A Children's Hospital team led by Cindy 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.''

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. Andrews' 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 Andrews.

Andrews 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 Andrews, 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.''

''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 Howard Hughes Medical Institute, the National Institutes of Health, and the Gottfried Wilhelm Leibniz prize funded the study.