The rheumatoid arthritis citrullinome is enriched in antigenic complement proteins

Area of Science:

• Immunology
• Proteomics
• Rheumatology

Background:

• Citrullination is a key post-translational modification and autoantigen in Rheumatoid Arthritis (RA).
• The specific citrullinated proteins driving the autoantibody response in RA remain incompletely understood.
• Understanding the circulating citrullinome is crucial for elucidating RA pathogenesis.

Purpose of the Study:

• To perform an unsupervised proteomic analysis of the circulating citrullinome in RA patients.
• To identify specific citrullinated proteins that may serve as autoantigens in RA.
• To determine the consequences of citrullination on protein structure and autoantibody generation in RA.

Main Methods:

• Mass spectrometry was used to analyze citrullinated serum proteins in RA patients and controls.
• Levels of citrullinated proteins (cit-C9, cit-CFI) and immune complexes were measured in a larger cohort.
• Autoantibodies against citrullinated C9 and its peptides were quantified, alongside in-silico structural analysis of citrullinated C9.

Main Results:

• Differential proteomic analysis revealed higher expression of complement proteins in the RA citrullinome.
• Elevated levels of citrullinated C9 (cit-C9) and Complement Factor I (cit-CFI) were observed in RA patients compared to controls.
• Cit-C9 immune complexes and autoantibodies were significantly increased in anti-citrullinated protein antibody (ACPA)-positive individuals (relatives and RA patients), with enriched reactivity to citrullinated C9 peptides in RA.

Conclusions:

• The study identified citrullinated complement proteins as significant autoantigens in the circulating RA citrullinome.
• These findings highlight the role of citrullinated complement factors in RA autoimmunity.
• The structural changes induced by citrullination in C9 may contribute to the autoimmune response in RA.