Citrullination facilitates cross-reactivity of rheumatoid factor with non-IgG1 Fc epitopes in rheumatoid arthritis

Malgorzata Trela,Paul N Nelson,Thomas Sheeran,Paul Rylance,Shantha Perera,Kesley Attridge

doi:10.1038/s41598-019-48176-3

Abstract

Rheumatoid 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.

Highlights

Rheumatoid Arthritis (RA) is an autoimmune disease characterised by the production of diverse autoantibodies, of which rheumatoid factor (RF) represents a hallmark of the disease, being detectable in up to 80% of rheumatoid arthritis (RA) patients[1]
To determine whether cross reactivity of Rheumatoid factor (RF) might play an important role in rheumatoid pathology, we searched for regions of homology between the sequences of IgG1 Fc
We utilised RF+ sera from RA patients seronegative for anti-citrullinated protein antibodies (ACPAs) to assess the ability of RF to react with citrullinated ACPA target proteins

Summary

Introduction

Rheumatoid Arthritis (RA) is an autoimmune disease characterised by the production of diverse autoantibodies, of which rheumatoid factor (RF) represents a hallmark of the disease, being detectable in up to 80% of RA patients[1]. The second major group of autoantibodies present in around 60–70% of RA patient sera constitute anti-citrullinated protein antibodies (ACPAs)[4]. These antibodies target epitopes that have been post-translationally modified by the deimination of arginine residues to citrulline. RF titres, we show that RF+ sera readily cross-reacts with fibrinogen after citrullination These data suggest that cross-reactivity of RF with citrullinated auto-antigens represents a novel route for the initiation/propagation of ACPA responses in RA, a finding with potential relevance across a spectrum of autoimmune diseases in which RF is known to play a role, such as Sjögren’s syndrome and lupus

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