Limits...
Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis

View Article: PubMed Central - PubMed

ABSTRACT

Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production.

Methods: A case–control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA.

Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean ± SEM; 152.7 ± 14.8 AU/ml) and in RA patients (114.4 ± 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 ± 0.59 and 9.29 ± 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis.

Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

Electronic supplementary material: The online version of this article (doi:10.1186/s13075-016-1100-4) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Pie charts illustrating the different sub-groups of pre-symptomatic individuals (one sample per individual, n = 251) (a) and RA patients (n = 188) (b), based on the presence/absence of anti-CCP2 and anti-CPP3 antibodies. Data presented as percentage
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5015325&req=5

Fig3: Pie charts illustrating the different sub-groups of pre-symptomatic individuals (one sample per individual, n = 251) (a) and RA patients (n = 188) (b), based on the presence/absence of anti-CCP2 and anti-CPP3 antibodies. Data presented as percentage

Mentions: The accumulated frequency of anti-CPP3 antibody positivity increased constantly over time until symptom onset (Fig. 2b). This pattern mimics that of the “classical” ACPA response (defined as antibodies against CCP2, CEP-1, cFibβ36-52 and cfilaggrin) from the same time points, although at a lower frequency (Fig. 2b). The majority of anti-CPP3 IgG-positive RA patients (11 positive/15 analysed) and also pre-symptomatic individuals (11 positive/17 analysed) were confined to the anti-CCP2-positive subset (Fig. 3a, b, and Additional file 1: Table S1). In pre-symptomatic individuals, anti-CPP3 positivity was associated with positivity for anti-cFibβ36-52 antibodies (OR = 3.22; 95 % CI 1.24–8.36, p < 0.05), and anti-CPP3 antibody levels correlated with the concentrations of both anti-CCP2 (rs = 0.14, p < 0.01) and anti-CEP-1 antibodies (rs = 0.11, p < 0.05). The median pre-dating time for anti-CPP3 antibody positivity was closer to onset (−3.42 years) compared with anti-CCP2 (−4.56 years), anti-cFibβ36-52 (−5.17 years) and anti-CEP-1 (−3.49 years) antibody positivity. There was also a significant correlation between anti-RgpB IgG levels and anti-CEP-1 antibodies (rs = 0.10, p < 0.05) in pre-symptomatic individuals (data not shown). No significant relationships were found between anti-RgpB or anti-CPP3 antibodies, respectively, and RF in the pre-symptomatic individuals or in RA patients (data not shown).Fig. 3


Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis
Pie charts illustrating the different sub-groups of pre-symptomatic individuals (one sample per individual, n = 251) (a) and RA patients (n = 188) (b), based on the presence/absence of anti-CCP2 and anti-CPP3 antibodies. Data presented as percentage
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015325&req=5

Fig3: Pie charts illustrating the different sub-groups of pre-symptomatic individuals (one sample per individual, n = 251) (a) and RA patients (n = 188) (b), based on the presence/absence of anti-CCP2 and anti-CPP3 antibodies. Data presented as percentage
Mentions: The accumulated frequency of anti-CPP3 antibody positivity increased constantly over time until symptom onset (Fig. 2b). This pattern mimics that of the “classical” ACPA response (defined as antibodies against CCP2, CEP-1, cFibβ36-52 and cfilaggrin) from the same time points, although at a lower frequency (Fig. 2b). The majority of anti-CPP3 IgG-positive RA patients (11 positive/15 analysed) and also pre-symptomatic individuals (11 positive/17 analysed) were confined to the anti-CCP2-positive subset (Fig. 3a, b, and Additional file 1: Table S1). In pre-symptomatic individuals, anti-CPP3 positivity was associated with positivity for anti-cFibβ36-52 antibodies (OR = 3.22; 95 % CI 1.24–8.36, p < 0.05), and anti-CPP3 antibody levels correlated with the concentrations of both anti-CCP2 (rs = 0.14, p < 0.01) and anti-CEP-1 antibodies (rs = 0.11, p < 0.05). The median pre-dating time for anti-CPP3 antibody positivity was closer to onset (−3.42 years) compared with anti-CCP2 (−4.56 years), anti-cFibβ36-52 (−5.17 years) and anti-CEP-1 (−3.49 years) antibody positivity. There was also a significant correlation between anti-RgpB IgG levels and anti-CEP-1 antibodies (rs = 0.10, p < 0.05) in pre-symptomatic individuals (data not shown). No significant relationships were found between anti-RgpB or anti-CPP3 antibodies, respectively, and RF in the pre-symptomatic individuals or in RA patients (data not shown).Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Background: The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production.

Methods: A case&ndash;control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n&thinsp;=&thinsp;422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA.

Results: Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean&thinsp;&plusmn;&thinsp;SEM; 152.7&thinsp;&plusmn;&thinsp;14.8&nbsp;AU/ml) and in RA patients (114.4&thinsp;&plusmn;&thinsp;16.9&nbsp;AU/ml), compared with controls (p&thinsp;&lt;&thinsp;0.001). Anti-CPP3 antibodies were detected in 5&nbsp;% of pre-symptomatic individuals and in 8&nbsp;% of RA patients, with elevated levels in both subsets (4.33&thinsp;&plusmn;&thinsp;0.59 and 9.29&thinsp;&plusmn;&thinsp;1.81&nbsp;AU/ml, respectively) compared with controls (p&thinsp;&lt;&thinsp;0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis.

Conclusions: Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

Electronic supplementary material: The online version of this article (doi:10.1186/s13075-016-1100-4) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus