Aug. 23, 2010 Scientists at the University Medical Center of Johannes Gutenberg University Mainz, Germany have taken a further step towards improving our understanding of how asthma develops. New findings show that the gene-regulating molecule "IRF4" plays a key role in the development of T helper 9 lymphocytes (Th9 cells), which can play a major part in the development of this chronic, inflammatory illness of the respiratory tract. The findings were shown for the first time in research carried out by the work group led by Dr. Tobias Bopp and Professor Dr. Edgar Schmitt from the Institute for Immunology, which was recently published in the internationally scientific journal Immunity.
Over the past 100 years, asthma has developed from a relatively rare lung disease into an epidemic. Around 300 million people suffer from asthma worldwide. And twice as many men suffer from the illness than women. We know that allergic immune reactions can contribute significantly to the development of asthma. Hyperreactive Th cells, which form part of the body's own immune system, play a major role in the manifestation of this illness.
Different T cells carry out various tasks in the body's immune defense: Cells with a helper function known as T helper (Th) cells produce various cytokines that enable the different immune defense cells to communicate with each other, which in turn helps them launch a coordinated attack on pathogens or even tumour cells. However, if these cells react disproportionately to harmless substances, they can also cause disease. T helper cells can be divided into several sub-groups, including Th9 cells. These Th9 cells were characterized in two phases: They were described for the first time in 1994 as interleukin (IL)-9-producing T helper cells by Professor Schmitt, and finally became known as Th9 cells in 2008.
"Until now, only evidence was provided for the existence of Th9 cells and the crucial importance of IL-9 in the pathogenesis of asthma. However, as other cells beside T cells can produce IL-9 the major source of this cytokine was far from being definitive. To enable targeted therapeutic intervention, however, it was necessary to uncover the basic molecular mechanism underlying the development and function of IL-9-producing Th9 cells. Our analyses finally showed that IRF4 -- a molecule that plays a key role in the regulation of genes -- is essential for the development and function of Th9 cells," explain Dr. Tobias Bopp and Professor Dr. Edgar Schmitt from the Institute for Immunology.
The functional studies were carried out mainly on mice. The starting point was the observation that T cells in mice missing an intact IRF4 molecule do not develop into Th9 cells and are therefore unable to produce significant quantities of IL-9. As IL-9 is responsible for a variety of different asthma symptoms, the scientists led by Dr. Tobias Bopp and Professor Dr. Edgar Schmitt investigated to what extent IRF4 and consequently Th9 cells contribute to development and manifestation of asthma. These experiments showed that a failure in Th9 development prevents IRF4-deficient mice from asthma. Transfer of Th9 cells led to reappearance of asthma symptoms in such mice confirming the importance of this Th-subpopulation for the induction of asthma.
Professor Dr. Hansjörg Schild, Director of the Institute for Immunology, stresses how important basic research is for the development of new therapeutic strategies: "Asthma has been on the increase for decades in industrial countries. The discovery of Dr. Tobias Bopp and Professor Dr. Edgar Schmitt could provide the first step to improve existing therapeutic treatments but we still have a long and arduous journey ahead." The next step of the research process is to screen substances, among them naturally occurring molecules/agents, that suppress the production of IL-9 to develop innovative approaches for the treatment of asthma.
This view is also shared by the Scientific Director of the University Medical Center Mainz, Professor Dr. Dr. Reinhard Urban: "Immunological illnesses are playing an ever greater role in our society. It is therefore only logical that the researchers in the University Medical Center should focus on the basic cellular mechanisms and use their results to help improve treatment for patients."
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- Valérie Staudt, Evita Bothur, Matthias Klein, Karen Lingnau, Sebastian Reuter, Nadine Grebe, Bastian Gerlitzki, Markus Hoffmann, Alexander Ulges, Christian Taube. Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells. Immunity, 2010; DOI: 10.1016/j.immuni.2010.07.014
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