Two pathways cause rheumatoid arthritis

Researchers from Johns Hopkins University and Boston University have identified two biological pathways as the major causes of the initiation of rheumatoid arthritis. The pathways, once activated, lead to a series of events that cause citrullinated proteins to build up, resulting in an autoimmune attack. They hope that this ground-breaking discovery can lead to new ways to stall the progression of and maybe even cure rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder that typically affects small joints in the hands and feet. Like all autoimmune disorders, this disease occurs when one’s immune system does not recognize its own tissues and starts to attack them. In RA, certain proteins have been citrullinated, or molecularly altered, which changes the way the proteins fold. The immune system tags these proteins as foreign, leading to an autoimmune response. This causes painful swelling in between the joints and eventually leads to joint deformity and bone erosion.

Currently, there is no way to completely cure RA – treatments consist of purely palliative measures. Painkillers and anti-inflammatory drugs can be taken to suppress the disease’s symptoms and physical therapy can alleviate the pain. However, no known methods can completely stop the progression of joint destruction.

Fortunately, researchers here in Baltimore, in collaboration with researchers from Boston, have made a discovery that might shed some light onto the disease’s origins and processes. They noticed that pathways that form pores in the membrane were activated in cells that contained an abnormal amount of citrullinated proteins. These two pathways, identified as perforin and complement (MAC), are involved with the immune system – they help create pores in a cell’s membrane for a more efficient immune response. The formation of pores produces calcium ions that activate certain enzymes, including the ones that cause protein citrullination in the joints of the hands and feet. This, in turn, triggers the inflammatory autoimmune response associated with RA.

In the three year study, the researchers first discovered that the joint cells collected from patients with RA have a strange pattern of citrullination, which they decided to call “hypercitrullination.” They stimulated different molecular pathways in normal cells in hopes of recreating that specific pattern. Of the different pathways they tested, only the stimulation of perforin and MAC produced similar patterns of hypercitrullination found in the joint cells of RA patients.

These discoveries have led to many changes in the predisposed ideas of RA as well as the immune system itself. MAC and perforin were originally believed to have secondary roles in immune response – this study is the first to show that they are active contributors. Now that researchers are aware of this, steps can be taken to discover new and alternative treatments for RA involving the inhibition of the perforin and MAC pathways.

The team is now looking to determine why the perforin and MAC pathways in patients with RA have been activated in the rheumatoid joints. This, they believe, will allow them to gain further insight on how the disease process is instigated. They also would like to understand and monitor the levels of citrullination presents in the different stages of RA by creating biomarkers for citrullinated proteins. By doing so, they hope to discover the best types of treatments for RA depending on the stages of disease progression.