Gene Critical To Activation Of Infection-Fighting Immune Cells Identified By Weill Cornell Team

Main Category: Immune System / Vaccines
Also Included In: Infectious Diseases / Bacteria / Viruses;  Genetics
Article Date: 03 Apr 2006 - 0:00 PDT

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Every time the human body encounters a virus, bacteria or other infectious agent, immune cells called B-lymphocytes multiply in lymph nodes and then swing into action to fight off the intruders.

When it works, it's wonderful: Germs ranging from the common cold to anthrax can be wiped out by these and other immune cells. But when this response is ineffective, serious illness can result.

That's why the discovery of a gene that's key to B-lymphocyte activation is so important, says Dr. Thomas N. Sato, Professor of Cell and Developmental Biology at Weill Medical College of Cornell University, in New York City.

"Essentially, any infectious disease or any autoimmune disease that involves B-lymphocyte activation has to go through this pathway that we've discovered, and that pathway is mediated by this gene, called KLHL6," says Dr. Sato, who joined Weill Cornell Medical College last year, and conducted much of the research leading to this discovery while at the University of Texas Southwestern, in Dallas.

The findings appear in a recent issue of Molecular and Cellular Biology.

According to Dr. Sato, "whole textbooks" have been written on the role of B-cell activity in the immune response, with myriad pathways governing this response already identified. "But the KLHL6 gene appears to be a novel component of these pathways," he says.

Here's how the response usually works: When foreign agents are detected in the body, lymphocytes first gather together in lymph nodes throughout the body and begin to proliferate, forming what experts call "germinal centers." They then spread out into the body, hunting and attacking invading germs.

"It's this growth in the germinal centers that causes your lymph nodes to swell when you've got a bad infection," Dr. Sato explains.

Previous research had uncovered a gene, and its related protein, called KLHL6, which looked like it might play a role in the B-lymphocyte process.

To find out for sure, Dr. Sato's team turned to both in vitro cell cultures and special "knock-out" mice genetically engineered to lack functional KLHL6.

"We found that in these mutant mice without a working KLHL6 gene, lymph node enlargement simply didn't occur," he said.

Just why this happens isn't entirely clear -- further studies showed that the gene wasn't essential for germinal center formation. Nevertheless, without KLHL6, B-lymphocyte activation grinds to a halt.

The next step, the Weill Cornell researcher says, is to find an agent that might enhance KLHL6 function.

"Ideally, in the presence of infection, you want proper B-lymphocyte activity or even enhanced activity," he explains. "So we plan on screening small molecules that might help with this pathway."

While the potential for KLHL6-enhancing agents isn't yet known, they might someday prove beneficial against a number of viral or bacterial illnesses, including HIV/AIDS.

"Further stimulating our bodies' ability to either up-regulate the expression of KLHL6 or other components of that pathway might make us less susceptible to infections," Dr. Sato says, "not only in helping us recover better from these types of illnesses, but in making us more resistant to infection in the first place."

The study was initially funded by a grant from the drug maker Pharmacia, and received later support from the National Institutes of Health and the Deutsche Forschungsgemeinschaft.

Co-researchers include lead researcher Drs. Jens Kroll, Xiaozhong Shi, Arianna Caprioli, Hong-Hsing Liu, Keng-Mean Lin, and Toru Miyazaki -- all of the University of Texas Southwestern, in Dallas; and Dr. Hans-Reimer Rodewald, of the University of Ulm, Germany.

Joan and Sanford I. Weill Medical College of Cornell University
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