In a new study, researchers link autophagy and post-translational changes (including protein carbamylation) in early rheumatoid arthritis (RA). “Our findings support the view that carbamylation represents an early trigger that precedes the appearance of RA-specific autoantibodies,” explains corresponding author Maurizio Sorice.

Credit: Cigdem Simsek/Alamy Stock Photo

Many autoantibodies in RA are directed against post-translationally modified protein antigens, such as the anti-citrullinated protein antibodies (ACPAs). Indeed, positivity for anti-cyclic citrullinated peptide (CCP) antibodies is a widely used diagnostic marker of RA. However, autoantibodies against proteins with other post-translational modifications, such as carbamylated proteins, have emerged in the past few years.

In a previous study, Sorice and his group implicated autophagy as a trigger of anti-CCP antibody production by linking autophagy and protein citrullination. In the new study, Sorice and colleagues sought to verify if autophagy can similarly induce protein carbamylation.

In vitro, induction of autophagy in human fibroblasts with tunicamycin (a reticulum stress inducer) or rapamycin (an activator of mTOR) resulted in carbamylation of multiple proteins, including vimentin. In a similar experiment with fibroblast-like synoviocytes, the induced levels of protein carbamylation were considerably higher in cells from patients with RA than in cells from patients with osteoarthritis.

To understand the in vivo relevance of this process, the researchers investigated cells from drug-naive patients with early active RA (who had a mean disease duration of 26 weeks). Monocytes from these patients had higher levels of carbamylated proteins than monocytes from healthy individuals; the amount of carbamylation correlated with the expression of an autophagic marker. Only 7 out of the 30 patients had detectable serum levels of anti-carbamylated protein antibodies, suggesting that this process occurs before the generation of autoantibodies.

Only 7 out of the 30 patients had detectable serum levels of anti-carbamylated protein antibodies

“In a follow-up study, we will evaluate whether assessing post-translational processing of proteins, including carbamylation, represents a useful tool for evaluating the future risk of disease progression,” says Sorice.