New clues to help patients with immune deficiency disease

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New clues to help patients with immune deficiency disease

09/03/2011 15:53:00

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Infection researchers at Umeå University have uncovered a new disease mechanism

in patients with Chronic Granulomatous Disease (CGD) in an international

clinical collaboration with the Children's Hospital in Zurich. Their new

findings are published in the Journal of Allergy and Clinical Immunology (online

publication 4 March 2011).

Fungal infections can cause life-threatening health problems for patients with

immune deficiency. Their health is weakened by infections and they cannot

undergo the treatment or surgery they need to survive. An example is Aspergillus

infection which is life threatening for these patients. In this condition, the

immune system is not able to kill the pathogen and the mould propagates from the

lungs and respiratory tract into the whole body.

Chronic Granulomatous Disease (GDC) is a heritable severe immune deficiency

disease that occurs at a frequency of one in 200,000 humans per year worldwide.

Children with CGD often suffer life-threatening microbial infections with

bacteria and fungi and die at young age without treatment. Particularly,

infections with Aspergilli fungi often kill CGD patients, before bone marrow

transplantations or gene therapy can be performed.

Scientists at the Swedish Laboratory for Molecular Infection Medicine (MIMS) in

Umeå have now found new treatment of CGD patients.

While healthy individuals' white blood cells, also called neutrophils, release

oxygen intermediates to kill and digest invading pathogens, the immune cells in

CGD patients lack the ability to kill the microbes.

Constantin Urban, research group leader at the MIMS laboratory in Umeå is

studying mechanisms of fungi infections. In earlier studies of Candida

infections, he found with his colleagues that neutrophils form extracellular

structures, called neutrophil extracellular traps or NET, which catch microbes

and fungi.

" NET is a very smart tool, " says Urban. " It is comparable with a spider's web,

catching and killing the trapped pathogen. We found in earlier studies that

these web-like structures are made of chromatin and decorated with antimicrobial

proteins. They also release oxygen intermediates and an antifungal substance

called calprotectin. "

In collaboration with clinical researchers at the Children's Hospital in Zurich,

the scientists from Umeå found new details behind CGD. They compared the

function of a CGD patient's neutrophils before and after gene therapy.

" Our results clearly show that calprotectin is also important for the

neutrophils immune defence against Aspergillus infection, " says Constantin

Urban.

Together with PhD student Joanna Niemiec in his group at MIMS and medical

doctors in Zurich, Constantin Urban found that neutrophils from the CGD patient

did not form NETs trap and were not able to release calprotectin. This was the

reason why the neutrophils were not able to kill and digest Aspergillus cells

anymore.

" We found that after gene therapy the neutrophils could produce calprotectin at

a normal level and even the NET structure was formed again, " says Joanna.

" Our experiment showed that calprotectin is a key player for the neutrophils'

defence against Aspergillus infection. We are now convinced that calprotectin

can be used as a " molecular support " to compensate the neutrophils cell defect

in CGD patients. "

" We are confident that our study may lead to new treatment of CGD patients in

the beginning of their life and prevent them from infections until they have the

possibility to receive gene therapy or bone marrow transplantation, which are

more sustainable treatments, " says Constatin Urban. " This possible treatment for

CGD patients may also be an opportunity in the future for patients with other

immune deficiency diseases. "

Original publication:

Matteo Bianchi, MSc, J Niemiec MSC, Ulrich Siler, Constantin F. Urban, and

Janice Reichenbach: Restoration of anti-Aspergillus defense by neutrophil

extracellular traps in human chronic granulomatous disease after gene therapy is

calprotectin-dependent.

Journal of Allergy and Clinical Immunology, online publication, 4th march 2011,

doi: 10.1016/j.jaci.2011.01.021

Contact:

Constantin Urban, researcher at The Laboratory for Molecular Infection Medicine

Sweden MIMS and Department of Molecular Biology, Umeå University

Phone: +46 90 7850806

Email: constantin.urban@...

Text draft: Eva- Diehl

Editor: Meyers

Tel: 090-786 95 98