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Understanding Inflammation

Inflammation that occurs due to CGD causes serious health problems, such as damage to vital organs. Greater understanding about the link between CGD and inflammation through studying the mechanisms and interactions between cells of the immune system may uncover new ways to treat severe inflammation in CGD.

Over the last 20 years the CGD Society has funded nine research projects, investing over £776,112. This funding has resulted in 13 publications, improved diagnosis of CGD and key therapeutic insights into inflammation. It has also provided proof of concept findings that have helped to secure funding from other organisations to progress research.

Investigating a new treatment for inflammation in CGD

Grant awarded to: Professor Donna Bratton and Dr Ruby Fernandez-Boyanapalli, National Jewish Health, Denver, USA

Amount: £98,466 over three years ending in 2014

Official title: ‘PPARg agonism enhances oxidant production and signalling by CGD
neutrophils for resolution of exaggerated inflammation’

Aim: To characterise the effects of the drug Pioglitazone on inflammation, using models of CGD.

Outcomes and benefits: In animal models of CGD, the drug Pioglitazone, used in the treatment of Type 2 diabetes, was shown to reduce and prevent inflammation and induce the ability of white cells to kill bacteria. This was a result of restoring oxidant production by the white blood cell populations affected in CGD. The oxidant source was determined to be the cells’ mitochondria, the ‘powerhouse’ for cellular energy supply. Significantly, this work provided preliminary data for a five-year award from the National Institutes of Health in the USA to continue these studies.

Publications resulting from this work:

Neutrophils regulate tissue neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine
Frasch SC, Fernandez-Boyanapalli RF, Zemski Berry KA, Murphy RC, Leslie CC, Nick JA, Henson PM, Bratton DL.
Journal of Biological Chemistry, 2013 Feb 15; 288(7): 4583–93.

Emerging roles for lysophosphatidylserine in resolution of inflammation
Frasch SC, Bratton DL.
Progress in Lipid Research, 2012 Jul; 51(3): 199–207.


Reversing inflammation in CGD

Grant awarded to: Professor Donna Bratton and Dr Ruby Fernandez-Boyanapalli, National Jewish Health, Denver, USA

Amount: £97,080 over two years ending in 2011

Official title: ‘Macrophage PPAR gamma signalling, efferocytosis, and exaggerated inflammation in CGD’

Aim: To investigate what mechanisms are responsible for excessive inflammation in CGD.

Outcomes and benefits: It is known that neutrophils are recruited from the blood into tissues following infection or injury. Once the recruited neutrophils have dealt with the infection or injury, they die in a manner that allows them to be recognised by cells called macrophages, which ‘eat’ them and recycle their components. This process stimulates the macrophages to signal that further recruitment of new neutrophils should stop and tissues should heal. However, in CGD, this does not happen and excessive inflammation and tissue damage occur as a result.

The work found that CGD neutrophils are not able to signal properly to macrophages for their ingestion and recycling. Instead they decompose and the cell products cause more tissue damage. Significantly, the researchers showed that they could restore proper signalling using a drug used currently to treat diabetes, known as Pioglitazone. The findings suggested that PPAR gamma signalling is a novel anti-inflammatory pathway that may be exploitable for treatment of CGD inflammation. On the strength of the findings, a follow-up grant award was made to explore this possibility.

Publications resulting from this work:

PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease
Fernandez-Boyanapalli R, Frasch SC, Riches DW, Vandivier RW, Henson PM, Bratton DL.
Blood, 2010 Nov 25; 116(22): 4512–22.

Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner
Fernandez-Boyanapalli R, McPhillips KA, Frasch SC, Janssen WJ, Dinauer MC, Riches DW, Henson PM, Byrne A, Bratton DL.
Journal of Immunology, 2010 Oct 1; 185(7): 4030–41.

Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity
Frasch SC, Fernandez-Boyanapalli RF, Berry KZ, Leslie CC, Bonventre JV, Murphy RC, Henson PM, Bratton DL.
Journal of Biological Chemistry, 2011 Apr 8; 286(14): 12108–12122.


How multiple immune system defects contribute to the severity of CGD

Grant awarded to: Dr Andrew Smith and Dr Farooq Rahman, Department of Medicine, University College London

Amount: £31,500 over one year ending in 2008

Official title: ‘Defective innate immune signalling contributes to the severity of CGD’

Aim: To identify and characterise specific immune pathways that are affected in CGD.

