Citrullinated Autoantigens: From Diagnostic Markers to Pathogenetic Mechanisms

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• 作者：Sylviane Muller ; Marko Radic
• 关键词：Autoantibodies ; Citrulline ; Histones ; Neutrophil extracellular traps (NETs)
• 刊名：Clinical Reviews in Allergy & Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：49
• 期：2
• 页码：232-239
• 全文大小：659 KB
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• 作者单位：Sylviane Muller (1)
  Marko Radic (2)
  
  1. Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
  2. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
  
• 刊物主题：Allergology; Immunology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-0267

文摘

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 96-8 %. 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. Keywords Autoantibodies Citrulline Histones Neutrophil extracellular traps (NETs)