A research team from Australia’s Walter and Eliza Hall Institute revealed details on how certain cells are involved with the prolonging of rheumatoid arthritis-based joint inflammation. In both laboratory models and human clinical samples, the team identified natural killer (NK) cells as an unexpected source of the inflammation protein GM-CSF—a clue that they contribute to the inflammatory disease in rheumatoid arthritis. The study team describes how GM-CSF triggers other immune cells to prolong inflammation while GM-CSF is also signaling to immune cells in healthy joints functions. The findings not only shine new light on the disease but also introduce new possible therapeutic targets for the reduction of joint inflammation.
The results of this study, led by Walter and Eliza Hall Institute, was published in the Journal of Experimental Medicine.
Rheumatoid arthritis is a long-term autoimmune disorder primarily affecting the joints. It typically results in warm, swollen and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. But the disease can affect different parts of the body. The cause is not clear but appears to originate from a combination of genetic and environmental factors but hormones and lifestyle may also be a factor. Underlying the disease is the immune system attacking the joints.
The disease afflicts between 41 out of 100,000 new cases per year. About 1.3 million Americans have the disease. Nearly 50,000 deaths can be attributed to the disease. The disease can shorten life expectancy by 10 to 15 years. Nearly 50,000 have reported to have died from Rheumatoid arthritis in one year.
A Walter and Eliza Hall Institute Discovery
GM-CSF was actually a discovery originally made at the Walter and Eliza Hall Institute as a growth factor for blood cells but now is increasingly connected with a key inflammatory mediator that triggers various autoimmune disorders. Apparently earlier research involving the institute’s Professor Ian Wicks and colleagues from University of Melbourne found that GM-CSF, a signaling protein, contributed significantly to joint inflammation in rheumatoid arthritis. In fact, according to their recent news release, this finding Down Under was key in support of current clinical trials of inhibitors of GM-CSF signaling as a new approach to treating rheumatoid arthritis according to Professor Wicks. He went on to comment for the Walter and Eliza Hall Institute news that “Although we knew that GM-CSF signaling was important in joint inflammation, which cells were producing GM-CSF within joints, and how this protein signaled after binding to its receptor on other immune cells, was not well understood.”
The team, including Dr. Cynthia Louis, discovered that GM-CSF was produced by natural killer (NK) cells. Quite surprising—after all these cells were known to be important for killing virus-infected or cancer cells, reported Dr. Louis. Hence, this novel discovery that NK cells contribute to the inflammation in certain diseases such as rheumatoid arthritis.
CIS a Clue for a New Treatment?
The team also found that CIS, a protein, helps ‘switch off’ GM-CSF signaling, a critical mechanism to restrain destructive inflammation in arthritis. Hence Dr. Louis reported, “In the absence of CIS, we saw hyperactivation of GM-CSF signaling and more severe arthritis. Hence the hypothesis: if a new dug could imitate CIS it could help to reduce the effects of GM-CSF in rheumatoid arthritis as well as possibly in other diseases involving inflammation.
The study was supported by the following:
· Australian National health and Medical Research Council
· John T Reid Charitable Trusts and Victorian Government
· National Breast Cancer Foundation
· Cure Cancer Australia
· Harry J Lloyd Charitable Trust
· Melanoma Research Alliance
· Tour de Cure
· Cancer Research Institute
· Ian Potter Foundation
Ian Wicks, Professor, Joint Division Head, Laboratory Head, Clinical Translation
Cynthia Louis, MD,
Nicholas Huntington, Professor (now at Monash University)
Fernando Souza-Fonseca-Guimaraes, MD (now at Univ. of Queensland)
Call to Action: The team has identified new aspects of cell signaling that warrants more investigation. Those interested in this topic should connect with this Australian-based group.