The fibrin-derived citrullinated peptide β60–74Cit<sub>60,72,74</sub>bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies

Cornillet, Martin; Sebbag, Mireille; Verrouil, Évelyne; Magyar, Anna; Babos, Fruzsina; Ruyssen‐Witrand, Adeline; Hudecz, Ferenc; Cantagrel, Alain; Serre, Guy; Nogueira, Léonor

doi:10.1136/annrheumdis-2012-202868

Cited by 36 publications

(32 citation statements)

References 35 publications

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“…It allowed the assay to reach a very good diagnosis performance for RA similar to that of AhFibA detection. Although the diagnostic performance obtained with this peptide needs to be confirmed on a larger cohort, this result shows that almost all AhFibA-positive sera recognized the bME and thus emphasized our previous conclusion that b60-74 bore the immunodominant epitope recognized by AhFibA (32,48).…”

Section: Discussionsupporting

confidence: 72%

“…AhFibA and Abs against the nonbiotinylated a36-50 and b60-74 reference peptides were detected by ELISA as previously described (23,32,33,35). AhFibA titers were considered as the OD obtained on citrullinated fibrin.…”

Section: Elisa Quantification Of Autoantibodies Directed Toward Citrumentioning

confidence: 99%

“…We demonstrated that citrullinated forms of fibrin are major in vivo targets of ACPA in RA synovial tissue (30), and we developed an efficient ELISA for the detection of anti-citrullinated human fibrinogen autoantibodies (AhFibA) (23). We also showed that two 15-mer citrulline containing peptides, called a36-50 and b60-74, derived from the sequences of the aand b-chains of fibrin, respectively, bear major AhFibA epitopes (31,32). We identified the amino acids necessary and sufficient to delineate two overlapping minimal epitopes (ME) on a36-50 (MEa and MEa') and one single ME on b60-74 (MEb) (33).…”

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confidence: 99%

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Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Cornillet

Babos

Magyar

et al. 2018

The Journal of Immunology

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Quantification of Abs toward a single epitope is critical to understanding immunobiological processes. In autoimmunity, the prognostic value of the serological profiles of patients draws much attention, but the detection of Abs toward a single epitope is not well controlled. Particularly, the rheumatoid arthritis (RA)–specific anti–citrullinated protein/peptide Abs (ACPA) are specific to a two-atom change on arginyl residues and are considered a heterogeneous family of Abs. As a model, we studied ACPA to decipher how peptide features used as immunosorbent impact Ab detection. We synthesized 30 peptides encompassing immunodominant epitopes of citrullinated fibrin differing by their length and biotin location and tested them using ELISA with 120 sera from RA and non-RA rheumatic disease controls, generating over 3000 experimental measurements. We showed that minor molecular changes in peptide chemical structure had dramatic consequences. Even when peptides exhibited the same epitope, measured Ab titers were extremely variable, and patients’ seropositivity was discordant in up to 50% of cases. The distance between epitope and biotin was the most critical parameter for efficient Ab detection irrespective of biotin position or peptide length. Finally, we identified a 15-mer peptide bearing a single citrullinated epitope detecting almost all ACPA-positive sera, thus revealing a high degree of homogeneity in RA autoimmune response. This integrative analysis deciphers the dramatic impact of the molecular design of peptide-based technologies for epitope-specific Ab quantification. It provides a model for assay development and highlights that the studies using such technologies can give a wrong perception of biological processes and therefore that medical use of data must be cautious.

