; however, more studies are needed to confirm this link, elucidate the potential mechanisms involved, and ascertain the temporal relationship between periodontitis and RA. Hence, the general aim of this thesis was to study the relationship between periodontitis and RA using population-based, clinical, immunohistochemical and experimental animal studies. Study I investigated the prevalence of periodontitis with special focus on ACPA status in the Swedish Epidemiological Investigation of RA (EIRA), a well-characterized population-based RA case-control cohort. Linking the EIRA registry with the Dental Health Registry (DHR) demonstrated no differences in the prevalence of periodontal diseases (gingivitis, periodontitis, or peri-implantitis) between RA patients and matched healthy controls. Additionally, among subjects with RA, we detected no differences in prevalence of periodontitis based on ACPA or rheumatoid factor (RF) antibody status. Study II explored the effect of pre-existing periodontitis on the development and the immune/inflammatory response of experimental arthritis in an animal model. Eight weeks prior to induction of pristane-induced arthritis, we induced experimental periodontitis in arthritis-susceptible Dark Agouti rats using ligatures in combination with swabs containing periodontal bacteria. After monitoring the progression and severity of both periodontitis and arthritis for another 7 weeks, we compared the results to animals with experimental arthritis only and to healthy animals without arthritis or periodontitis. We detected increased levels of antibodies against citrullinated P. gingivalis peptidylarginine deiminase (PPAD) proteins in rats with both pre-existing periodontitis and pristane-induced arthritis compared to arthritic animals without pre-existing periodontitis. However, the pre-existence of periodontitis did not affect the development or severity of pristane-induced arthritis in rats. Study III examined the presence of citrullinated proteins and the expression of human peptidylarginine deiminase (PAD2 and PAD4) enzymes in relation to the presence of P. gingivalis in gingival tissue biopsies from patients with periodontitis and healthy controls. In gingival connective tissue, we detected citrullinated proteins in 80% of the subjects with periodontitis compared to in 25% of healthy controls. Analysis of the sections also showed increased expression of PAD2 and PAD4 in the gingival connective tissue of patients with periodontitis. We found no differences in the presence of P. gingivalis in the epithelium or connective tissue of gingival biopsies from patients with periodontitis and healthy controls without periodontitis. Moreover, we observed no correlations between the presence of P. gingivalis and citrullinated proteins or citrullinating enzymes in gingival tissue from patients with periodontitis and healthy controls. Study IV was a clinical study that further explored the association between RA and the severity of periodontitis. This pilot study aimed to investigate the severity of periodontitis in relation to ACPA/RF status, immunological parameters associated with RA, and the presence of subgingival P. gingivalis DNA in patients with established RA. The findings showed that the majority of patients with RA had moderate/severe periodontitis (75%), while the others had no/mild periodontal disease. ACPA positivity was significantly more common in RA subjects with moderate/severe periodontitis compared to those with no/mild periodontal disease. We detected no differences in the presence of P. gingivalis in subgingival plaque samples based on periodontitis severity or ACPA status. Nor did we detect any between-group differences in RA disease duration or disease activity or type of RA treatment/medication. Cytokine profiling of serum, saliva, and gingival crevicular fluid samples showed that the levels of several inflammatory mediators were up-regulated in patients with moderate/severe periodontitis. Interestingly, the levels of a proliferation-inducing ligand (APRIL), implicated in B-cell survival and maturation, were significantly higher in both serum and saliva samples of patients with moderate/severe periodontitis compared to those with no/mild periodontal disease. In conclusion, we found no evidence of an increased prevalence of periodontitis in patients with established RA relative to healthy controls, in the large population-based registry study. However, the clinical study showed that the more severe forms of periodontitis, defined as moderate/severe periodontitis, were frequent in subjects with established RA, and associated with ACPA positivity. Our findings also demonstrate that the presence of citrullinated proteins and expression of human citrullinating PAD enzymes are increased in gingival tissue of non-RA subjects with chronic periodontitis, and that the pre-existence of periodontitis can induce a systemic antibody response against citrullinated proteins derived from P. gingivalis PAD enzyme in animals with experimental arthritis. Taken together, the results indicate that periodontal infection could possibly contribute to the autoimmunity against citrullinated proteins associated with RA. Since ACPA status may be associated with periodontitis severity, future studies on the association between periodontitis and RA should focus on investigating the potential beneficial effects of periodontal treatment in patients with RA. Moreover, additional research into predisposing risk factors and molecular mechanisms connecting periodontitis with RA are also warranted.
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| 5. |
- Lundmark, Anna, et al.
(author)
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Mucin 4 and matrix metalloproteinase 7 as novel salivary biomarkers for periodontitis
- 2017
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In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 44:3, s. 247-254
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Journal article (peer-reviewed)abstract
- Aim: Periodontitis is a chronic inflammatory disease, characterized by irreversible destruction of tooth-supporting tissue including alveolar bone. We recently reported mucin 4 ( MUC4) and matrix metalloproteinase 7 (MMP7) as highly associated with periodontitis in gingival tissue biopsies. The aim of this study was to further investigate the levels of MUC4 and MMP7 in saliva and gingival crevicular fluid (GCF) samples of patients with periodontitis. Materials and Methods: Saliva and GCF samples were collected from periodontitis patients and healthy controls. The levels of MUC4, MMP7, and total protein concentrations were analysed using ELISA or Bradford assay. Results: MUC4 levels were significantly lower in saliva and GCF from periodontitis patients relative to healthy controls. MMP7 levels were significantly higher in saliva and GCF from periodontitis patients. Multivariate analysis revealed that MUC4 was significantly associated with periodontitis after adjusting for age and smoking habits and, moreover, that the combination of MUC4 and MMP7 accurately discriminated periodontitis from healthy controls. Conclusions: MUC4 and MMP7 may be utilized as possible novel biomarkers for periodontitis.
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| 6. |
- Sherina, Natalia, et al.
(author)
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Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells : Implications for a Bacterial Origin in RA Etiology
- 2022
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.
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