Research ArticleRheumatoid Arthritis

Erosive Rheumatoid Arthritis Is Associated with Antibodies That Activate PAD4 by Increasing Calcium Sensitivity

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Science Translational Medicine  22 May 2013:
Vol. 5, Issue 186, pp. 186ra65
DOI: 10.1126/scitranslmed.3005370

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PADding the Calcium Response in Rheumatoid Arthritis

One of the main challenges in translational medicine is ensuring physiological relevance. Just because you can make something happen in a dish or even a mouse doesn’t mean that that’s the way it really works. One example is the putative pathological role of PADs (peptidylarginine deiminases) in rheumatoid arthritis (RA). PADs catalyze a reaction that results in production of citrulline, one of the primary autoantibody targets in RA patients. However, this reaction requires concentrations of calcium not found in physiological situations. Now, Darrah et al. show that an autoantibody to PADs found in a subset of severe RA patients actually changes the calcium sensitivity of PADs.

The authors found that PAD4-specific autoantibodies that cross-react with PAD3 increased the enzyme’s ability to respond to lower physiological level of calciums. A subset of patients with more severe RA expressed these antibodies, which were absent in healthy individuals. It’s possible that these autoantibodies create a feed-forward loop: Anti-PAD autoantibodies activate PAD, which produces more citrulline and therefore more targets for anti-RA autoantibodies, worsening disease. If these data can be verified in additional human cohorts, these antibodies may serve as markers for patients who would benefit from treatments targeting PADs.

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