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Section: Discussionsupporting

confidence: 72%

Section: Elisa Quantification Of Autoantibodies Directed Toward Citrumentioning

confidence: 99%

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confidence: 99%

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Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Cornillet

Babos

Magyar

et al. 2018

The Journal of Immunology

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“…Assays using peptides that contain citrulline (deiminated arginine residues) are highly predictive and specific for the diagnosis of rheumatoid arthritis [16]. Recently, two distinct subfamilies of anti-citrulline antibodies against citrullinated fibrin-derived peptides were identified [17]. In addition, two citrullinated histone H4 peptides were shown to be preferentially recognized by autoantibodies present in the majority of patients with rheumatoid arthritis, but not in SLE [18].…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis

et al. 2016

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Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of anti-chromatin/chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4pac), H2B peptide acetylated at lysine 12 (H2Bpac), H3 peptide trimethylated at lysine 27 (H3pme), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4pac showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bpac exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3pme appeared not specific for SLE. Anti-H4pac and anti-H2Bpac reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bpac and a more pronounced reactivity with the modified equivalent of H3pme and H2Bpac. In conclusion, reactivity with H4pac and H2Bpac is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bpac is in particular associated with lupus nephritis.

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“…Several studies have identified and validated some of the cit-Fib epitopes in RA using different approaches [8, 16–20]. Cit-Fib has also been verified as an ACPA target in patients with RA throughout the world [21–23] with recognition of the α subunit peptide 36-52 and the β subunit peptide 60-74 being the most prominent.…”

Section: Introductionmentioning

confidence: 99%

Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells

et al. 2016

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BackgroundAntibodies against citrullinated proteins (ACPA) are common in patients with rheumatoid arthritis (RA). ACPA can appear before disease onset and target many self-antigens. Citrullinated fibrin/fibrinogen represents a classical ACPA target antigen, and mass spectrometry of RA synovial fluid reveals elevated citrullinated (cit) fibrinogen (Fib) peptides compared to non-RA controls. We investigated the extent to which these less-studied peptides represent autoantibody targets and sought to visualize the corresponding cit-Fib-reactive B cells in RA patients.MethodsAn in-house ELISA was established against four cit-Fib α-subunit peptides (cit-Fib α-35; cit-Fib α-216,218; cit-Fib α-263,271 and cit-Fib α-425,426) and serum from patients with established RA (n = 347) and disease controls with psoriatic arthritis (PsA) or ankylosing spondylitis (AS) (n = 236) were analyzed. RA patients were genotyped for HLA-DR alleles, PTPN22 R620W and screened for anti-CCP2 and cit-Fib protein antibodies. The cit-Fib peptides were also used to assemble antigen tetramers to identify cit-Fib-reactive B cells in peripheral blood by flow cytometry.ResultsThe frequencies of autoantibodies against different cit-Fib epitopes in RA patients compared to PsA/AS patients were: cit-Fib α-35 (RA 20%, vs PsA/AS 1%); cit-Fib α-216,218 (13% vs 0.5%); cit-Fib α-263,271 (21% vs 0.5%) and cit-Fib α-425,426 (17% vs 1%). The presence of autoantibodies against these peptides was associated with presence of anti-CCP2 and anti-cit-Fib protein antibodies. No association was found between HLA-DR shared epitope and antibodies to the different cit-Fib peptides. However, association was observed between the PTPN22 risk allele and positivity to cit-Fib α-35 and cit-Fib α-263,271. B cells carrying surface Ig reactive to these cit-Fib peptides were found in RA peripheral blood and these tend to be more common in PTPN22 risk allele carriers.ConclusionsOur data show that several cit-Fib peptides are targeted by autoantibodies in RA, but not in PsA/AS, implicating that these are not due to arthritis but more specific for RA etiology. The RA-associated anti-cit protein response is broad with many parallel immune responses. The association between cit-Fib autoantibodies and the PTPN22 R620W risk allele supports the hypothesis of altered B cell regulation, such as autoreactive B cells evading tolerance checkpoints.

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The fibrin-derived citrullinated peptide β60–74Cit_60,72,74bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies

Cited by 36 publications

References 35 publications

Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis

Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells

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The fibrin-derived citrullinated peptide β60–74Cit60,72,74bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies

Cited by 36 publications

References 35 publications

Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti–Citrullinated Protein/Peptide Antibody

Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis

Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells

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The fibrin-derived citrullinated peptide β60–74Cit_60,72,74bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies