User:RichardGautney/Sandbox

=Microglia= Microglia are a type of glial cell that acts as the first and main form of active immune defense in the central nervous system(CNS). Microglia constitute 20% of the total glial cell population within the brain. Unlike Astrocytes, individual microglia are distributed in large non-overlapping regions throughout the brain and spine. Microglia are constantly moving and analyzing the CNS for damaged neurons, plaques, and infectious agents. Since the brain and spine are “immune privileged” organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier microglial cells must react quickly to increase inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (antibodies are too large to cross the blood-brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.

Origin
Microglial cells differentiate from myeloid progenitor cells, which are normally found in the bone marrow. During early development, a group of myeloid progenitor cells travel from the newly formed bone marrow to the brain where they settle and differentiate. Myeloid progenitor cells can also differentiate into dendrites and macrophages in the peripheral systems. Similar to Macrophages in the rest of the body, Microglia primarily use phagocytic and cytotoxic mechanisms to destroy foreign materials. Microglia and Macrophages both contribute to pro-inflammation and homeostatic mechanisms within the body through the secretion of cytokines and other signaling molecules. They are also both antigen-presenting cells, however macrophages are considered “professional” antigen presenting cells because they are always ready and able to act in this capacity, while microglial cells are considered “non-professional” because they must be “activated” prior to antigen presentation or phagocytosis. In their downregulated form, microglia lack the MHC class I/MHC class II proteins, CD45 antigens, and many other surface receptors required to act in the antigen-presenting, phagocytic, and cytotoxic roles the hallmark normal macrophages. Microglia also differ from macrophages in that they are much more tightly regulated spatially and temporally in order to maintain an precise immune response.

Another difference between microglia and other cells that differentiate from Myeloid Progenitor cells is the turnover rate. Macrophages and dendrites are constantly being used up and replaced by myeloid progenitor cells which differentiate into the needed type. Due to the blood brain barrier, it would be fairly difficult to be constantly replacing microglia. Therefore, instead of constantly being replaced with myeloid progenitor cells, the microglia maintain their status quo while in their quiescent state, and then, when they are activated, they rapidly proliferate in order to keep their numbers up. Bone Chimera studies have shown, however, that in cases of extreme infection the blood brain barrier will weaken, and microglia will be replaced with haematogenous, bone-marrow derived cells, namely myeloid progenitor cells and macrophages. Once the infection has decreased the disconnect between peripheral and central systems is reestablished and only microglia are present for the recovery and regrowth period.

History
The ability to view and characterize different neural cells including microglia occurred in 1980 when Nissl staining was developed by Franz Nissl. Franz Nissl and F. Robertson first described microglial cells during their histology experiments. The cell staining techniques in the 1980s showed that microglia are related to macrophages. The activation of microglia and formation of ramified microglial clusters was first noted by Babes while studying a rabies case in 1897. Babes noted the cells were found in a variety of viral brain infections but did not know what the clusters of microglia he saw were. Pio del Rio-Hortega, a student of Santiago Ramón y Cajal, first called the cells "microglia" around 1920. He went on to characterize microglial response to brain lesions in 1927 and note the “fountains of microglia” present in the corpus collasum and other perinatal white matter areas in 1932. After many years of research Rio-Hortega became generally considered as the “Father of Microglia.” For a long period of time little improvement was made in our knowledge of microglia. Then, in 1998, Hickey and Kimura showed that perivascular microglial cells are bone-marrow derived, and express high levels of MHC class II proteins used for antigen presentation. This confirmed Pio Del Rio-Hortega’s postulate that microglial cells functioned similarly to macrophages by undergoing phagocytosis and antigen presentation.

Types of Microglia
Microglial cells are extremely plastic, and undergo a variety of structural changes based on their location and current role. This level of plasticity is required to fulfill the vast variety of immunological functions that microglia perform, as well as maintaining homeostasis within the brain. If microglia were not capable of this they would need to be replaced on a regular basis like macrophages, and would not be available to the CNS immune defense on extremely short notice without causing immunological imbalance under normal conditions.

Ameboid: This form of microglial cell is found mainly within the perinatal white mater areas in the corpus callosum known as the “Fountains of Microglia.” This shape allows the microglial free movement throughout the neural tissue, which allows it to fulfill its role as a scavenger cell. Ameboid microglia are able to phagocytose debris, but do not fulfill the same antigen-presenting and inflammatory roles as activated microglia. Ameboid microglia are especially prevalent during the development and rewiring of the brain, when there are large amounts of extracellular debris and apoptotic cells to remove.

Ramified (Quiescent): This form of microglial cell is commonly found at strategic locations throughout the entire brain and spinal cord in the absence of foreign material or dying cells. This “resting” form of microglia is composed of long branching processes and a small cellular body. Unlike the ameboid forms of microglia the cell body of the ramified form remains fairly motionless, while its branches are constantly moving and surveying the surrounding area. The branches are very sensitive to small changes in physiological condition and require very specific culture conditions to observe in vitro. Unlike activated or ameboid microglia, ramified microglia are unable to phagocytose cells and display little or no immunomolecules. This includes the MHC class I/II proteins normally used by macrophages and dendrites to present antigens to t-cells, and as a result ramified microglia function extremely poorly as antigen presenters. The purpose of this state is to maintain a constant level of available microglia to detect and fight infection, while maintaining an immunologically silent environment.