Outcomes and benefits: The results highlight additional abnormalities in macrophage function associated with CGD.

This study involved analysing macrophages isolated from blood of CGD patients and comparing responses to bacterial challenge with healthy cells. The studies showed that CGD macrophages produce abnormal levels of both pro- and anti-inflammatory cell mediators.

This study also investigated the link between inflammatory bowel disease in CGD and the clinical features of Crohn’s disease, with the results supporting the possibility of similar mechanisms being involved in the pathogenesis of both conditions. Significantly, by analysing the oxidative burst of cells from 100 people with Crohn’s disease, two people were found to have abnormally low responses indicative of CGD. Further investigation showed that the people concerned had been misdiagnosed, that they had CGD and could be given appropriate antibiotic and antifungal prophylactic treatment. This finding highlights the need for a diagnosis of CGD to be considered in people with Crohn’s disease.

Work is ongoing to further characterise immunological abnormalities in CGD, with the aim of identifying new cellular pathways so that novel drugs can be developed to improve the clinical management of CGD.

Publications resulting from this work:

Impaired macrophage function following bacterial stimulation in chronic granulomatous disease
Rahman FZ, Hayee B, Chee R, Segal AW, Smith AM.
Immunology, 2009 Oct; 128(2): 253–9.

The prevalence of undiagnosed disorders of neutrophil function mimicking Crohn’s disease
A. Smith and F. Rahman.
Digestive Disease Week Meeting, San Diego, USA, May 2008.
Published in Gastroenterology, 2008; 134 (Suppl 1): A14.


Investigating inflammation in CGD

Grant awarded to: Dr Joanne Brown, Professor David Goldblatt and Professor Christine Kinnon, Department of Immunobiology, Institute of Child Health, University College London

Amount: £109,682 over three years ending in 2005

Official title: ‘Investigation of chronic inflammation in CGD’

Aim: People with CGD can overcome many infections with new antibiotics, but inflammation can have a serious impact on their quality of life. This project studied the mechanisms involved in tissue inflammation in CGD.

Outcomes and benefits: This work provided key insights into why inflammation persists in CGD. Differences were found between the profile of anti-inflammatory and pro-inflammatory chemicals produced by CGD cells and normal, healthy cells. The group examined the mechanisms behind this lack of production of certain key anti-inflammatory factors in CGD cells and investigated if specific drugs affected their production.

Publications resulting from this work:

Chronic granulomatous disease; fundamental stages in our understanding of CGD
Assari T.
Medical Immunology, 2006 Sep 21; 5: 4.


What causes persistent inflammation in CGD?

Grant awarded to: Professors David Goldblatt, Christine Kinnon and Adrian Thrasher, Department of Immunobiology, Institute of Child Health, University College London

Amount: £97,476 over three years ending in 2003

Official title: ‘Therapeutic strategies for the treatment of CGD: Part II: Investigation of sterile inflammatory responses in CGD’

Aim: This project studied the mechanisms involved in tissue inflammation and granuloma formation in CGD patients. This inflammation can affect various tissues, including the lungs, liver, joints and gastrointestinal tract.

Outcomes and benefits: Normally, the inflammation occurs when the patient’s cells fight infection. Once the infection has been eliminated, the inflammatory process is turned off through the production of specialised anti-inflammatory chemicals. CGD patients appear to lack the means to ‘switch off’ the inflammatory reactions, so those sites of inflammation continue to build up and become granulomas or abscesses.

This study found that CGD phagocytes, the cell type responsible for the killing and the clearing of bacteria and fungi, produce fewer of two key anti-inflammatory molecules compared with normal cells. It is thought that the deficient production of these factors leads to the inefficient clearing of cellular debris from the site of inflammation. This continual presence of uncleared remains of cells then leads to a prolonged inflammatory response. By defining this altered production of anti-inflammatory molecules in CGD, novel treatments can be better tailored to specifically treat inflammation in CGD patients.

Publications resulting from this work:

Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD)
Brown JR, Goldblatt D, Buddle J, Morton L, Thrasher AJ.
Journal of Leukocyte Biology, 2003 May, 73(5): 591–9.


