A citrullinating enzyme, PAD-4, predicts the prognosis of rheumatoid arthritis (RA) and may be a potential therapeutic target, say scientists.
Antibodies against citrullinated peptides are found in the early stages of RA and often precede development of a diagnostic phenotype, suggesting that these antibodies may be markers of the specific events that initiate autoimmunity in RA.
The citrullination reaction is catalyzed by a family of enzymes known as peptidyl arginine deiminases (PADs), of which five isoforms have been identified.
One of these isoforms (PAD-4) "has received particular attention in RA, since it is expressed in myelomonocytes, can be detected in inflamed RA synovium, and has recently been genetically associated with RA," note Anthony Rosen (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) and co-workers.
Specifically, research has suggested that increased levels of PAD-4 promote citrullination and the generation of antibodies against citrullinated peptides.
Noting that "significant direct support for this model is still lacking," Rosen et al studied the activity of PAD-4 in 38 patients with RA, 32 generally-healthy control volunteers, and 126 patients with other systemic autoimmune diseases.
Analysis revealed that the presence of auto-antibodies against PAD-4 independently and significantly predicted RA prognosis, with elevated levels of the auto-antibodies positively correlated with more severe joint damage and erosion.
Of note, the researchers confirmed a previously reported association between levels of anti-PAD-4 auto-antibodies and variation in the gene that encodes the PAD-4 enzyme, known as PADI4.
Indeed, levels of antibodies against PAD-4 were significantly associated with the PADI4-susceptibility haplotype and the heterozygous diplotype, giving odds ratios of 2.59 and 4.02, respectively, for the presence of elevated auto-antibody levels.
Finally, Rosen and team showed that the epitopes recognized by anti-PAD-4 antibodies include the N-terminal region of PAD-4, which was found to contain variation known to predict RA susceptibility.
"Taken together, these findings implicate unique PAD-4 structure and/or function in the generation of a PAD-4-specific immune response and, potentially, the downstream augmentation of joint damage in RA," conclude the investigators in the journal Arthritis and Rheumatism.
Thanks Lynn as alwaysYou're very welcome :)