Journal
CURRENT OPINION IN RHEUMATOLOGY
Volume 30, Issue 1, Pages 72-78Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/BOR.0000000000000452
Keywords
anticitrullinated protein antibody; citrullination; citrullinome; leukotoxic hypercitrullination; peptidylarginine deiminase; rheumatoid arthritis
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Funding
- Rheumatology Research Foundation
- Jerome L. Greene Foundation
- Ira T. Fine Discovery Fund
- Department of Defence (DoD) office of the Congressionally Directed Medical Research Programs (CDMRP) [W81XWH-15-1-0159]
- National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIAMS)/National Institutes of Health (NIH) [R01 AR069569]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR069569] Funding Source: NIH RePORTER
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Purpose of review Dysregulated citrullination is a key element that drives the production and maintenance of antibodies to citrullinated proteins, a hallmark in rheumatoid arthritis (RA). This article reviews recent literature on the origin of citrullinated antigens in RA. Recent findings The study of synovial fluid from patients with RA has provided important insights into the identity of citrullinated proteins that accumulate in the RA joint (the RA citrullinome) and mechanisms that control their generation. Summary Citrullinating enzymes (peptidylarginine deiminases, PADs) are tightly controlled to limit their hyperactivation. Calcium and redox conditions are important regulators of PAD activity. Studies suggest that citrullination is dysregulated both intra-and extracellularly in RA. In neutrophils, host (i.e., perforin and the membrane attack complex) and bacterial (i.e., toxins) pore-forming proteins induce prominent calcium influx, cytolysis, and hyperactivation of PADs. These factors likely drive hypercitrullination in the RA joint and at extraarticular sites of disease initiation, respectively. As oxidizing conditions present in the extracellular environment are known to inactivate PADs, extracellular citrullination in RA probably requires the constant release of active enzymes from dying cells and may be accelerated by autoantibodies that activate PADs.
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