Activated Non-Phagocytic: This state is actually part of a graded response as microglia move from their ramified form to their fully active phagocytic form. Microglia can be activated by a variety of factors including glutamate receptor agonists, pro-inflamatory cytokines, cell necrosis factors, and changes in extracellular potassium (indicative of ruptured cells). Once activated the cells undergo several key morphological changes including the thickening and retraction of branches, uptake of MHC class I/II proteins, expression of immunomolecules, secretion of cytotoxic factors, secretion of recruitment molecules, and secretion of pro-inflammatory signaling molecules (resulting in a pro-inflammation signal cascade). In addition, the microglia also undergo rapid proliferation in order to increase their numbers for the upcoming battle. Activated non-phagocytic microglia generally appear as “bushy,” “rods,” or small ameboids depending on how far along the ramified to full phagocytic transformation gradient they are.

Activated Phagocytic: Activated phagocytic microglia are the maximally immune responsive form of microglia. These cells generally take on a large, ameboid shape, although some variance has been observed. In addition to having the antigen presenting, cytotoxic and inflammatory mediating signaling of activated non-phagocytic microglia, they are also able to phagocytose foreign materials and display the resulting immunomolecules for T-cell activation. Phagocytic microglia travel to the site of the injury, engulf the offending material, and secrete pro-inflammatory factors to promote more cells to proliferate and do the same. Activated phagocytic microglia also interact with astrocytes and neural cells to fight off the infection as quickly as possible with minimal damage to the healthy brain cells.

Gitter Cells (Compound Granular corpuscle): Gitter cells are the eventual result of microglial cell’s phagocytosis of infectious material. Eventually, after engulfing a certain amount of material, the phagocytic microglia becomes unable to phagocytose any further materials. The resulting cellular mass is known as a granular corpuscle, named for its ‘grainy’ appearance. By looking at tissues stained to reveal gitter cells, scientists can see post-infection areas that have healed.

Perivascular Microglia: Unlike the other types of microglia mentioned above perivascular microglia refers to the location of the cell rather than its form/function. Perivascular microglia are mainly found encased within the walls of the basal lamina. They perform normal microglial functions, but unlike normal microglia they are replaced by bone marrow derived precursor cells on a regular basis and express MHC class II antigens regardless of the outside environment. Perivascular microglia also react strongly to macrophage differentiation antigens. These microglia have been shown to be essential to repair of vascular walls, as shown by Ritter’s experiments and observations on ischemic retinopathy. Perivascular microglia promote endothelial cell proliferation allowing new vessels to be formed and damaged vessels to be repaired. During repair and development, myeloid recruitment and differentiation into microglial cells is highly accelerated to accomplish these tasks.

Juxtavascular: Like perivascular microglia, juxtavascular microglia can be distinguished mainly by their location. Juxtavascular microglia are found making direct contact with the basal lamina wall of blood vessels but are not found within the walls. Like perivascular cells, they express MHC class II proteins even at low levels of inflammatory cytokine activity. Unlike perivascular cells, but similar to resident microglia, juxtavascular microglia do not exhibit rapid turnover or replacement with myeloid precursor cells on a regular basis.

Normal Functions of Microglial Cells
Microglial cells fulfill an astonishing variety of different tasks within the CNS mainly related to both immune response and maintaining homeostasis. The following are some of the major known functions carried out by these cells.

Scavenging: In addition to being very sensitive to small changes in their environment, each microglial cell also physically surveys its domain on a regular basis. This action is carried out in the ameboid and resting states. While moving through its set region if the microglial cell finds any foreign material, damaged cells, apoptotic cells, neural tangles, DNA fragments, or plaques it will activate and phagocytose the material or cell. In this manner microglial cells also act as “housekeepers” cleaning up random cellular debris. During developmental wiring of the brain, microglial play a large role removing unwanted excess cellular matter. Post development, the majority of dead or apoptotic cells are found in the cerebral cortex and the subcortical white matter. This may explain why the majority of ameboid microglial cells are found within the “fountains of microglia” in the cerebral cortex.

Phagocytosis: The main role of microglia, phagocytosis involves the engulfing of various materials. Engulfed materials generally consist of cellular debris, lipids, and apoptotic cells in the non-inflamed state, and invading viruses, bacteria, or other foreign materials in the inflamed state. Once the microglial cell is “full” it stops phagocytic activity and changes into a non-reactive gitter cell.

Cytotoxicity: In addition to being able to destroy infectious organisms through cell to cell contact via phagocytosis, microglia can also release a variety of cytotoxic substances. Microglia in culture secrete large amounts of H2O2 and NO in a process known as ‘respiratory burst’. Both of these chemicals can directly damage cells and lead to neuronal cell death. Proteases secreted by microglia catabolise specific proteins causing direct cellular damage, while cytokines like IL-1 promote demyelination of neuronal axons. Finally, microglia can injure neurons through NMDA receptor-mediated processes by secreting glutamate and aspartate. Cytotoxic secretion is aimed at destroying infected neurons, viruses, and bacteria, but can also cause large amounts of collateral neural damage. As a result, chronic inflammatory response can result in large scale neural damage as the microglia ravage the brain in an attempt to destroy the invading infection.

