Abstract
IntroductionAnti-citrullinated protein antibodies have a diagnostic role in rheumatoid arthritis (RA); however, little is known about their origins and contribution to pathogenesis. Citrullination is the post-translational conversion of arginine to citrulline by peptidyl arginine deiminase, and increased citrullination of proteins is observed in the joint tissue in RA and in brain tissue in multiple sclerosis (MS).MethodsWe applied synovial and myelin protein arrays to examine epitope spreading of B cell responses to citrullinated epitopes in both the collagen-induced arthritis (CIA) model for RA and the experimental autoimmune encephalomyelitis (EAE) model for MS. Synovial and myelin protein arrays contain a spectrum of proteins and peptides, including native and citrullinated forms, representing candidate autoantigens in RA and MS, respectively. We applied these arrays to characterise the specificity of autoantibodies in serial serum samples derived from mice with acute and chronic stages of CIA and EAE.ResultsIn samples from pre-disease CIA and acute-disease EAE, we observed autoantibody targeting of the immunising antigen and responses to a limited set of citrullinated epitopes. Over the course of diseases, the autoantibody responses expanded to target multiple citrullinated epitopes in both CIA and EAE. Using immunoblotting and mass spectrometry analysis, we identified citrullination of multiple polypeptides in CIA joint and EAE brain tissue that have not previously been described as citrullinated.ConclusionsOur results suggest that anti-citrulline antibody responses develop in the early stages of CIA and EAE, and that autoimmune inflammation results in citrullination of joint proteins in CIA and brain proteins in EAE, thereby creating neoantigens that become additional targets in epitope spreading of autoimmune responses.
Highlights
Anti-citrullinated protein antibodies have a diagnostic role in rheumatoid arthritis (RA); little is known about their origins and contribution to pathogenesis
Our results suggest that anti-citrulline antibody responses develop in the early stages of collagen-induced arthritis (CIA) and EAE, and that autoimmune inflammation results in citrullination of joint proteins in CIA and brain proteins in EAE, thereby creating neoantigens that become additional targets in epitope spreading of autoimmune responses
We demonstrate targeting of a limited number of citrullinated polypeptides in pre-disease samples derived from mice with collagen-induced arthritis (CIA) and early disease samples derived from mice with EAE, and expansion of responses to target multiple citrullinated molecules in established and long-standing disease
Summary
Anti-citrullinated protein antibodies have a diagnostic role in rheumatoid arthritis (RA); little is known about their origins and contribution to pathogenesis. A post-translational modification of importance in rheumatoid arthritis (RA) is the conversion of peptidylarginine to peptidylcitrulline by peptidyl arginine deiminase (PAD) [3,4]. This enzymatic modification is termed citrullination, and detection of antibodies targeting citrullinated epitopes has become a key diagnostic marker for the diagnosis of RA, with a sensitivity of about 60% and a specificity of 95% [5,6,7,8,9,10]. It is possible that cigarette smoking represents an environmental trigger that induces anti-citrulline antibody responses in genetically susceptible individuals and thereby contributes to the development of RA [13]
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