Removal of Key Catalyst Leads to Creation of Disease

ScienceDaily (Sep. 8, 2010) — Elimination of a molecular gatekeeper leads to the development of arthritis in mice, scientists report in a study published in The Journal of Experimental Medicine. The newly discovered gatekeeper is a protein that determines the fate — survival or death — of damaging cells that mistakenly attack the body’s own tissues and lead to autoimmune disorders such as arthritis.

Better understanding how arthritis develops will offer scientists an opportunity to explore new types of treatments for patients whose arthritis has not been effectively treated with current therapies.

“This finding is an encouraging step forward for researchers, clinicians and arthritis sufferers, many of whom fail available therapies,” said lead researcher Frances Lund, Ph.D., professor of Medicine in the Division of Allergy/Immunology and Rheumatology at the University of Rochester Medical Center. “An added bonus is that this finding may help in the search for new treatments for other autoimmune disorders, such as lupus.”

The catalyst at the heart of the new find, familiar as G?q (G alpha q), is break of a larger signaling path that City and collaborators from crossways the Conjugated States and China investigated in mice. G?q regulates B cells, one type of immune radiotelephone that the embody maintains to fighting off invaders like bacteria, viruses and parasites. Time most B cells cater hold the embody, some B cells are autoreactive — they movement against the embody’s own tissues.

In mice, G?q commonly stops autoreactive B cells from structure up in tissues by suppressing the pro-survival communication path bare by Lund’s group. When G?q is eliminated, autoreactive B cells are fit to strait through inner ‘checkpoints’ that typically get rid of these toxic cells, creating a buildup of the cells that contributes to the processing of autoimmune disease.

Individual new studies expanding on the rife uncovering are in the activity, including investigation whether drug compounds that redact the manifestation or process of G?q in mice can andante the utilisation of autoimmunity. Beyond preclinical investigation in mice, researchers also comedian to start showing G?q levels in patients to learn many about how the catalyst mechanism in humans.

According to Metropolis, “There is a subset of cardiac patients who, due to an inherited inheritable sport, bonk enlarged levels of G?q. We are now perception to see if any arthritis patients feature mutations that token diminished levels of G?q. If we exploit these patients, someday we may be fit to arrangement targeted, personalized therapy for this subpopulation of arthritis sufferers.”

“In the ago few decades, nearly all of the really arch advances in rheumatology hump started with staple studies equal this one,” said Richard John Looney, M.D., a rheumatologist and academician of Treat at the University of Rochester Medical Building. “I gift be peculiarly fascinated in the travel studies that leave be play presently, as they may termination in new applications much as assessing the danger someone may meliorate t.b. or another autoimmune diseases.”

Lund’s research also led to the creation of a new mouse model of arthritis. By eliminating Gαq, the disease just happens in mice, as opposed to previous mouse models which require injecting an antigen or foreign body, such as collagen, into mice to trigger an immune response. The new model more closely mirrors how autoimmunity starts and progresses in humans, and may be used in the future to test new drugs in development.

“Our goal is to move the knowledge we’ve gained from basic research to meaningful results that will ultimately help patients, and our main finding coupled with the creation of an improved mouse model puts us in a very strong position to do that,” said Lund.

As with many discoveries, the new finding came about unexpectedly. Scientists in Lund’s lab were looking at cell migration to try to identify the molecular signals that cause inflammation in tissues in Gαq knockout mice. They noticed that as they grew older, the mice’s joints swelled and it appeared as though they were getting arthritis. Lund’s team pursued the lead, which led to the discovery of the protein’s role in the development of the disease and the creation of the new mouse model.

In addition to Lund, Ravi Misra, Ph.D., Betty Mousseau, Kim Kusser, and Troy Randall, Ph.D., from the University of Rochester Medical Center contributed to the research. Scientists from Sichuan University, China, the University of Washington, Seattle Children’s Research Institute, the Trudeau Institute, the University of Massachusetts Medical School, and the University of California, San Diego, School of Medicine were also part of the research team. Biogen Idec and Human Genome Sciences provided biologic drugs that were used to test whether B cells in the Gαq deficient mice were responsible for causing arthritis in the mice.

The research was funded by the National Institute of Allergy and Infectious Disease at the National Institutes of Health and the University of Rochester Medical Center.