Ground breaking research by Professor Luigina Romani and co-workers has shed light on new mechanisms that explain and help treat inflammation in CGD. The results published in the journal Nature are a milestone discovery in understanding why this inflammation occurs and how we might be able to prevent it. Importantly the work has highlighted a previously undiscovered role for superoxide in explaining recurrent infections and exaggerated inflammation in CGD.
The CGD Research Trust funds work related to this project in the laboratory of the lead author, Professor Luigina Romani at the University of Perugia in Italy and co-author, Dr Brahm Segal at Roswell Park Cancer Institute in Buffalo, USA. Professor Romani explains 'As we all know CGD derives its name from the formation of granulomas. Granulomas are solid masses of inflamed tissue that are formed due to the excessive accumulation of inflammatory cells and large collections of different cell types such as neutrophils and lymphocytes. They are sites of 'super' inflammation where the exaggerated inflammatory response itself can be as damaging to the body as the inability to fight off the infection. Although granulomas are often formed at sites of infection in CGD we have now come to realise that granulomas may form at sites in CGD patients that are clearly not infected. This led researchers to believe that granuloma formation is fundamentally linked to the molecular defect in CGD and that the condition is not just simply a failure to kill and clear infections caused by bacteria and fungi. We now have discovered what mechanisms are involved and how we might help resolve inflammation and better fight infections in CGD'.
People affected by CGD can suffer from the formation of severely painful obstructive granulomas in their bladder and stomach leading to severe problems. Inflammatory bowel disease is also a major problem and up until now little has been known on how to prevent or treat granulomas and inflammation in CGD. 'The genetic defect in CGD means that cells cannot produce superoxide molecules. What we have done is identify a key pathway, involved in inflammatory responses and immune responses in CGD mice, that is dependent for its normal working on the production of superoxides. When the superoxides are not present the pathway is unable to be switched off through a feedback mechanism so we get the hyperinflammation. We need inflammation to clear infections but when it is becomes out of control such as in CGD it can actually interfere with the control of infections and cause problems such as granulomas' states Professor Romani.
These studies use mouse models of CGD that have been infected by the fungus Aspergillus. The results show for the first time, that CGD is associated with a defect in the metabolism of an amino acid known as tryptophan through the kynurenine pathway. 'This defect is associated with impaired ability to defend against Aspergillus, a fungus that is a major threat in CGD and an inability to restrain excessive inflammation' comments Dr Brahm Segal, a co-author on the publication. 'But what is particularly important is that we have uncovered other findings that may have important implications for treatment of CGD. Firstly, the defect in the kynurenine pathway allows the excessive differentiation of a type of white blood cell, a T lymphocyte, that produces lots of a chemical signal known as interleukin -17. This chemical trigger sets up conditions for hyperinflammation and granuloma formation. And secondly, this scenario actually interferes with the control of the Aspergillus infection in CGD mice', continues Dr Segal.
Professor Romani adds 'What is most exciting is that when we give the Aspergillus infected CGD mice L-kynurenine, the metabolite of tryptophan, or neutralise the interleukin-17 activity, we see a reversal of the excessive inflammation and increased the survival of the mice from Aspergillus infection. This means we may be able to reactivate pathways downstream of the superoxide dependent step and so help people with CGD fight infections.'
In other words, the overwhelmingly encouraging news is that the scientists have increased their understanding of the mechanisms that enable the body to fight Aspergillus infections. Armed with this knowledge, they will now be able to focus on work to find ways of helping people affected by CGD overcome such grave infections.
The work also has broader implications. Dr Segal explains, “How the enzyme affected in CGD regulates inflammation is centrally relevant to CGD, but it is broadly important to disorders of inflammation such as autoimmune disorders and cancer”.
So what happens next? Dr Segal comments 'Our future work will use the CGD mouse model and white cells from CGD patients to further understand how NADPH oxidase controls inflammation. We hope to be able to translate these laboratory findings into a clinical trial in CGD patients.'
Reference http://www.nature.com/nature/journal/v451/n7175/abs/nature06471.html
Quotes from leading CGD researchers and clinicians
Professor Steve Holland, Laboratory of Clinical Infectious Diseases, National Institutes of Health, USA.
'These are impressive and unexpected findings from the mouse model of CGD, showing that aberrant inflammation in mice with CGD is due to abnormal metabolism of an amino acid, tryptophan, and that that has consequences for fungal infections. These data will need extension to humans, but if they hold true, provide important insights into disease and therapeutic opportunities'.
Professor Dirk Roos, Sanquin Research Centre in Amsterdam, is a biochemist and has been involved in CGD research for the last 30 years.
'The implications of this work are very important for CGD patients. Of course, it remains to be proven that the whole series of events now discovered to be of importance in mice also takes place in man, but I expect that to be proven soon.'
Professor Taco Kuijpers, Pediatric Immunologist & Head of Division of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, The Netherlands.
'This finding is very important for our understanding which factors are involved in the formation of the granuloma in CGD patients. However, at the present time L-kynurenine cannot be given to humans, because it induces epileptic fits. Perhaps in future it will be possible to construct drugs that correct the inflammatory status without these side effects, but at present these are not available.'
Dr Harry Malech, Head, Genetic Immunotherapy Section
Chief, Laboratory of Host Defenses, National Institutes of Health, USA.
'This is the first firmly convincing demonstration that excessive inflammation of CGD might itself be detrimental to infection control, and furthermore, it suggests that intervening in this way in infected CGD patients might help these patients survive some types of very severe and highly inflammatory infections. A final caveat of course is that there are differences between mice and humans in some of the inflammation pathways, and because of this, the metabolic disturbances observed in CGD mice must be shown to apply in human patients with CGD. However, I expect that it is likely that many of the observations will hold up as applying to human patients with CGD.'
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
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