Developing a new method to unravel the inflammatory mechanism in CGD

Grant awarded to: Dr Dean Willis, Faculty of Life Sciences, University College London

Amount: £26,454 over one year ending in 2003

Official title: ‘Preliminary investigation into the regulatory role of NADPH oxidase on the production of pro- and anti-inflammatory mediators in stimulated human macrophages’

Aim: Persistent inflammation is a common occurrence in CGD and it is important to find ways of switching it off. This project examined which parts of the enzyme NADPH oxidase might be responsible for the production of inflammatory molecules.

Outcomes and benefits: A new method was used, called RNA interference, to inhibit the specific function of parts of the enzyme affected in CGD. In ‘proof of principle’ experiments, specially designed reagents were used successfully to inhibit the function of specific parts of the oxidase enzyme to look at their function. It was envisaged that this new method would dissect out and unravel the precise roles of key parts of the NADPH oxidase enzyme and could help highlight possible ways to control chronic inflammation.


Studying inflammatory bowel disease and tissue inflammation in CGD

Grant awarded to: Dr Marcus Harbord and Professor Anthony Segal, Department of Medicine, University College London

Amount: £210,000 over three years ending in 2002

Official title: ‘Investigation of bowel pathology and response to infection in the p47-phox (CGD) knock out mouse’

Aim: Inflammatory bowel disease can be a recurrent and severe problem in CGD. This project aimed to study bowel inflammation by examining the response to infection in the p47phox animal model.

Outcomes and benefits: The work discovered that crystals form at sites of chronic inflammation, such as the lungs and stomach in this CGD model. The crystals were found to contain a protein, called Ym1, that is present in neutrophils. Crystal formation was thought to be a result of the excessive turnover of neutrophils at sites of inflammation in the CGD model.

The study helped to improve understanding of bowel inflammation in CGD.

Publications resulting from this work:

Association between p47phox pseudogenes and inflammatory bowel disease
Harbord M, Hankin A, Bloom S, Mitchison H.
Blood, 2003 Apr 15; 101(8): 3337.

Ym1 is a neutrophil granule protein that crystallizes in p47phox-deficient mice
Harbord M, Novelli M, Canas B, Power D, Davis C, Godovac-Zimmermann J, Roes J, Segal AW.
Journal of Biological Chemistry, 2002 Feb 15; 277(7): 5468–75. Epub 2001 Dec 3.

Impaired neutrophil chemotaxis in Crohn’s disease relates to reduced production of chemokines and can be augmented by granulocyte-colony stimulating factor
Harbord MW, Marks DJ, Forbes A, Bloom SL, Day RM, Segal AW.
Alimentary Pharmacology and Therapeutics, 2006 Aug 15; 24(4): 651–60.


Developing a model of granuloma formation in CGD

Grant awarded to: Professor A Rosen-Woolf, Dr H von B Bernuth and Professor J Roesler, Department of Clinical Research, University of Dresden, Germany

Amount: £20,000 over one year ending in 2002

Official title: ‘Evaluation of granuloma formation in CGD’

Aim: The formation of granulomas (abscesses) is a hallmark of CGD and can be very painful. Abscesses form when cells don’t die as they should, causing sites of inflammation. This project aimed to establish a laboratory model of granuloma formation to study the processes involved.

Outcomes and benefits: The laboratory model of granuloma formation was established, which allowed a time-lapse study of the formation of this inflammatory tissue to be examined. The group were able to determine the profile of chemical factors produced at different stages of formation of the granuloma tissue. They showed that an over abundance of pro-inflammatory factors actively promotes granuloma formation.

This study helped to improve understanding of how granulomas form.


Development of models to study inflammation in CGD

Grant awarded to: Dr Marcus Harbord and Professor Anthony Segal, Department of Medicine, University College London

Amount: £85,000 over two years ending in 2000

Official title: ‘Development of a model of granulomatous enteritis using mice with deficiencies in granulocyte function’

Aim: This project aimed to establish models to study bowel inflammation in CGD.

Outcomes and benefits: Models were successfully set up that were subsequently used to shed light on the mechanisms of disease caused by neutrophil defects, such as CGD. A new technique, cantharidin blisters, was also established that allowed the investigation of acute inflammation in patients. The technique ‘cantharidin blisters’ continues to be of use for characterising the inflammatory response in both CGD and Crohn’s disease.

Publications resulting from this work:

Cantharidin blisters: a technique for investigating leukocyte trafficking and cytokine production at sites of inflammation in humans
Day RM, Harbord M, Forbes A, Segal AW.
Journal of Immunological Methods, 2001 Nov 1; 257(1–2): 213–20.


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