New research could PAC punch against arthritis

RESEARCHERS in Sydney have discovered that an enzyme only found in immune cells plays a key role in promoting rheumatoid arthritis. The work raises the possibility of new and better treatments for the painful and debilitating condition, which affects about one in a thousand Australians of all ages.

Dr Kate Jeffrey and her colleagues at the Garvan Institute of Medical Research found that the enzyme known as PAC-1 is responsible for directing the activities of the immune cells which cause rheumatoid arthritis. Their work was published recently in the respected scientific journal, Nature Immunology.

“PAC-1 helps immune cells to respond to the body’s signals for help against infection in three critical ways,” Jeffrey says. “It assists the immune cells to survive, to migrate to where the emergency is, and to release potent inflammatory compounds at the site. And PAC-1 is only one member of a whole family of enzymes that can instruct immune cells in this way. So our studies may lead to better therapies for many other autoimmune and inflammatory diseases.”

Rheumatoid arthritis differs from the more common degenerative arthritis of the elderly, osteoarthritis. It is caused by over-protective immune cells which mistakenly attack the body’s own cartilage, the material which lubricates the movement of joints. As the cartilage deteriorates, the movement of bone against bone becomes very painful.

“Despite mounting knowledge of how and why the disease develops, effective treatments are limited,” says Jeffrey. “At present they focus on damping down the activity of the cartilage-damaging compounds the immune cells release, using drugs such as TNF-inhibitors, the controversial COX-2 inhibitors like VIOXX or broad-spectrum immunosuppressants. Many patients either do not respond to these drugs or develop severe side effects.”

Jeffrey and her colleagues found the enzyme by scanning all of the genes present in human immune cells. They discovered that the gene for PAC-1 was only ever “switched on” in immune cells. It produces high amounts of the enzyme when the immune cells are triggered into action by encountering a threat to the body, such as a bacterium. But the enzyme is also produced in abundance where overactive immune cells accumulate in human rheumatoid joint tissue.

Animals lacking PAC-1-where the gene is “knocked-out” in mice, for instance-fail to show any symptoms of rheumatoid arthritis such as swollen joints, Jeffrey says. “Inhibition of PAC-1 is therefore a real potential strategy for controlling the overactive immune cells responsible for rheumatoid arthritis without affecting other systems in the body. This is a completely different approach to current therapies.”

The research team is now engaged in collaborative research aimed at developing and trialling a drug which can inhibit PAC-1.

Kate Jeffrey is one of 16 Fresh Scientists who are presenting their research to school students and the general public for the first time thanks to Fresh Science, a national program hosted by the Melbourne Museum and sponsored by the Federal and Victorian governments, New Scientist, The Australian and Quantum Communications Victoria.  One of the Fresh Scientists will win a trip to the UK courtesy of the British Council to present his or her work to the Royal Institution.

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