A new disease mechanism unveiled in rheumatoid arthritis

What is it about?

Rheumatoid arthritis (RA) is an incurable autoimmune disease in which the body’s own immune system causes chronic inflammation to the joints, leading to irreversible and even disabling joint damage in affected individuals. In this study, we describe for the first time that monocytes, a type of white blood cell that invades and causes inflammation in the RA joint, have a protein called peptidylarginine deiminase IV (PAD4) on their surface. PAD4 is an enzyme responsible for generating citrullinated proteins, which are normally found in the body, but for reasons that are not fully understood, become recognized by the immune system in people with RA (including by antibodies). We show that PAD4 on the monocyte surface is able to generate citrullinated proteins, both on the surface of the monocyte and in the environment outside of the cell, that are recognized by antibodies from some people with RA. Through this study, we identified a new target of antibodies in RA that is present on the monocyte surface – i.e., citrullinated Mac-1, a molecule involved in monocyte cell migration and activation. The patients with antibodies to citrullinated Mac-1 had more evidence of inflammation on average, compared to those without. In summary, our study shows that monocytes, because of the presence of PAD4 on their surface, may play a more crucial role in driving immune responses and inflammation in RA than previously appreciated.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

RA affects roughly 1-2% of the global population, but why some people get RA, why their immune systems attack citrullinated proteins, and how these citrullinated proteins are generated are not fully known. Up to 80% of RA patients have antibodies in their blood that recognize citrullinated proteins, a feature uncommon in people without RA, underscoring the importance of protein citrullination and PAD4 in the disease process. Prior to our study, PAD4 was thought to be present mostly in the nucleus of cells (a structure deep within the cell that houses the genetic material), so the only way that PAD4 could be unleashed to citrullinate proteins outside the cell was through cell death and release of PAD4 into the external environment. However, our study shows a new way that citrullination could occur and reveals that monocytes can contribute to the generation of citrullinated proteins by carrying active PAD4 enzymes on their cell surface. Our study expands the number of known proteins that can be citrullinated by PAD4 to include multiple cell surface proteins and suggests that particular antibodies, such as those to citrullinated Mac-1 found in our study, could play a role in the disease process. These findings have implications for how patients are treated, since antibodies to citrullinated Mac-1 may be helpful in identifying patients with more severe disease that may respond better to certain medications. Future studies are needed to determine if these antibodies could help doctors make treatment decisions and to learn more about how the presence of PAD4 on the monocyte surface and citrullinated of surface proteins affects monocyte functions and inflammation in RA.