Antigen Presentation: As mentioned above, resident non-activated microglia act as poor antigen presenting cells due to their lack of MHC class I/II proteins. Upon activation they rapidly uptake MHC class I/II proteins and quickly become efficient antigen presenters. In some cases, microglia can also be activated by INF-γ to present antigens, but do not function as effectively as if they had undergone uptake of MHC class I/II proteins. During inflammation, T-cells cross the blood brain barrier thanks to specialized surface markers and then directly bind to microglia in order to receive antigens. Once they have been presented with antigens, T-cells go on to fulfill a variety of roles including pro-inflammatory recruitment, formation of immunomemories, secretion of cytotoxic materials, and direct attacks on the plasma membranes of foreign cells.

Synaptic Stripping: A phenomenon first noticed spinal lesions by Blinzinger and Kreutzberg in 1968, post-inflammation microglia remove the branches from nerves near damaged tissue. This helps promote regrowth and remapping of damaged neural circuitry.

Promotion of Repair: Post-inflammation, microglia undergo several steps to promote regrowth of neural tissue. These include synaptic stripping, secretion of anti-inflammatory cytokines, recruitment of neurons and astrocytes to the damaged area, and formation of gitter cells. Without microglial cells regrowth and remapping would be considerably slower in the resident areas of the CNS and almost impossible in many of the vascular systems surrounding the brain and eyes.

Extracellular Signaling: A large part of microglial cell’s role in the brain is maintaining homeostasis in non-infected regions and promoting inflammation in infected or damaged tissue. Microglia accomplish this through an extremely complicated series of extracellular signaling molecules which allow them to communicate with other microglia, astrocytes, nerves, T-cells, and myeloid progenitor cells. As mentioned above the cytokine INF-γ can be used to activate microglial cells. In addition, after becoming activated with INF-γ, microglia also release more INF-γ into the extracellular space. This activates more microglia and starts a cytokine induced activation cascade rapidly activating all nearby microglia. Microglia produced TNF-α causes neural tissue to undergo apoptosis and increases inflammation. IL-8 promotes B-cell growth and differentiation, allowing it to assist microglia in fighting infection. Another cytokine, IL-1, inhibits the cytokines IL-10 and TGF-β, which downregulate antigen presentation and pro-inflammatory signaling. Additional dendrites and T-cells are recruited to the site of injury through the microglial production of the chemotactic molecules like MDC, IL-8, and MIP-3β. Finally, PGE2 and other prostanoids help prevent chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating Th1 (T-helper cell) response.

Kreutzberg, G.W., (1995). The First Line of Defense in Brain Pathologies, Drug-	Research, 45(1): 357-360 Gehrmann, J., Matsumoto, Y., Kreutzberg, G.W., (1995). Microglia: intrinsic immuneffector cell of the brain, Brain Research Reviews, 20: 269-287. Dissing-Olesen, L., Ladeby, L., Nielsen, H.H., Toft-Hansen, H., Dalmau, I., Finsen, B., (2007). Axonal lesion-induced microglial proliferation and microglial cluster formation in the mouse, Neuroscience, 149(1): 112-122. Ritter, M.R., Banin, E., Moreno, S.K., Aguilar, E., Dorrel, M.I., Friedlander, M., (2006). Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy, Journal of Clinical Investination, 116 (12): 3266-3276. Aloisi, F., (2001). Immune Function of Microglia, Glia 36: 165-179. Gehrmann, J., (1996). Microglia: a sensor to threats in the nervous system? Research in Virology, 147: 79-88. Babes, V.S., (1892). Certains caractères des lesions histologiques de la rage. Ann Inst Pasteur Lille 6: 209–223. del Rio-Hortega, P., Penfield, W., (1927). Cerebral Cicatrix: the Reaction of Neuroglia and Microglia to Brain Wounds, Bulletin of the Johns Hopkins Hospital, 41: 278-303. del Rio-Hortega, P., (1937). Microglia. Cytology and Cellular Pathology of the nervous System, 481-534. Ferrer, I., Bernet, E., Soriano, E., Del Rio, T., Fonseca, M., (1990). Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes. Neuroscience, 39: 451-458. Rissi, D.R., Oliveira, F.N., Rech, R.R., Pierezen, F., Lemos, R.A.A., Barros, C.S.L., (2006). Epidemiology, clinical signs and distribution of the encephalic lesions in cattle affected by meningoencephalitis caused by bovine herpesvirus-5. Pwsquisa Vetreinaria Brasileira, 26(2): 123-132.

History
who discovered, previous theories on function etc

Functions
Immune system scavenging, removal of plaques, extracellular signalling

Role in Acute Inflammation
head injury Encephalitis

Links
Category:Nuerology

22:00, 19 October 2007 (UTC)