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Nettavis for Universitetet i Bergen - lørdag 21. november 2009
5.1.2007
Rare condition provides information about common illnesses


Postdoctor Anette S. Bøe Wolff and Professor Eystein Husebye are among the researchers who have studied the rare disease APS-1 in Norway. They now hope that this research can benefit hundreds of thousands of patients suffering from autoimmune diseases. (Photo: Lars Holger Ursin)

Facts/APS-1
Autoimmune polyendocrine syndrome, or APS-1, is a serious monogenic disease which affects about one in 90,000 Norwegians. It is less widespread in other countries, but it is much more common in some areas, such as Finland and Sardinia and among Iranian Jews, where it may affect as many as one in 9,000.

The disease is caused by a mutation in the AIRE gene, which stands for autoimmune regulator. This gene plays a very important part in the structure of the immune system, in the thymus: It is responsible for what is known in medicine as “central tolerance” – that the immune system is able to distinguish between what belongs to its own body and what is foreign.


When the immune system cells are exposed to antigens, substances from outside the body that cause an immune response, they are supposed to produce antibodies to neutralise the antigens. However, the cells must not respond in the same way to antigens produced by the body itself, the self antigens. They are therefore exposed to such self antigens in the thymus. If an immune system cell recognises them, it will be destroyed. It is a tough weeding-out process – only about 5 per cent of the newly-formed immune system cells make it through.

“Isn’t that a very complicated way of sorting the immune system cells?”


“Not really. It ensures diversity in the immune system – after all, the cells need to be able to respond broadly, to substances they have never encountered before. Therefore, it is no good checking whether they attack the right substances – it is more rational to check whether they do not attack the ones that belong there,” says Anette S. Bøe Wolff.


However, only the self antigens present in the blood stream are present in the thymus, and that is not enough to be sure that the cells will not attack tissue in other parts of the body. This is where AIRE comes into the picture: AIRE can express the genes of the tissue-specific self antigens – for example the ones that the cells may later encounter in the pancreas, the testicles or the adrenal glands.


If AIRE is disabled, the self antigens from other organs will not be expressed in the thymus, the eye of the needle will widen, and immune system cells which should have been destroyed will be released and could harm the body. This causes great problems: These cells can then attack healthy tissue that belongs in the body – first and foremost in the hormone-producing glands. In all, about 15 organs in the body can be attacked – and the disease could be fatal.


“But, if diagnosed early, patients can be treated with drugs and live a good life,” Ms Bøe Wolff explains.

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Anette S. Bøe Wolff has collected data about 36 Norwegian patients suffering from the rare hormone disorder APS-1. This information may benefit hundreds of thousands of Norwegians.

By Lars Holger Ursin

Patients suffering from psoriasis, multiple sclerosis, type 1 diabetes, rheumatoid arthritis and lupus have one important thing in common: They all suffer from an autoimmune disease, this means a condition where the body’s immune system reacts not only to foreign substances, as it is supposed to do, but also to substances that belong in the body.


“Autoimmunity is not unnatural, it is a normal process which is out of balance,” Anette S. Bøe Wolff emphasises. She is one of the scientists working on APS-1, one of the rarest autoimmune diseases. Ironically, new knowledge about this rare disease can provide new insight into the entire phenomenon of autoimmunity. APS-1 is very suitable for use as a model disease.

“The reason for this is that it is a monogenic disease. This means that a mutation in one gene is sufficient to develop the disease," Ms Bøe Wolff explains.


Hope for autoimmunity patients
“In APS-1, the defect is in AIRE gene, which we know plays a central part in the immune system,” Ms Bøe Wolff explains.


If the underlying causality is this clear, then researchers can focus on how the disease manifests itself, not only because this gives them knowledge about autoimmunity in general, but also because it can give patients who suffer from this rare disease hope of better treatment in future.


Researchers from UiB have contacted hospitals all over Norway looking for patients with certain symptoms that are characteristic for APS-1. Ms Bøe Wolff has then collected tissue samples from the recruited patients and tested them for mutations in the AIRE gene.


“All of them had a mutation in this gene. We identified a total of 11 different mutations – two of them are common, but we also found five that have not been described before,” she tells us.


New method for early diagnosis
Ms Bøe Wolff and her colleagues have also been interested in identifying new diagnostic markers for the disease – that is, whether there are simpler ways for doctors to find out at an early stage whether patients have APS-1. For this reason, they have followed patients over a period of time after they contracted the disease in order to study the development of symptoms.


Among other things, APS-1 causes the cells of the body’s immune system to produce autoantibodies against a number of proteins (antigens) which occur naturally in the body. Among other things, they found autoantibodies against interferon omega in all the patients.

“We find this in patients before they develop the disease itself. Therefore, this may be a method well suited to identifying patients early so that they can start treatment sooner. Having a possible diagnostic marker that can identify all patients is unusual in medicine,” Ms Bøe Wolff explains.

The research on APS-1 at the University of Bergen is part of a larger international project coordinated by Uppsala University. The project involves 17 partner institutions, including two Australian institutions and one from Hong Kong. The great international interest is, among other things, connected to the fact that APS-1 is a suitable model disease for autoimmunity. At the same time, it is so rare that obtaining a sufficiently large material demands coordinated international efforts.


Helpful mice
“It is easier to study such processes in monogenic diseases than in the more typical polygenically inherited autoimmune diseases, where it is assumed that tens of genes may be involved – and much of the time it is not mutations that are involved, but variations in different genes,” explains Professor Eystein Husebye of the Institute of Medicine. He is the head of the research group in which Ms Wolff works as a postdoc, and he is involved in the project coordinated by Uppsala, which is financed by EU’s Sixth Framework Programme.


“Among other things, we are trying to collect data about all patients in Europe, and to study the mutations of the AIRE gene as well as which autoantibodies they produce,” he explains.


Animal tests on mice which do not have the AIRE gene have already provided the researchers with a lot of new information, but, because of a few small differences in how the disease manifests itself in mice and humans, many questions remain unanswered.

“Data from mice have provided a lot of new knowledge, but it is limited by the fact that the disease affects different organs in mice – and they do not develop fungal infections, which is common in APS-1 patients. That makes these patient data quite invaluable. When we finally obtain an overview of the effects of this defect in the AIRE gene, that will increase our understanding of autoimmunity in general,” Mr Husebye explains.

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