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	Thu 9th September 2010

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BSCB Science Writing Prize 2009

The Immune System: The hidden emergency service | Back

By Sophie Hidden, University of Birmingham.

We all know what it feels like when we are sick or under the weather. Lethargic, fuzzy head, aches and pains inconveniencing us for a day or two until the illness passes. This may be a rare occurrence for most of us, but have you ever thought what is responsible for protecting your body from all the nasties circling the environment we inhabit? Our immune system quietly surveys our bodies, a cellular police force searching out not criminals, but pathogens, preventing them from causing infection. White blood cells (leukocytes) constantly move through the body in the bloodstream checking for pathogens (immune surveillance) and also responding to signals from specialised immune cells (macrophages) rapidly moving into tissues to fight infection and inflammation. So how do these cells reach every inch of the body, from the tops of your fingers to the tips of your toes? Over the years, many scientists have studied the immune system and the process of ‘leukocyte recruitment’. They formulated a model of a highly regulated series of events, which researchers have been breaking down to expose the intricate workings of this process. In order to exit the blood stream into the tissues, to fight infection, leukocytes are pushed towards the vessel wall by the faster central flow of red blood cells where the flow rate is slower. This increases the chances of contact with endothelial cells, a highly specialised type of cell that lines the whole of the vasculature. These endothelial cells are covered with a variety of different cell surface receptors, which can be regulated by the cell in response to the local environment. These adhesion molecules interact with white blood cells, grabbing them from the circulation, once grabbed they roll along the surface of the vessel and finally squeeze between endothelial cells to penetrate the tissues. Once in the tissue, leukocytes sense and migrate towards a gradient of chemokines (hormones of the immune system) radiating out from the source of inflammation in a process called chemotaxis. If we can understand how leukocytes are recruited to tissues we can manipulate the system to treat diseases where recruitment malfunctions. In one such disease, Leukocyte Adhesion Deficiency (LAD), specialised adhesion molecules on the endothelial cells are not present so the leukocytes cannot bind to the vessel wall and subsequently escape into the tissue to fight infection. In addition, although leukocytes are designed to protect us, they can be a double-edged sword. Neutrophils (a type of white blood cell) produce toxic compounds and enzymes at the site of inflammation to kill the pathogen. Think of them as fire fighters putting out the fire of inflammation, but if these cells aren’t cleared from tissues effectively or if large numbers are recruited due to over expression of adhesion molecules, they leave behind water damage to the surrounding tissue. One of the major factors that we think can affect leukocyte recruitment is the local environment that endothelial cells are exposed to, which varies throughout all tissues and levels of the vascular tree. Factors affecting the physiochemical environment include, cytokines (chemicals produced by immune cells in response to infection), shear stress (forces imposed on endothelial cells by blood flow) and substances in the bloodstream. It is the ability of the leukocytes and endothelial cells to adapt to and to sense their environment and situation that interests me. Our experiments involve looking at which adhesion molecules are expressed on endothelial cells derived from different organs and to see whether the levels of adhesion molecules are altered by stimulating the cells with cytokines or exposing them to varying shear stresses. We also want to know how these alterations affect the ability of these endothelial cells to recruit different types of leukocytes. We hypothesise that if you were to take endothelial cells from the liver, and expose them to the local physiochemical environment of the heart they would take on the properties of resident cardiac endothelial cells. If we found differences we could manipulate the cells to treat chronic inflammatory diseases, such as rheumatoid arthritis and autoimmune diseases by altering the regulation of leukocyte recruitment and manipulating the system itself.