30th March 05:00
The immune system in iron overload / 12 Jul 2005 (diabetes lymphocytes hemochromatosis haemochromatosis eye)
The immune system in hemochromatosis - more than meets the eye?
12 Jul 2005
Hereditary haemochromatosis (HH) is a disease characterised by
excessive absorbance and storage of iron in the body, which results
from a mutation in HFE, a gene involved in iron regulation. In
addition, HH patients have an abnormal immune system (IS), and it has
been suggested that the IS is also involved in HH iron deregulation.
And now, research by a team of Portuguese scientists about to be
published on the 1st of August issue of the journal Blood, shows, that
the HFE gene seems to be involved, not only in iron regulation, but
also in the immune response. The discovery not only helps to understand
better the mechanism behind the disease, but proves, for the first
time, the existence of a molecular link between iron homeostasis and
the IS, suggesting what a few scientists have proposed before - that
the IS might be involved in more functions in the body beside the fight
Hereditary hemochromatosis is the most common genetic illness among
people of North European ancestry where it affects as many as 1 in
200-300 individuals. The disease results in excessive storage of iron
in the body tissues leading to damage, and if not treated, organ
failure and even death. Symptoms vary from mild to life-threatening
heart and liver disease, arthritis or even diabetes mellitus depending
on the damaged organ.
An interesting characteristic of the disease is that individuals with
the same HFE mutations can, nevertheless, present a large range of
disease severities, what shows that other factors, beside HFE, seem to
be involved in disease outcome. And in fact HH patients are also
immuno-suppressed presenting, among other problems, low numbers of
specific subsets of white blood cell, the IS "responders" against
intruders. Research seems to indicate that these immunological problems
are involved, together with the mutated HFE gene, in the excessive
absorbance and storage of iron observed in HH although the reason
behind such deficiencies is unknown.
But now Sérgio F. De Almeida, Isabel F. Carvalho, Maria De Sousa and
colleagues at the Institute for Molecular and Cell Biology (IBMC) and
ICBAS, Oporto, Portugal and The Netherlands Cancer Institute in
Amsterdam, might have put together the first piece of the puzzle.
The team of scientists decided to compare the blood of HH patients
carrying the C282Y mutation - which is responsible for 80% of the HH
cases - with the blood of healthy controls. To their surprise, they
found that in the patients' blood, a key component of the immune
response, the MHC-I molecule, was found to be unstable and therefore
non-functional. MHC molecules (I and II) are crucial for the immune
response where they bind and "present" disease-inducing-intruders
to white blood cells, the "responders" of the IS. When the complex
intruder-MHC engages with a "fitting" white blood cell, this leads
to the activation of the immune response.
Confirming the hypothesis that this immune abnormality resulted from
the mutated HFE gene, patients with two mutated copies of the gene had
a much higher number of non-functional MHC-I molecules than patients
with one mutated and one normal copy
To Dr. Hal Drakesmith, a molecular biologist working on hemochromatosis
at Oxford University, this is no doubt an important discovery "we
only had observational studies on a possible crosstalk between iron
metabolism and the IS in HH, this is the first molecular biology data
showing a very clear effect... the fact that the work is done with
cells, straight from the individual, gives further credibility to the
results and makes us believe that there is definitely something going
on...", he says.
For Prof. De Sousa this work is the beggining of the end in a long path
trying to prove that the IS has a role in iron regulation. "Already
in 1978 I got tired of believing that the IS was only for what the
books said, how could all the species that do not have a complex IS
survive?", she says. And while studying cell migration in the body
she realised that in some diseases, where lymphocytes ac***ulate in
"wrong" places, these places had very high iron concentrations.
"Iron , or potential iron toxicity coming from the red blood cell
circulation, seemed a good reason for having a circulation of
lymphocytes", she says.
The truth is that the more complex a biological system becomes, more
energy it needs for its sustainance, and as result, organisms only tend
to become more complex if that gives them survival advantage. And if
simpler IS could fight infection efficiently, as De Sousa says, then
more complex IS, like the ones in mammals, might in fact have
additional functions as important for survival.
And now, almost thirthy years after, the puzzle seems to start to take
shape with Almeida, Carvalho, De Sousa and colleagues' latest
results, which provide the first molecular evidence of a direct link
between iron homeostasis and the IS.
"The importance of this paper is that HFE, a protein generally
thought to affect iron metabolism now is shown to have a clear
immunological function through MHC class I" says De Sousa.
If De Sousa's theory proves to be correct - that the IS is involved in
maintaining iron homeostasis - this will challenge one of the better
guarded dogmas of immunology/biology - that this biological system
evolved in order to fight infection and will no doubt raise much
discussion. Dogmas are after all difficult to change. But whatever
happens, this is no doubt a very interesting story and one worthwhile
to keep an eye on.
Original paper's authors:
S. F. de Almeida
Maria de Sousa (email@example.com)
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