The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis?

2013 ◽  
Vol 73 (3) ◽  
pp. 580-586 ◽  
Author(s):  
Paola de Pablo ◽  
Thomas Dietrich ◽  
Iain L C Chapple ◽  
Michael Milward ◽  
Muslima Chowdhury ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Negative Control ◽  
Autoimmune Response ◽  
Serum Samples ◽  
Autoantibody Response ◽  
Normal Frequency ◽  
Citrullinated Proteins ◽  
Citrullinated Vimentin ◽  
Loss Of Tolerance ◽  
Citrullinated Peptide

BackgroundStudies suggest that periodontitis may be a risk factor for rheumatoid arthritis (RA). The purpose of this study was to determine whether periodontitis is associated with autoantibodies characteristic of RA.MethodsSerum samples were tested for anti-cyclic citrullinated peptide (CCP), anti-mutated citrullinated vimentin (MCV), anti-citrullinated α-enolase peptide-1 (CEP-1), anti-citrullinated vimentin (cit-vim), anti-citrullinated fibrinogen (cit-fib) and their uncitrullinated forms anti-CParg (negative control for anti-CCP), anti-arginine-containing α-enolase peptide-1 (REP-1), anti-vimentin and anti-fibrinogen antibodies in patients with and without periodontitis, none of whom had RA.ResultsPeriodontitis, compared with non-periodontitis, was associated with a normal frequency of anti-CCP and anti-MCV (∼1%) but a higher frequency of positive anti-CEP-1 (12% vs 3%; p=0.02) and its uncitrullinated form anti-REP-1 (16% vs 2%; p<0.001). Positive antibodies against uncitrullinated fibrinogen and CParg were also more common among those with periodontitis compared to non-periodontitis patients (26% vs 3%; p<0.001, and 9% vs 3%; p=0.06). After adjusting for confounders, patients with periodontitis had 43% (p=0.03), 71% (p=0.002) and 114% (p<0.001) higher anti-CEP-1, anti-REP-1 and anti-fibrinogen titres, compared with non-periodontitis. Non-smokers with periodontitis, compared with non-periodontitis, had significantly higher titres of anti-CEP-1 (103%, p<0.001), anti-REP-1 (91%, p=0.001), anti-vimentin (87%, p=0.002), and anti-fibrinogen (124%, p<0.001), independent of confounders, confirming that the autoantibody response in periodontitis was not due to smoking.ConclusionsWe have shown that the antibody response in periodontitis is predominantly directed to the uncitrullinated peptides of the RA autoantigens examined in this study. We propose that this loss of tolerance could then lead to epitope spreading to citrullinated epitopes as the autoimmune response in periodontitis evolves into that of presymptomatic RA.

scholarly journals POS0465 DIFFERENT CLINICAL RELEVANCE OF ANTI-CITRULLINATED PROTEINS ANTIBODIES IN RA PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 464-464
Author(s):  
A. Avdeeva ◽  
M. Cherkasova ◽  
E. Nasonov
Keyword(s):  
Disease Duration ◽  
Bone Destruction ◽  
Positive Correlation ◽  
Early Ra ◽  
Das 28 ◽  
Conventional Dmards ◽  
Citrullinated Proteins ◽  
Citrullinated Vimentin ◽  
Citrullinated Peptide ◽  
Treatment Table

