Rare condition provides information about common illnesses

[Guest guest]

Rare condition provides information about common illnesses

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

På Høyden - Bergen,Hordaland,Norway

http://nyheter.uib.no/?modus=vis_engelsk & id=34765

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.

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.