RESEARCH - Could the key to RA lie in letting wayward cells self-destruct?

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Could the key to RA lie in letting wayward cells self-destruct?

Rheumawire

May 30, 2005

Gandey

St Louis, MO - Researchers studying mice have identified a gene that helps

immune cells protect themselves from inflammatory chemicals [1]. By knocking

out the gene known as Foxo3a, the group found that the cells fall victim to

their own damaging secretions.

" It was a surprise finding, " senior author Dr Stanford Peng (Washington

University School of Medicine, St Louis, MO) told the press. " We really

didn't expect to see this kind of response. " The work, which appears online

May 15, 2005 in Nature Medicine and is scheduled to be published in the June

issue, could have important implications for researchers seeking a

therapeutic target for inflammation.

" We already know a great deal about Foxo3a from studies of its role in some

cancers, and hopefully that puts us in a good position to devise ways to

manipulate its activity, " Peng said. " If the human version of this gene

functions in a similar fashion, modifying its activity may be a useful

approach for arthritis therapy even when the disease is already well under

way. "

Newly identified role for Foxo3a may provide new targets for treatment

The researchers point out that cognate lymphocytes have long been considered

instigators of autoimmunity in inflammatory arthritis. Neutrophils and mast

cells cause most of the acute and ongoing inflammation. Still, the molecular

mechanisms that govern them have remained largely unknown, note the

researchers, led by Dr Helena Jonsson (Washington University School of

Medicine).

Last year Peng et al found that knocking out Foxj1 produced a lupuslike

condition in mice. Both Foxj1 and Foxo3a belong to the forkhead family of

genes, which regulates the activity of other genes and has been connected to

cancer and longevity. The two genes are now thought to play similar roles

with regard to T cells, since knockout mice lacking Foxo3a were protected

from an experimental rheumatoid-arthritis-like condition. Peng suspects that

Foxo3a provides a sort of body armor for cells mediating ongoing

inflammation.

" It seems that evolution has somehow provided protective mechanisms for

innate immune cells when they go into the hazardous inflammatory

environments they create, " Peng said. " They need ways to keep themselves

alive, and Foxo3a is one of those ways. "

Peng explained, " Classically, everyone thought that the T cells somehow

recognized something specific in the joint like collagen or some other

protein and attacked it. In recent years, though, it's become more accepted

that rheumatoid arthritis is also the result of a less specific but still

harmful inflammation generated by cells from the other branch of the immune

systemthe innate immune system. "

The newly identified role for Foxo3a may provide new targets for treating

arthritic conditions caused by immune dysfunction. Currently, most

treatments in development for these disorders focus either on preventing

cells from attacking the joints or on reducing the ability of these cells to

open fire. The new results suggest it may be just as helpful to let these

cells kill themselves and each other.

The investigators are working to understand the role of Foxo3a with respect

to neutrophils, including the pathways the gene activates to block

apoptosis. They will also be looking for drugs that inhibit Foxo3a and will

test them in the mice as potential antiarthritis drugs.

Source

1. Jonsson H, P, Peng SL. Inflammatory arthritis

requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat Med;

DOI:10.1038/nm1248.

Not an MD

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Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org