Transparent Zebrafish Provide Clues to Immune System Breakdown
Madison, Wisconsin - A small transparent fish is showing University of Wisconsin-Madison scientists how the human immune system sometimes fails to fight serious infections.
The see-through zebrafish sheds light on a serious genetic disorder in infants and on the problem that often compromises the immune systems of adult cancer patients undergoing chemotherapy.
In recent experiments with the fish, the researchers saw that defective infection-fighting white blood cells called neutrophils stayed in the circulation instead of traveling to an infection site in the fish's ear, where they should have fought the inflammation.
Zebrafish have been very useful for Dr. Anna Huttenlocher, a pediatric rheumatologist and immunologist at American Family Children's Hospital. She uses them to create models of some of the immune disorders she sees in her young patients.
"The zebrafish is a powerful tool that has helped us understand things about the immune system we didn't know before," says Huttenlocher, also a professor of medical microbiology and immunology at the University of Wisconsin School of Medicine and Public Health.
In the current study, published in Development Cell, she and post doctoral fellow Dr. Qing Deng report creating a zebrafish model for leukocyte adhesion deficiency (LAD), a genetic disorder that results in recurring and at times life-threatening bacterial infections. The problem usually occurs most acutely in newborns but can also arise later in life in a less severe form.
The zebrafish model the UW School of Medicine and Public Health scientists created was based on a specific mutation in the RAC2 gene that Huttenlocher and her collaborators discovered earlier in one pediatric patient with a form of LAD. The gene affects how neutrophils work.
"We knew that with LAD, neutrophils either didn't get recruited normally to infection sites or they didn't function normally once they were there," Huttenlocher says.
The researchers depleted normal RAC2 or inserted the mutated RAC2 gene into the zebrafish, then observed how the fish responded to a bacterial infection introduced to the ear. No neutrophils moved to the infection under those conditions, but without alterations to the RAC2 gene they did.
The researchers were surprised to learn what role defective RAC2 played in the process.
"We didn't know if it caused neutrophils to be trapped in the blood or stay in the bone marrow tissue," Huttenlocher says.
Knowing now that RAC2 prevents neutrophils from leaving bone marrow raises the possibility of new drug treatments for neutropenia, which occurs when chemotherapy suppresses the immune systems of cancer patients and makes them susceptible to infections.
Strategies to mobilize neutrophils away from bone marrow could help those patients' immune systems become stronger. Libraries of existing compounds could be screened to see if any of them modify neutrophil responses.
"But it may not be as simple as it sounds," Huttenlocher says, "because finding a way to release neutrophils does not necessarily mean they will go to the right place."
The most common treatment for an infant with LAD today is a bone marrow transplant, she adds.
Many researchers use zebrafish to study developmental biology and cancer, but Huttenlocher and her team are among the first to use the fish to create models that mimic human immune conditions.
"Zebrafish let you do live imaging of cell activity," she says, making the fish extremely useful for studying immune cell movement to infection and wound sites.
Zebrafish are also better than mice for screening drugs, she adds, since thousands of fish are easily obtainable at a much lower cost.
Date Published: 10/26/2011