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Discuss this statement in relation to normal homeostasis and the pathophysiological roles of these cells

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Institute of Psychiatry MSc Neuroscience 2007 - 2008 FULL TIME STUDENT ESSAY Module 4: Essay Question No: 10 TITLE Microglia are dynamic cells that act as pathological sensors within the adult nervous system. Discuss this statement in relation to normal homeostasis and the pathophysiological roles of these cells. WORD COUNT: 2953 MARKER'S COMMENTS: CANDIDATE NUMBER: K22563 PAGE NUMBER:19 Microglia is dynamic cells that act as pathological sensors within the adult nervous system.Discuss this statement in relation to normal homeostasis and the pathophysiological roles of these cells? In my essay I will be focussing on how resting microglial cells function as sensors and scan the tissue in the normal brain and how this microglia change in morphology and transform into activated microglia in response to injury. I will also focus on how these activated microglial cells respond to injury and the immune responses involved in clearing cellular debris, aid tissue repair by producing growth factors and engulf invading microorganisms. In the central nervous system, microglia were found to be the third glial cell type by Del Rio Hortega amongst all of the possible glial cell types (Tanaka et al, 2003). In 1932, Rio-Hortega described these microglia in silver carbonate stained brain preparation as consisting of long and branched processes. They are mesodermal, monocytic or ectodermal in origin (Lee et al, 2002). The brain, the spinal cord parenchyma and the CNS proper consists of microglias which are a group of cells related to monocytes and dendritic cells and are intrinsic immune cells. These groups of cells provide a first line of defence against neural infection. The microglia makes up 5-20% of all glial cells in the normal adult brain and is found uniformly in a scattered array.Microglial cells play an important role as immunocompetent and phagocytic cells in the CNS (Perry and Gordon, 1988; McGeer and McGeer, 1995).In the early stages of brain development, microglia demonstrate a macrophage-like morphology with a big cell body and short processes. ...read more.


ICAM-1 is the ligand for CD11a and complement proteins are the ligands for CD11b and CD11c.The receptors for Fc chain of immunoglobulin are increasingly expressed in microglia. In reactive microglia, MHC class II antigens are particularly expressed (Woodroofe et al, 1991). Some microglia display both MHC class I and class II antigens and interact with T helper and T cytotoxic classes of lymphocytes. Figure 2: Figure 3b shows that parenchymal microglia or macrophages in their resting state do not express CD14 and following traumatic brain injury, the numbers of CD14 increased in brain parenchyma. In figure 3c following injury, the early expression of CD14 forms an important part of the acute inflammatory CNS response (Beschorner et al, 2002). In human microglia, B7-1 and B7-2 are expressed in a cytokine-regulated manner. B7-1 and B7-2 are part of the members of the B7 family of cell surface glycoproteins. Activated microglia-derived macrophages express the antigens and at sites of inflammation cell mediated immune responses occur. Many cytokines such as IL-2, IL-4, IFN-? and GMCSF increase the expression of B7 on antigen presenting cells and is downregulated by IL-10 (Azuma et al, 1993). Figure 3: This figure shows the expression of various cytokines and chemokine receptors in microglia (Hanisch, 2002). Microglial cells are characterized by monocyte/macrophage antigens. As well as the monocyte-origin theory, there is also a neuroectodermal-origin theory which suggests that microglia are born in neuroectodermal derived glioblasts.Microglia is the main defence line of the brain because when the central nervous system is infected, ramified microglia change into phagocytes and engulf the infectious microbes. Dying cells present in the central nervous system are phagocytosed by ramified microglia-derived macrophages. When the blood brain barrier is disturbed, microglia work as antigen presenting cells in the immune system. Furthermore, microglia releases many biologically active substances which stimulate inflammation and cell death and therefore maintain regenerative processes. Hence microglia acts as a "sensor" for pathological events in the brain. ...read more.


Experiments show that macrophages, which enter the CNS after injury, did not display P2Y12 receptors when they were in the resting phenotype. P2Y12 protein was restricted to the microglial cells surface and also the ramified processes. Studies were conducted to observe the change in microglial morphology in response to injury and these type of studies involved using imaged microglia in brain slices. Highly motile protrusions continuously inspect the environment and pick up the tissue debris. The movement and growth of microglia is driven by filamentous actin, which are held in large amounts in the microglia. Microglia has a neuroprotective function because microlesion experiments show that injured sites are shielded. The early appearance of inclusions shaped as spheres demonstrate that microglia have an immediate phagocytic function which engulf components and clear out damaged tissue or leaked blood components. Therefore this proves that microglia provide the first line of defence. Studies show that in response to ATP the microglia in rat brain and mouse demonstrates activation of a cation conductance mediated by P2X and delayed stimulation of an outward directed K+ current, which is mediated by P2X receptors (Farber et al, 2006). The stimulation of both P2X and P2Y receptors leads to a rise in intracellular calcium concentration. So in conclusion, microglia in their 'resting state' characterised by their ramified morphology are increasingly active and they continuously survey their microenvironment with their mobile processes and protrusions. In a response to any pathological events, such as stroke or trauma, the resting microglial cells alter into an activated amoeboid form, where they can proliferate, migrate chemotactically to sites of injury and secrete many cytokines and chemokines and so this demonstrates that microglial cells are able to sense factors involved in the pathological point of view. This microglia changes their behaviour from patrolling to shielding of the injured site. So therefore microglia is busy and cautious housekeepers in the brain. ...read more.

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