Hemochromatosis, Inflammation and Anemia: Researchers Discover a Surprising Link
Patients with inflammatory diseases such as arthritis, chronic infections and some types of cancer, often become anemic – a condition called anemia of chronic disease (ACD). While ACD rarely kills patients, it can make their lives miserable. A discovery at EMBL, in collaboration with researchers at Children’s Hospital Boston and Harvard Medical School, now links the gene HFE to ACD. The HFE gene is mutated in patients suffering from the common iron overload disease hemochromatosis. This finding gives hope that one day an effective and specific therapy may be developed to treat ACD (featured in Nature Genetics, April 18, 2004).
When people are infected with microbes, the level of iron in their blood drops. This has an important function: iron is essential for the growth of infectious microbes, so one way for the body to fight back is to lower the amount of iron in circulation.
“Unfortunately, while this decrease in iron hinders the spread of parasites and is beneficial in the short term, it can cause anemia," notes EMBL Group Leader Matthias Hentze. “During a long term inflammatory condition, low levels of iron can starve the bone marrow of this metal which is essential for blood cells, leading to ACD.”
Because the anemia is a consequence of a natural immune defense, it has been difficult to think of a therapy that wouldn’t also disturb the immune system itself.
Now scientists may have found a way to combat the anemia of chronic diseases by blocking the action of only one gene – HFE – without having much effect on the rest of the immune response, and without any serious consequences for the organism.
HFE is the gene mutated in the common genetic disease hemochromatosis, a condition in which the body becomes overloaded with iron. Researchers believe that when there are increased iron levels in the body, HFE signals to another molecule, an iron hormone called hepcidin. The role of hepcidin is to decrease the level of iron in the blood.
The EMBL and Children’s/Harvard research groups have now proved that HFE also plays a role in controlling the production of hepcidin when there is inflammation. They also showed that HFE is apparently not needed for any of the other common immune responses.
During long-term inflammatory conditions, hepcidin continues to bring down the level of iron – making patients anemic. So by blocking HFE, hepcidin production is reduced, and iron level no longer decreases. A therapy aimed at blocking HFE would be able to treat the anemia and would not affect the rest of the immune system. This would be beneficial to those ACD patients where the disadvantages of the anemia outweigh the benefits of withholding iron (e.g. in autoimmune diseases or arthritis).
EMBL scientist Martina Muckenthaler and the Hentze Group collaborated closely with researcher Nancy Andrews and her team at Children’s Hospital Boston and Harvard Medical School to find this link. The Children’s/Harvard team developed special strains of mice, in which researchers could study the effects of inflammation on an organism where HFE was blocked. The results were remarkable.
“Our results clearly link HFE to the development of this type of anemia. And 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 ACD.”
Trista Dawson | EMBL
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