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.
Highlights
CITRULLINATION IN RHEUMATOID ARTHRITISCitrullination, the post-translational conversion of arginine to citrulline residues by peptidylarginine deiminase enzymes (PADs), is thought to be an essential contributor to the rheumatoid arthritis (RA) disease pathogenesis.[1]
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, predicting erosive disease
Of particular relevance to this hypothesis is the finding that Porphyromonas gingivalis is uniquely able to modify arginine residues to citrulline by virtue of having its own isoform of peptidylarginine deiminase enzymes (PADs)
Summary
Citrullination, the post-translational conversion of arginine to citrulline residues by peptidylarginine deiminase enzymes (PADs), is thought to be an essential contributor to the rheumatoid arthritis (RA) disease pathogenesis.[1]. The discovery of well-developed IgA ACPA responses in at-risk individuals and in the stored serum of RA patients obtained at the preclinical phase of disease suggests that the immune pathogenesis occurs at mucosal surfaces in the earliest phases of RA and may serve as a trigger of systemic autoimmunity.[15,16] Of particular relevance to this hypothesis is the finding that Porphyromonas gingivalis (a bacterium associated with periodontal disease,[17] a condition which is more prevalent in new-onset, treatment-naive RA patients than healthy controls18,19) is uniquely able to modify arginine residues to citrulline by virtue of having its own isoform of PAD This isoform is thought to citrullinate molecular targets not normally accessible to endogenous human PADs.[20] Additional support for the mucosal origin of autoimmunity is work implicating the lung in RA disease pathogenesis. Several studies have reported that smoking, the greatest known environmental risk factor for RA development, increases the citrullination of lung proteins and is associated with ACPA formation in patients with the HLA-DRB1*04:01 and *04:04 RA susceptibility haplotype.[11,21]
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