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

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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.


Antibody responses during the pre-dating time until the time point for onset of symptoms of RA, from pre-symptomatic individuals who donated multiple blood samples pre-dating the onset of symptoms of RA (n = 422) and from patients with RA (n = 192). Logarithmic mean concentrations during 2-year periods of anti-RgpB and anti-CPP3 antibodies in pre-symptomatic individuals, patients with RA and controls (n = 198) (a). Accumulated percentages of antibody positivity for anti-CPP3, anti-CCP2, anti-cfibrinogenβ36-52 (cFibβ36-52), anti-CEP-1 (α-enolase) and anti-cfilaggrin (cFilaggrin) antibodies in pre-symptomatic individuals and in patients with RA (b). 0 time point for onset of RA symptoms
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Fig2: Antibody responses during the pre-dating time until the time point for onset of symptoms of RA, from pre-symptomatic individuals who donated multiple blood samples pre-dating the onset of symptoms of RA (n = 422) and from patients with RA (n = 192). Logarithmic mean concentrations during 2-year periods of anti-RgpB and anti-CPP3 antibodies in pre-symptomatic individuals, patients with RA and controls (n = 198) (a). Accumulated percentages of antibody positivity for anti-CPP3, anti-CCP2, anti-cfibrinogenβ36-52 (cFibβ36-52), anti-CEP-1 (α-enolase) and anti-cfilaggrin (cFilaggrin) antibodies in pre-symptomatic individuals and in patients with RA (b). 0 time point for onset of RA symptoms

Mentions: Anti-RgpB IgG levels increased over time until symptom onset of RA, with a significant increase observed when analysing individuals with four consecutive pre-dating samples (p < 0.05; data not shown). There was a trend towards lower levels following diagnosis of RA (p < 0.088) (Fig. 2a). Similar to the anti-RgpB IgG response, the levels of anti-CPP3 IgG were found to increase constantly over the pre-dating time (Fig. 2a). However, no relationship was found between anti-CPP3 antibody positivity and the levels of anti-RgpB IgG (data not shown). The mean concentration of anti-RgpB antibodies in pre-symptomatic individuals (n = 64) exceeded that of the controls already 12 years before symptom onset, whilst the corresponding time for anti-CPP3 (n = 126) was 8 years before symptom onset. However, anti-CPP3 antibody concentrations above the mean value of the controls were detected in 11 out of 64 (17.2 %) pre-symptomatic individuals more than 10 years before symptom onset. A significantly higher number of pre-symptomatic individuals (26/64, i.e. 40.6 %) had a concentration of anti-RgpB antibodies above the mean value of controls at this time point (p < 0.001).Fig. 2


Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis
Antibody responses during the pre-dating time until the time point for onset of symptoms of RA, from pre-symptomatic individuals who donated multiple blood samples pre-dating the onset of symptoms of RA (n = 422) and from patients with RA (n = 192). Logarithmic mean concentrations during 2-year periods of anti-RgpB and anti-CPP3 antibodies in pre-symptomatic individuals, patients with RA and controls (n = 198) (a). Accumulated percentages of antibody positivity for anti-CPP3, anti-CCP2, anti-cfibrinogenβ36-52 (cFibβ36-52), anti-CEP-1 (α-enolase) and anti-cfilaggrin (cFilaggrin) antibodies in pre-symptomatic individuals and in patients with RA (b). 0 time point for onset of RA symptoms
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Antibody responses during the pre-dating time until the time point for onset of symptoms of RA, from pre-symptomatic individuals who donated multiple blood samples pre-dating the onset of symptoms of RA (n = 422) and from patients with RA (n = 192). Logarithmic mean concentrations during 2-year periods of anti-RgpB and anti-CPP3 antibodies in pre-symptomatic individuals, patients with RA and controls (n = 198) (a). Accumulated percentages of antibody positivity for anti-CPP3, anti-CCP2, anti-cfibrinogenβ36-52 (cFibβ36-52), anti-CEP-1 (α-enolase) and anti-cfilaggrin (cFilaggrin) antibodies in pre-symptomatic individuals and in patients with RA (b). 0 time point for onset of RA symptoms
Mentions: Anti-RgpB IgG levels increased over time until symptom onset of RA, with a significant increase observed when analysing individuals with four consecutive pre-dating samples (p < 0.05; data not shown). There was a trend towards lower levels following diagnosis of RA (p < 0.088) (Fig. 2a). Similar to the anti-RgpB IgG response, the levels of anti-CPP3 IgG were found to increase constantly over the pre-dating time (Fig. 2a). However, no relationship was found between anti-CPP3 antibody positivity and the levels of anti-RgpB IgG (data not shown). The mean concentration of anti-RgpB antibodies in pre-symptomatic individuals (n = 64) exceeded that of the controls already 12 years before symptom onset, whilst the corresponding time for anti-CPP3 (n = 126) was 8 years before symptom onset. However, anti-CPP3 antibody concentrations above the mean value of the controls were detected in 11 out of 64 (17.2 %) pre-symptomatic individuals more than 10 years before symptom onset. A significantly higher number of pre-symptomatic individuals (26/64, i.e. 40.6 %) had a concentration of anti-RgpB antibodies above the mean value of controls at this time point (p < 0.001).Fig. 2

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.