Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis
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AbstractRheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the two most prevalent autoantibodies in rheumatoid arthritis (RA), and are thought to have distinct autoantigen targets. Whilst RF targets the Fc region of antibodies, ACPAs target a far broader spectrum of citrullinated peptides. Here we demonstrate significant sequence and structural homology between proposed RF target epitopes in IgG1 Fc and the ACPA target fibrinogen. Two of the three homologous sequences were susceptible to citrullination, and this modification, which occurs extensively in RA, permitted significant cross-reactivity of RF+ patient sera with fibrinogen in both western blots and ELISAs. Crucially, this reactivity was specific to RF as it was absent in RF− patient and healthy control sera, and could be inhibited by pre-incubation with IgG1 Fc. These studies establish fibrinogen as a common target for both RF and ACPAs, and suggest a new mechanism in RF-mediated autoimmune diseases wherein RF may act as a precursor from which the ACPA response evolves.
CitationMalgorzata, T., Perera, S., Sheeran, T., Rylance, P., Nelson, P. N. and Attridge, K. (2019) Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis, Scientific Reports, 9: 12068.
PublisherSpringer Science and Business Media LLC
Description© 2019 The Authors. Published by Nature Publishing Group. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/s41598-019-48176-3
SponsorsThis work was supported by grants from the South Staffordshire Medical Foundation Rotha Abraham Bequest, the Royal Wolverhampton Hospital Charity, the New Cross Kidney Patients Association, and The James Beattie Charitable Trust.
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0/