Finding out what role two important parts of the immune system play in AMD
Research details
- Type of funding: Project Grant
- Grant Holder: Dr Heping Xu
- Institute: Queen's University Belfast
- Region: Northern Ireland
- Start date: November 2011
- End Date: March 2015
- Priority:
- Eye Category:
Overview
Age-related macular degeneration (AMD) is a condition in which the central part of the retina (the macula) degenerates with age. AMD is the leading cause of blindness in older people, accounting for almost 1 in 2 people registered blind in the UK from this age group. Current treatments are unsatisfactory and new effective therapies are urgently needed.
Old age, environmental factors and genetics all contribute to AMD. Environmental risk factors damage the macula, and this gets worse with age. The body’s immune system can normally protect and heal tissue, which maintains health. But this defence may break-down under certain conditions. The team thinks that AMD is caused by an imbalance between the amount of damage to the macula caused by environmental factors such as old age on the one hand, and the ability of the immune system to do repairs on the other. In this project the team investigated how the immune system deals with retinal damage caused by light, the most common environmental risk factor for AMD, in normal healthy mice and in two types of mice with specific genes that make them more likely to get AMD.
The team studied two components of the immune system that might not work properly in people with AMD patients. The aim was to discover specific chains of events (molecular pathways) in the immune system that are responsible for damage to the retina in AMD, in response to light. This is information for developing safe and effective immune therapy.-
Scientific summary
The role of monocytes and complement activation in age-related macular degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries although its pathogenesis is not fully understood. Old age, environmental and genetic risk factors all contribute to AMD.
Polymorphisms in complement and monocyte-receptor related genes are well-established risk factors for AMD, indicating a role for immune dysregulation in initiation and progression of AMD.
The team hypothesised that AMD results from an imbalance between the level of macular dysfunction caused by old age and environmental factors and the capacity of the immune system to cope with tissue damage. In this project, they investigated how the immune system deals with the most common environmental risk factor, light-mediated retinal damage. This was then be related to how immune dysregulation contributes to AMD. Using the ccl2/cx3cr1 double knockout mouse, which is an accepted model of AMD, several questions were addressed:
- How does the immune system respond to light-mediated retinal damage?
- Why does deletion of ccl2 and cx3cr1 lead to an AMD-like phenotype?
- What is the role of complement system in coping with light-mediated retinal damage, and whether blocking the complement activation pathways attenuate or exacerbate lesion progression in the ccl2/cx3cr1 double knockout mice?
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Research update
The team studied two parts of the body’s defence system (the immune system) to see what role they play in developing AMD. The first was the monocyte system – monocytes are a type of white blood cell – and the complement system, which is so called because it helps complement the body’s ability to clear out infection.
Their results showed that if the monocyte system isn’t working due to genetic fault, this makes the retina more likely to be damaged by light- older age and oxidative stress. They also found that blocking the complement system was able to reduce wet AMD damage to the retina in their mice (but didn’t have any effect on their mouse version of dry AMD).
They are following up the work in a Fight for Sight PhD studentship:
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Publications
- Chen M, Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol2015 Aug 20;jlb.3RI0615–239R.
- Zhao J, Chen M, Xu H. Experimental autoimmune uveoretinitis (EAU)-related tissue damage and angiogenesis is reduced in CCL2⁻/⁻CX₃CR1gfp/gfp mice. Invest Ophthalmol Vis Sci. 2014 Nov;55(11):7572–82.
- Hombrebueno JR, Luo C, Guo L, Chen M, Xu H. Intravitreal Injection of Normal Saline Induces Retinal Degeneration in the C57BL/6J Mouse. Transl Vis Sci Technol. 2014 Mar;3(2):3.
- Devarajan G, Chen M, Muckersie E, Xu H. Culture and characterization of microglia from the adult murine retina. Scientific World Journal. 2014;2014:894368.
- Soundara Pandi SP, Chen M, Guduric-Fuchs J, Xu H, Simpson DA. Extremely complex populations of small RNAs in the mouse retina and RPE/choroid. Invest Ophthalmol Vis Sci. 2013 Dec;54(13):8140–51.
- Luo C, Zhao J, Madden A, Chen M, Xu H. Complement expression in retinal pigment epithelial cells is modulated by activated macrophages. Exp Eye Res. 2013 Jul;112:93–101.
- Chen M, Luo C, Penalva R, Xu H. Paraquat-induced retinal degeneration is exaggerated in CX3CR1-deficient mice and is associated with increased retinal inflammation. Invest Ophthalmol Vis Sci. 2013 Jan;54(1):682–90.
- Chen M, Hombrebueno JR, Luo C, Penalva R, Zhao J, Colhoun L, et al. Age- and light-dependent development of localised retinal atrophy in CCL2(-/-)CX3CR1(GFP/GFP) mice. PLoS ONE. 2013;8(4):e61381.