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Citrullinated Autoantigens: From Diagnostic Markers to Pathogenetic Mechanisms

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Abstract

The conversion of an arginine residue in a protein to a citrulline residue, a reaction carried out by enzymes called peptidylarginine deiminases (PADs), is rather subtle. One of the terminal imide groups in arginine is replaced by oxygen in citrulline, thus resulting in the loss of positive charge and the gain of 1 dalton. This post-translational modification by PAD enzymes is conserved in vertebrates and affects specific substrates during development and in various mature cell lineages. Citrullination offers a unique perspective on autoimmunity because PAD activity is stringently regulated, yet autoantibodies to citrullinated proteins predictably arise. Autoantigens recognized by anti-citrullinated protein antibodies (ACPA) include extracellular proteins such as filaggrin, collagen II, fibrinogen, and calreticulin; membrane-associated proteins such as myelin basic protein; cytoplasmic proteins such as vimentin and enolase; and even nuclear proteins such as histones. Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. In patients with RA, ACPA may attain a sensitivity that exceeds 70 % and specificity that approaches 96–98 %. The biological context that may account for the induction of ACPA emerges from studies of the cellular response of the innate immune system to acute or chronic stimuli. In response to infections or inflammation, neutrophil granulocytes activate PAD, citrullinate multiple autoantigens, and expel chromatin from the cell. The externalized chromatin is called a neutrophil extracellular “trap” (NET). Citrullination of core and linker histones occurs prior to the release of chromatin from neutrophils, thus implicating the regulation of citrullinated chromatin release in the development of autoreactivity. The citrullination of extracellular autoantigens likely follows the release of NETs and associated PADs. Autoantibodies to citrullinated histones arise in RA, systemic lupus erythematosus, and Felty’s syndrome patients. The citrullination of linker histone H1 may play a key role in NET release because the H1 histone regulates the entry and exit of DNA from the nucleosome. Juxtaposition of citrullinated histones with infectious pathogens and complement and immune complexes may compromise tolerance of nuclear autoantigens and promote autoimmunity.

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Acknowledgments

Research in the SM’s laboratory is financially supported by the French Centre National de la Recherche Scientifique, Région Alsace, Laboratory of Excellence Medalis (ANR-10-LABX-0034), EquipEx program I2MC (ANR-11-EQPX-022), Initiative of Excellence (IdEx), Strasbourg University, and ImmuPharma France. Research in the MR’s laboratory is financially supported by The Lupus Research Institute of New York and the ORR Fund of Memphis, TN. We gratefully acknowledge the kind gift of the anti-PAD4 monoclonal antibody from Dr. Katsuhiko Nakashima of the National Cancer Center Institute of Japan. The authors thank Dr. Gilbert de Murcia, CNRS, who took the original images shown in Fig. 3b. We are grateful to Dr. Indira Neeli and Dr. Teruki Hagiwara for their helpful comments that improved this manuscript.

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  1. Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France

    Sylviane Muller

  2. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA

    Marko Radic

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Muller, S., Radic, M. Citrullinated Autoantigens: From Diagnostic Markers to Pathogenetic Mechanisms. Clinic Rev Allerg Immunol 49, 232–239 (2015). https://doi.org/10.1007/s12016-014-8459-2

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