Iron regulation and the immune system link

[Guest guest]

Iron regulation and the immune system link

19 Apr 2004

Patients with chronic inflammatory disorders, including infections,

inflammatory bowel disease, arthritis and cancer, commonly become anemic.

The anemia can make them sicker, is sometimes severe enough to require a

blood transfusion, and responds only partially to current treatments.

Researchers at Children's Hospital Boston, Harvard Medical School, and the

European Molecular Biology Laboratory have unraveled the complicated biology

behind this type of anemia and propose new targets for drug development.

They report their findings in the April 18 edition of Nature Genetics.

A Children's Hospital team led by Roy in CHB's Division of

Hematology/Oncology previously showed that anemia of chronic disease results

from over-activation of hepcidin, a hormone involved in controlling iron in

the body.

Hepcidin is triggered by inflammation and may also help fight infection,

both by directly inactivating pathogens and by reducing the amount of iron

circulating in the blood.

This " iron withholding " deprives infectious pathogens of a nutrient they

need to proliferate, but it also reduces the iron available to developing

red blood cells. As a result, patients become anemic.

Now, Roy and colleagues have identified a key regulator of hepcidin, a

protein called HFE. The researchers showed that genetically engineered mice

with deficiencies in HFE maintained elevated levels of iron in the blood

during inflammation. " What we've shown is that unless you have the HFE

protein, you can't mount this iron-withholding response, " says Roy, who

holds a doctorate in cell biology. " By turning off HFE, you turn off

hepcidin and it's ability to respond to inflammation. "

Anemia of chronic disease is often treated with iron or erythropoietin, a

growth hormone for red blood cells, but neither is fully effective because

hepcidin blocks the necessary iron from getting to the red cells. " An

important next step is to determine whether drugs that inhibit HFE or

hepcidin will be useful, " says Senior Investigator Dr. s, a

Medical Institute investigator at Children's Hospital Boston

and the Leland Fikes Professor of Pediatrics at Harvard Medical School.

Roy notes that it may not be desirable to inactivate hepcidin completely.

The hormone's antimicrobial properties would be lost and allowing too much

iron to circulate also can promote infection. " It's going to be a balance, "

Roy says.

" If we manipulate hepcidin activity, we have to be very careful not to

encourage infection while we're trying to resolve the anemia. The ideal

would be to control infection while allowing enough iron for red blood cell

production. "

HFE has long been known to control iron absorption. s' lab has

previously shown that a lack or a defect in HFE causes an opposite condition

-- hereditary hemochromatosis (iron overload). People with this condition

absorb too much iron, and as iron levels build up, they can develop liver

cancer, heart disease, and other fatal conditions.

" Living organisms have evolved intricate mechanisms to regulate iron uptake

and distribution so they can exploit iron's useful properties while avoiding

toxicity, " notes s.

s and Roy are intrigued by the interaction of HFE and hepcidin,

because it suggests that HFE has an immunologic function as well as an

iron-regulating function.

" We don't yet understand the immunity connection, " says s, who also

holds a doctorate in biology. " Many molecules important in iron metabolism

are also involved in immune defense, or are related to molecules involved in

immune defense. But we don't yet know why. "

EMBL Scientists a Muckenthaler and Matthias Hentze collaborated

closely with the Children's/Harvard team to identify this link.

" Our results clearly link HFE to the development of this type of anemia.

More importantly, it seems that you can affect HFE function without

disrupting the immune system itself, " notes Muckenthaler. " This is the first

time that a link has been made between HFE, inflammation and anemia ­ giving

us a clear target to aim for a new treatment for anemia of chronic disease. "

The Medical Institute, the National Institutes of Health, and

the Gottfried Wilhelm Leibniz prize funded the study.

Children's Hospital Boston is home to the world's largest research

enterprise based at a pediatric medical center, where its discoveries have

benefited both children and adults for more than 130 years. More than 500

scientists, including seven members of the National Academy of Sciences,

nine members of the Institute of Medicine and 10 members of the

Medical Institute comprise Children's research community. Children's

is the primary pediatric teaching affiliate of Harvard Medical School. For

more information about the hospital visit: http://www.childrenshospital.org.

Contact: -Ellen Shay

mary.shay@...

617-355-6420

Children's Hospital Boston