Citrullination in Rheumatoid Arthritis—A Process Promoted by Neutrophil Lysis?

Abstract

Anti-citrullinated protein antibodies (ACPAs) are highly specific serologic markers for rheumatoid arthritis (RA) and can pre-date clinical disease onset by up to 10 years, also predicting erosive disease. The process of citrullination, the post-translational conversion of arginine to citrulline residues, is mediated by peptidylarginine deiminase (PAD) enzymes present in polymorphonuclear cells (PMNs). Calcium ions (Ca2+) are required for PAD activation, but the intracellular Ca2+ concentration in normal cells is much lower than the optimal Ca2+ concentration needed for PAD activation. For this reason, it has been proposed that PAD activation, and thus citrullination, occurs only during PMN cell death when PAD enzymes leak out of the cells into the extracellular matrix, or extracellular Ca2+ enters the cells, with the high Ca2+ concentration activating PAD. Recently, using artificial in vitro systems to corroborate their hypothesis, Romero et al. demonstrated that “hypercitrullination,” citrullination of multiple intracellular proteins, occurs within synovial fluid (SF) cells of RA patients, and that only modes of death leading to membranolysis such as perforin-granzyme pathway or complement membrane attack complex activation cause hypercitrullination. In order for Romero’s hypothesis to hold, it is reasonable to surmise that PMN-directed lysis should occur in the rheumatoid joint or the circulation of RA patients. Research conducted thus far has shown that immunoglobulin G (IgG) targeting PMNs are present in RA SF and mediate PMN activation. However, the role of anti-PMN IgG in mediating complement activation and subsequent PMN lysis and hypercitrullination has not been fully evaluated.

Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy

“…Arginine is also involved in two metabolic pathways critical to RA disease pathogenesis, i.e., nitric oxide synthase uncoupling and citrullination. The conversion of arginine to citrulline has been shown to be upregulated in synovial fluid of patients with RA due to a process known as" hypercitrullination" [31]. The observed reduction of arginine in RA may be due to both hypercitrullination, and arginine's role in the production of reactive oxygen species (ROS), a hallmark trait of inflamed tissues [32][33][34].…”

Armed to the Teeth—The Oral Mucosa Immunity System and Microbiota

“…This changes the basic properties of the protein such as its charge, conformation, and antigenicity. This results in the formation of antibodies to citrullinated proteins and an alteration of the immune response that may, as indicated in the literature, result in the development of rheumatoid arthritis [ 103 , 104 ].…”

Anti-citrullinated Protein Antibody Generation, Pathogenesis, Clinical Application, and Prospects

“…High Ca 2+ concentration can occur locally in cells or in extreme conditions like apoptosis or necrosis ( 3 ). PADs are activated during cell death when PADs leak out of cells into the extracellular matrix or extracellular Ca 2+ enters into cells ( 7 ). Accumulated citrullinated proteins have increased immunogenicity and are converted into autoantigens ( 8 ).…”