The relevance of citrullinated vimentin in the production of antibodies against citrullinated proteins and the pathogenesis of rheumatoid arthritis

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.

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Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays

Scientific Reports ◽

10.1038/s41598-021-96675-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Thomas B. G. Poulsen ◽

Dres Damgaard ◽

Malene M. Jørgensen ◽

Ladislav Senolt ◽

Jonathan M. Blackburn ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Protein Microarray ◽

Specific Protein ◽

Immune Reactivity ◽

Igg Antibodies ◽

Native Proteins ◽

Array Technology ◽

Citrullinated Proteins ◽

Folded Proteins

AbstractThe presence or absence of autoantibodies against citrullinated proteins (ACPAs) distinguishes two main groups of rheumatoid arthritis (RA) patients with different etiologies, prognoses, disease severities, and, presumably, disease pathogenesis. The heterogeneous responses of RA patients to various biologics, even among ACPA-positive patients, emphasize the need for further stratification of the patients. We used high-density protein array technology for fingerprinting of ACPA reactivity. Identification of the proteome recognized by ACPAs may be a step to stratify RA patients according to immune reactivity. Pooled plasma samples from 10 anti-CCP-negative and 15 anti-CCP-positive RA patients were assessed for ACPA content using a modified protein microarray containing 1631 different natively folded proteins citrullinated in situ by protein arginine deiminases (PADs) 2 and PAD4. IgG antibodies from anti-CCP-positive RA plasma showed high-intensity binding to 87 proteins citrullinated by PAD2 and 99 proteins citrullinated by PAD4 without binding significantly to the corresponding native proteins. Curiously, the binding of IgG antibodies in anti-CCP-negative plasma was also enhanced by PAD2- and PAD4-mediated citrullination of 29 and 26 proteins, respectively. For only four proteins, significantly more ACPA binding occurred after citrullination with PAD2 compared to citrullination with PAD4, while the opposite was true for one protein. We demonstrate that PAD2 and PAD4 are equally efficient in generating citrullinated autoantigens recognized by ACPAs. Patterns of proteins recognized by ACPAs may serve as a future diagnostic tool for further subtyping of RA patients.

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

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2320 ◽

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

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Anti-Mutated Citrullinated Vimentin (Anti-MCV) Antibodies as a Diagnostic Aid for Rheumatoid Arthritis

Journal of Clinical & Cellular Immunology ◽

10.4172/2155-9899.1000263 ◽

2014 ◽

Vol 05 (05) ◽

Cited By ~ 1

Author(s):

Khaled S Osman

Keyword(s):

Rheumatoid Arthritis ◽

Diagnostic Aid ◽

Citrullinated Vimentin

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Identification and function of T cells reactive with citrullinated vimentin in HLA-DRB1*0401 humanised mice and rheumatoid arthritis patients

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.129668v ◽

2010 ◽

Vol 69 (Suppl 2) ◽

pp. A73-A73

Author(s):

O Snir ◽

M Rieck ◽

K Klich ◽

L Klareskog ◽

J H Buckner ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Citrullinated Vimentin ◽

Humanised Mice ◽

And Function

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Autoimmune Response to Post-Translationally Modified (Citrullinated) Proteins: Prime Suspect in the Pathophysiology of Rheumatoid Arthritis

The Epigenetics of Autoimmune Diseases ◽

10.1002/9780470743553.ch16 ◽

2009 ◽

pp. 279-308

Author(s):

Mireille Sebbag ◽

Cyril Clavel ◽

Leonor Nogueira ◽

Jacques Arnaud ◽

Guy Serre

Keyword(s):

Rheumatoid Arthritis ◽

Autoimmune Response ◽

Citrullinated Proteins

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Rheumatoid Arthritis: Etiology and Pathogenesis

10.2310/im.1431 ◽

2014 ◽

Author(s):

Gary S. Firestein ◽

Anna-Karin H. Ekwall

Keyword(s):

Rheumatoid Arthritis ◽

Intracellular Signaling ◽

Cartilage Damage ◽

Signs And Symptoms ◽

American College Of Rheumatology ◽

European League Against Rheumatism ◽

Citrullinated Proteins ◽

Definition Of

Rheumatoid arthritis (RA) is among the most common forms of chronic inflammatory arthritis. It affects approximately 1% of adults and is two to three times more prevalent in women than in men. There are no specific laboratory tests for RA; diagnosis depends on a constellation of signs and symptoms that can be supported by serology and radiographs. The disease evolves over many years as a consequence of repeated environmental stress causing inflammation and immune activation followed by a breakdown of tolerance in individuals with a specific genetic background. This review describes the definition of RA; its etiology, including genetics, infections, the role of smoking and citrullination of proteins, and epigenetic mechanisms; and its pathogenesis, including synovial histopathology, bone and cartilage damage, adaptive and innate immunity, and the role of cytokines and intracellular signaling. Tables include the 1987 American Rheumatism Association criteria for the classification of RA and the 2010 American College of Rheumatology/European League Against Rheumatism classification for RA. Figures show citrullinated proteins in airway cells, a section of a proliferative synovium from a patient with a classic RA, and scalloped regions of erosion at the junction between a proliferative inflamed rheumatoid synovium and the bone. This review contains 3 highly rendered figures, 2 tables, and 71 references.

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