Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients

Abstract

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.

Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Biomarkers towards Personalized Rheumatology

“…For the first time, we described a novel peptide-based antigen bearing citrulline, homocitrulline and acetyl-lysine into the same peptide sequence to consistently detect severe phenotypes in CFFCHAP positive RA patients. We demonstrated an association between the presence and levels of AMPA titers and severe manifestations of RA such as joint destruction and ILD [5].…”

Interplay between the Chaperone System and Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus Pathogenesis: Is Molecular Mimicry the Missing Link between Those Two Factors?

“…Synthetic peptides mimicking post-translationally modified autoantigens have been successfully used for the development of specific in vitro diagnostic/prognostic assays of autoimmune diseases, including SLE [ 125 ]. Moreover, the use of post-translationally modified peptides has allowed identification of autoantibodies associated with the most severe phenotypes [ 126 ].…”

Implications of Post-Translational Modifications in Autoimmunity with Emphasis on Citrullination, Homocitrullination and Acetylation for the Pathogenesis, Diagnosis and Prognosis of Rheumatoid Arthritis

“…In the same line, Niijar et al [105] recently reported that the optimal prediction of erosive radiographic progression in patients with new-onset RA requires study of the effect of AMPA combinations. Considering that the overlap between the three families of autoantibodies (ACPAs, anti-CarP and anti-APA) is characteristic of RA, novel peptide-based antigens bearing citrulline, homocitrulline and/or acetyl-lysine were designed to further study the role of AM-PAs as biomarkers linked to the presence of ILD as well as the severity of joint destruction [116]. Based on the previously defined synthetic peptide structures (CFFCP1 and CFFHP), three novel citrullinated/homocitrullinated (CFFCHP1, CFFCHP2 and CFFCHP3) and one citrullinated/homocitrullinated/acetylated (CFFCHAP) chimeric peptides were synthesized by SPPS preserving the citrulline at the 630 position of the α-fibrin (617-631) domain, taking into account the important role of this specific position for autoantibody binding that was previously reported [83,86].…”

“…To the best of our knowledge, in Ref. [116] is reported for the first time in the litera- To the best of our knowledge, in Ref. [116] is reported for the first time in the literature a peptide that simultaneously contains the three most relevant PTMs for RA at specific positions of their unique primary structure as an antigenic target of the autoantibodies associated with severe clinical phenotypes of RA.…”