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Centre Cambridge


proflachmann"Age related macular degeneration" led by Professor Sir Peter Lachmann at the Cambridge Veterinary School.

Age related macular degeneration (AMD) is the commonest cause of blindness in old age. The complement system is a part of the immune system that helps the ability of antibodies and immune cells to clear pathogens from the body. It had been shown that variations in certain genes that are responsible for components of the complement pathway, known as risk variants, can result in an increased risk of AMD. 

Using samples donated by Cambridge BioResource volunteers, we have been able to demonstrate that the blood of those carrying three of these risk variants does indeed show increased activity of the complement pathway. We have studied how this increased activity can be reduced by the addition of one component of this pathway - Factor I. We have shown that the addition of quite modest amounts of Factor I proved very effective in bringing the response back to ‘normal’ even in the highest risk sera. These results give strong support to the idea of using Factor I to treat AMD. This strategy is now to be taken to the clinic by a new company.

The genotyped bloods provided by Cambridge BioResource have been invaluable for this research.

smith ken"Investigation of the role of tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamily member polymorphisms in autoimmunity" led by Professor Ken Smith in the Cambridge Institute for Medical Research.

We are investigating one of the genetic changes that has previously been found to alter risk for inflammatory bowel disease (IBD, comprising Crohn’s disease and ulcerative colitis). Such subtle genetic variants are very common in the population and only alter the risk of getting IBD to a very small degree. However, by understanding how these genetic variants affect the body, we can begin to understand how the disease starts and perhaps identify new targets for treatment.

In this particular case, the genetic variant is near genes for members of a family of immune-regulating proteins, known as the tumor necrosis factor, or TNF, family. Through our work with the Cambridge BioResource, we have been able to recruit healthy volunteers with or without this common genetic variant to compare how their blood immune cells behave. We have been examining abundances of immune cell types, levels of inflammatory proteins, and strength of cell-cell communication. Thus far, our results indicate that the genetic variant alters the level of a particular inflammatory protein in some types of immune cells and consequently changes the capacity for signalling between cells. We are now finishing this project with some lab work to understand the implications of these exciting immune changes, in the hope that they might provide new insight into the disease mechanism and perhaps new approaches to treatment.

"The role of Melanocortin receptors in intracellular killing of M.tuberculosis" led by Dr Andres Floto in the Cambridge Institute for Medical Research.

The link between immune cells and bacterial infection control is well established across a number of diseases. Thanks to the volunteers and the Cambridge BioResource we have now completed recruitment of samples with different genetic backgrounds.

In this study we have focused on individuals with variability in the melanocortin receptor family. We are about to begin infection analyses on the samples to uncover the role these receptors may play in controlling bacterial infection. Once all the samples have been processed, we can detect whether different melanocortin receptor types alter bacterial survival in the innate immune system. These results will increase understanding of how the immune system signals in early bacterial infection and could generate new targets for treatments.

"Gene susceptibility and environmental factors: their interplay in the pathogenesis of PSC – the CD28/vitamin D axis" led by Dr Gideon Hirschfield, Centre for Liver Research and NIHR Biomedical Research Unit at the University of Birmingham.

We seek treatments for patients in whom their immune system attacks their liver. One particular illness, seen across all ages, is primary sclerosing cholangitis (PSC), in which over time damage to bile ducts in the liver causes bile duct obstruction, secondary liver scarring and a risk of cancer. At present the majority of patients ultimately need a liver transplant because no medical treatment helps.

A mixture of environment and genes are important in why someone gets PSC.  Environmental factors are diffuse for autoimmune disorders, but one factor that stands out is the association with low vitamin D levels. Amongst genes associated with risk of getting PSC is one called CD28, which makes a protein important in controlling how cells respond to injury.

With this project we aimed to study how a change in the CD28 gene, found in some PSC patients but also in some healthy individuals, affects the function of specific cells called T cells and how vitamin D can influence these changes. The use of blood from healthy volunteers with/without such changes in their CD28 genes is very important for this project as it helps us to better understand the role of this gene variation; in patients additional defects would interfere with the results.

"Function and Fate of Human Granulocytes" led by Dr Murray Clarke, in Cardiovascular Medicine.

We are interested in how interleukin-1 alpha (IL-1α), a key factor that induces inflammation, is activated and controlled. IL-1α is a vital part of the immune system that helps stop infections and keeps you healthy, but it can also cause disease if activated inappropriately.

IL-1α is normally inactive, but after being chopped into two smaller pieces it gains activity. Individuals recruited to this study have a small change in the region where IL-1α is cut, we which thought might change how much is activated. Indeed, the study has shown this to be true, with significantly less IL-1α (~50%) activated in one group compared to the other.

This information will help us identify and understand the role IL-1α normally plays in keeping people healthy and also what it does during disease.

"Genetic and cellular mechanisms protecting from tuberculosis (TB)" led by Dr Sergey Nejentsev at the University of Cambridge Department of Medicine

Every year tuberculosis (TB) kills more than 1 million people around the world. To design efficient vaccines against TB, researchers need to better understand biological mechanisms of infection and immunological protection from TB. Some people are known to be more susceptible to TB than others. The reasons are partly genetic, but specific genes remain largely unknown.

To uncover mechanisms involved in protection from TB, our laboratory collected blood samples from Cambridge BioResource volunteers, isolated immune cells from their blood and infected those cells with the bacterium that causes TB. We then studied how cells of different people responded to infection and how genetic differences affected these responses. We also compared genes of the volunteers with genes of people who suffered from TB. Our analyses have already discovered new protective biological mechanisms that are activated in human immune cells after infection. Future studies should clarify how we can influence these newly found important mechanisms to design novel efficient vaccines and drugs in order to protect people from TB.

"Functional validation of genetic variation associated with ANCA associated vasculitis" led by Dr Paul Lyons in the Cambridge Institute for Medical Research.

ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis (AAV) is a rare disease which causes the body’s white blood cells to attack the body rather than the germs and ‘invaders’ that they would normally attack.  This leads to swelling and damage in the blood vessels and other organs in the body.  AAV can affect many parts of the body including the kidneys, skin, lungs, nerves and eyes.  The underlying cause of AAV remains unclear and the treatments for this condition, whilst effective, are associated with significant side effects including long-term risk of infection and cancer.

A research technique known as a genome-wide association study (GWAS) allowed researchers to study the variations in DNA sequence between vasculitis patients and healthy subjects.  This research has recently identified a number of genetic variations that are associated with the disease.  

The participation of Cambridge BioResource volunteers as healthy controls in this study was crucial, as it helps us to unravel the mystery of how these genetic variants contribute to the development of the disease.  By having a better understanding of how this disease occurs, we will be able to create better tests to speed up diagnosis in patients with suspected vasculitis.  We will also be able to predict disease severity, which will allow for a more personalized treatment depending on individual disease behavior, and aid the design of newer medications or therapies with fewer side effects to fight this disease.