Background:Anti-citrullinated proteins antibodies (ACPA) are a broad group of antibodies, including antibodies to citrullinated fibrinogen, antibodies to cyclic citrullinated peptide (anti-CCP), antibodies to modified citrullinated vimentin (anti-MCV), antibodies to citrullinated α-enolase.Objectives:To find a potential relationship between ACPA and disease activity, bone destruction, and ACPAs responses to various therapeutic regimens.Methods:The study included 232 patients (pts) with rheumatoid arthritis (RA); 90 pts (74 women, Me;IQR age 53.0 (38.0–58.5) years had early RA, with mean disease duration 5.0 (4.0–9.0) months, DAS 28 5.3 (4.4–6.1)); 142 pts had advanced stage of the disease (123 women, median age 51.0 (43.0–60.0) years, disease duration 56.0 (24.0–96.0) months, DAS 28 6.2 (5.5–6.8)). Pts with early RA received methotrexate (MTX) subcutaneously at average 17.5 mg dose once weekly. Pts with advanced RA received the following anti-B-cell therapy: 34 pts - rituximab (RTX); 20 pts - RTX biosimilar; 43 pts - tocilizumab (TCZ) in combination with conventional DMARDs. Serum anti-CCP and anti-MCV concentrations were measured using ELISA.Results:77 (85.6%) pts with early RA were high positive for anti-CCP, and 29 (70.7%) pts - high positive for anti-MCV. A positive correlation was found between anti-MCV and DAS 28 (r=0.4, p=0.04). As for advanced RA, 78 (80.4%) pts were high positive for anti-CCP, and 70 (79.5%) - for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r=0.4, p=0.02), as well as CDAI (r=0.4, p=0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0-122.0)) were found in pts high positive for anti-MCV (n=79), compared to low-positive/negative (57.0 (31.0–88.0), respectively, (n=27, p<0.05). anti-MCV levels dropped significantly in pts on RTX and TCZ therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment (Table 1)Conclusion:anti-MCV levels correlated with inflammatory activity and development of bone destruction, and were decreasing in pts on treatment. Anti-CCP was less responsive, showed minor changes during treatment, therefore its’ thorough monitoring was not feasible.Disclosure of Interests:None declared

scholarly journals Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins

2010 ◽  
Vol 12 (4) ◽  
pp. R132 ◽  
Author(s):  
Katleen Van Steendam ◽  
Kelly Tilleman ◽  
Marlies De Ceuleneer ◽  
Filip De Keyser ◽  
Dirk Elewaut ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Immune Complexes ◽  
Citrullinated Proteins ◽  
Citrullinated Vimentin

Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis

2016 ◽  
Vol 75 (11) ◽  
pp. 2022-2028 ◽  
Author(s):  
Maximilian F Konig ◽  
Jon T Giles ◽  
Peter A Nigrovic ◽  
Felipe Andrade
Keyword(s):  
Rheumatoid Arthritis ◽  
Splice Variants ◽  
Humoral Response ◽  
Native Protein ◽  
Erosive Disease ◽  
Rapid Disease Progression ◽  
Citrullinated Proteins ◽  
Loss Of Tolerance ◽  
Disease Initiation ◽  
Major Target

BackgroundAnti-citrullinated protein antibodies (ACPAs) are the hallmark of rheumatoid arthritis (RA). Protein citrullination is believed to drive autoantigen selection in RA. Nonetheless, several autoantigens in RA are targeted as native (unmodified) proteins. Here, the study of hnRNP A2/B1 (RA33) provides a framework to understand the humoral response to native and citrullinated autoantigens in RA.MethodsRA synovial fluid (SF) cells were analysed by immunoblotting and mass spectrometry. RA33 was cloned from RASF cells and splice variants expressed as recombinant proteins. Antibodies against native and citrullinated RA33 were characterised by ELISA, immunoblotting and immunoprecipitation.ResultsRA33 is citrullinated in the rheumatoid joint and targeted either as a citrullinated or native protein in distinct patient subsets with RA. A novel splice variant (hnRNP B1b) previously associated with disease initiation in experimental arthritis was identified in the RA joint and acts as the major target of the anti-RA33 response. Antibodies exclusively targeting citrullinated RA33 were positively associated with disease duration and erosive disease. In contrast, anti-(native) RA33 antibodies were detected almost exclusively in early RA and identified patients with low radiographic erosion scores. Finally, a unique subset of double-reactive patients demonstrated intermediate severity, but rapid disease progression, suggesting a transitional disease phase in the evolution of an anti-native protein antibody to ACPA response in RA.ConclusionsThese data suggest that native and citrullinated proteins targeted by autoantibodies in RA may be part of a single antibody system and challenge the paradigm of citrullination as the unifying principle underlying loss of tolerance in RA.

scholarly journals Association of anti–cyclic citrullinated peptide and anti-Sa/citrullinated vimentin autoantibodies in rheumatoid arthritis

2006 ◽  
Vol 55 (4) ◽  
pp. 657-661 ◽  
Author(s):  
Margarita Rodríguez-Mahou ◽  
Francisco Javier López-Longo ◽  
Silvia Sánchez-Ramón ◽  
Ana Estecha ◽  
Aurea García-Segovia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cyclic Citrullinated Peptide ◽  
Citrullinated Vimentin ◽  
Citrullinated Peptide

scholarly journals Antihomocitrullinated Fibrinogen Antibodies are Specific to Rheumatoid Arthritis and Frequently Bind Citrullinated Proteins/peptides

