The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides

Brink, Mikael; Hansson, Monika; Rönnelid, Johan; Klareskog, Lars; Rantapää-Dahlqvist, Solbritt

doi:10.1136/annrheumdis-2014-205498

Cited by 13 publications

(15 citation statements)

References 3 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The largely arginine‐specific autoantibody response that we observed in patients with BR was remarkably similar to that observed in patients with periodontitis . This pattern of response was also recently observed in a study by Brink et al , in which antibodies against arginine‐containing peptides (including REP‐1, vimentin [aa 60–75], and fibrinogen β‐chain [aa 36–52]) from RA autoantigens were observed before the development of citrulline‐specific ACPAs in serum samples obtained from patients with RA years before symptoms of RA developed. Importantly, that study also included sequential samples.…”

Section: Discussionsupporting

confidence: 87%

“…Although we did not examine antibody avidity in this study, a longitudinal study of patients with presymptomatic RA showed that antibody avidity gradually increased as the onset of joint disease approached . Therefore, if certain bacterial infections lead to the initiation of an ACPA response, our study and others suggest that infections such as periodontitis, BR, and others yet to be defined induce a low‐titer, low‐avidity, non–citrulline‐specific ACPA response in the early phases of tolerance breakdown, which subsequently evolves into the higher‐avidity, higher‐titer, and highly citrulline‐specific responses that characterize RA.…”

Section: Discussionmentioning

confidence: 80%

See 1 more Smart Citation

Bronchiectasis Is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis

Quirke

Perry

Cartwright

et al. 2015

Arthritis & Rheumatology

View full text Add to dashboard Cite

ObjectiveTo examine the potential of chronic severe bacterial infection to generate rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs), by studying patients with bronchiectasis (BR) alone and BR patients with rheumatoid arthritis (BR/RA).MethodsWe studied 122 patients with BR alone, 50 patients with BR/RA, and 50 RA patients without lung disease, as well as 87 patients with asthma and 79 healthy subjects as controls. RF levels were measured using an automated analyzer, and cyclic citrullinated peptide 2 (CCP‐2) was used to detect ACPAs. The fine specificities of citrullinated α‐enolase peptide 1 (CEP‐1), Cit‐vimentin, and Cit‐fibrinogen to their arginine‐containing control peptides (arginine‐containing α‐enolase peptide 1 [REP‐1], vimentin, and fibrinogen) were measured by enzyme‐linked immunosorbent assay.ResultsAmong the BR patients and control subjects, 39% and 42%, respectively, were ever‐smokers. The frequency of RF positivity in serum was increased in BR patients compared with controls (25% versus 10%), as were the frequencies of antibodies to CCP‐2 (5% versus 0%), CEP‐1 (7% versus 4%), Cit‐vimentin (7% versus 4%), and Cit‐fibrinogen (12% versus 4%), although only the differences for RF and Cit‐fibrinogen were significant (P < 0.05). We observed a corresponding increase in the frequency of antibodies to the arginine‐containing control peptides in BR patients compared with controls (for REP‐1, 19% versus 4% [P < 0.01]; for vimentin, 16% versus 4% [P < 0.05]), demonstrating that the ACPA response in patients with BR is not citrulline specific. The lack of citrulline specificity was further confirmed by absorption studies. In BR/RA patients, all ACPA responses were highly citrulline specific.ConclusionBronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that the ACPA response is not citrulline specific during the early stages of tolerance breakdown but becomes more specific in patients with BR in whom BR/RA develops.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 80%

Bronchiectasis Is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis

Quirke

Perry

Cartwright

et al. 2015

Arthritis & Rheumatology

View full text Add to dashboard Cite

show abstract

“…1 D ). This finding is consistent with reports that human autoantibodies recognize both an uncitrullinated and citrullinated variant of peptides deriving from common autoantigens (31, 32). …”

Section: Resultssupporting

confidence: 93%

General Approach for Tetramer-Based Identification of Autoantigen-Reactive B Cells: Characterization of La- and snRNP-Reactive B Cells in Autoimmune BXD2 Mice

Hamilton

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Autoreactive B cells are associated with the development of several autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The low frequency of these cells represents a major barrier to their analysis. Antigen-tetramers prepared from linear epitopes represent a promising strategy for the identification of small subsets of antigen-reactive immune cells. This is challenging given the requirement for identification and validation of linear epitopes and the complexity of autoantibody responses, including the broad spectrum of autoantibody specificities and the contribution of isotype to pathogenicity. We therefore tested a two-tiered peptide microarray approach, coupled with epitope mapping of known autoantigens, to identify and characterize autoepitopes using the BXD2 autoimmune mouse model. Microarray results were verified through comparison with established age-associated profiles of autoantigen specificities and autoantibody class switching in BXD2 and control (B6) mice and high-throughput ELISA and ELISPOT analyses of synthetic peptides. Tetramers were prepared from two linear peptides derived from two ribonucleic acid binding proteins (RBP): lupus La and 70 kDa U1 small nuclear ribonucleoprotein (snRNP). Flow cyotmetric analysis of tetramer-reactive B-cell subsets revealed a significantly higher frequency and greater numbers of RBP-reactive marginal zone precursor (MZ-P), transitional T3 and PDL-2+CD80+ memory B cells, with significantly elevated CD69 and CD86 observed in RBP+ MZ-P B cells in the spleens of BXD2 compared to B6 mice, suggesting a regulatory defect. This study establishes a feasible strategy for the characterization of autoantigen-specific B-cell subsets in different models of autoimmunity and, potentially, humans.

show abstract

“…The phenotypically distinct population of patients with anti-RA33/citRA33 DR antibodies described herein may identify this transitional state in the subset of established RA that still evolves to ACPA-positive disease after diagnosis. Third, a recent study reported that reactivity against native peptides derived from RA autoantigens was detectable in a subset of presymptomatic RA (pre-RA),35 where the median time of first positivity preceded that of the matched citrullinated peptides. As is the case with our cross-sectional findings, these data do not reflect antibody evolution in individual patients but show that antibodies against native peptides may occur prior to their anti-citrullinated peptide counterparts.…”

Section: Discussionmentioning

confidence: 99%

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

Konig

Giles

Nigrović

et al. 2016

Annals of the Rheumatic Diseases

View full text Add to dashboard Cite

show abstract

The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Antibodies against uncitrullinated peptides seem to occur prior to the antibodies to the corresponding citrullinated peptides

Cited by 13 publications

References 3 publications

Bronchiectasis Is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis

Bronchiectasis Is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis

General Approach for Tetramer-Based Identification of Autoantigen-Reactive B Cells: Characterization of La- and snRNP-Reactive B Cells in Autoimmune BXD2 Mice

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

Contact Info

Product

Resources

About