2014 ◽  
Vol 41 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Mathias Scinocca ◽  
David A. Bell ◽  
Maud Racapé ◽  
Radha Joseph ◽  
Gary Shaw ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mass Spectrometry ◽  
Computer Modeling ◽  
Lupus Erythematosus ◽  
Shared Epitope ◽  
Affinity Purification ◽  
Peptide Antibody ◽  
Citrullinated Proteins ◽  
Peptide Interaction ◽  
Citrullinated Peptide

Objective.Anticitrullinated protein/peptide antibodies (ACPA) are implicated in rheumatoid arthritis (RA) pathogenesis and linked to the shared epitope (SE). Citrulline modification is very similar to a different modified amino acid, homocitrulline. We investigated antihomocitrullinated protein/ peptide antibody (AHCPA) specificity for RA, whether ACPA were also able to bind homocitrullinated targets, and whether the SE could accommodate homocitrullinated peptide.Methods.Homocitrullinated fibrinogen was used to screen sera from patients with RA, psoriatic arthritis, and systemic lupus erythematosus, and healthy subjects for AHCPA using ELISA. Homocitrullination sites on fibrinogen were identified by mass spectrometry. ACPA were affinity-purified using a synthetic citrullinated peptide and tested for binding to homocitrullinated protein/peptide. Inhibition of antihomocitrullinated fibrinogen antibody binding was examined. Homocitrullinated peptide interaction with the SE was studied using computer modeling.Results.IgG antihomocitrullinated fibrinogen antibodies were found specifically in 49% of patients with RA. Enrichment of ACPA by affinity purification from 5 patients with RA also enriched AHCPA. Serum AHCPA was inhibited by citrullinated fibrinogen and more significantly by homocitrullinated fibrinogen. Computer modeling indicated that the SE could accommodate a homocitrullinated peptide without steric hindrance. Mass spectrometry identified that 89/103 lysines of fibrinogen could be homocitrullinated, and 5 peptides that could be both citrullinated and homocitrullinated and are predicted to bind the SE.Conclusion.Antihomocitrullinated fibrinogen antibodies are specific to RA. The presence of AHCPA coincides with ACPA, and AHCPA copurifies with ACPA in affinity purification and is inhibited by citrullinated and homocitrullinated antigens. Thus AHCPA and ACPA are frequently cross-reactive and homocitrullinated proteins/peptides may bind the SE.

scholarly journals Evaluation of Anti-Mutated Citrullinated Vimentin Antibodies, Anti-Cyclic Citrullinated Peptide Antibodies and Rheumatoid Factor in Omani Patients with Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Ahmed Al-Shukaili ◽  
Saif Al-Ghafri ◽  
Safia Al-Marhoobi ◽  
Juma Alkaabi
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Factor ◽  
Predictive Test ◽  
Diagnostic Specificity ◽  
Term Study ◽  
Cyclic Citrullinated Peptide ◽  
Long Term Study ◽  
Citrullinated Vimentin ◽  
Citrullinated Peptide

Rheumatoid factor (RF) is currently used in the diagnosis of rheumatoid arthritis (RA). The discovery of anticitrullinated protein autoantibodies has led to the development of various new tests, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies, and anti-mutated citrullinated vimentin (anti-MCV) antibodies, to diagnose RA. The aims of this study were to determine the sensitivity and specificity of anti-MCV antibodies in comparison with anti-CCP antibodies and RF in Omani Arab patients with RA and compare our findings with published values from different ethnic groups. The sensitivity of anti-MCV antibodies was 72% with 87% specificity. For anti-CCP antibodies the sensitivity was 52% and the specificity was 97%. The sensitivity of RF was 57% with 94% specificity. Anti-CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti-MCV antibodies. Anti-MCV antibodies have the highest sensitivity when compared to anti-CCP antibodies and RF. Anti-MCV antibodies do not appear to be very useful in the diagnosis of RA. However, long-term study is required to find out whether anti-MCV antibodies can be used as predictive test for incidence of RA.

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