cells due to their lack of mhc class i/ii proteins. upon activation they rapidly express mhc class i/ii proteins and quickly become efficient antigen presenters. in some cases, microglia can also be activated by ifn-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. 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 hydrogen peroxide and nitric oxide 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, aspartate and quinolinic acid. cytotoxic secretion is aimed at destroying infected neurons, virus, 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. edaravone, a radical scavenger, precludes oxidative neurotoxicity precipitated by activated microglia. synaptic stripping in a phenomenon first noticed in 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. it has also been shown that microglia are involved in the process of synaptic pruning during brain development. 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. recent research verified, that microglial processes constantly monitor neuronal functions through specialized somatic junctions, and sense the "well-being" of nerve cells. via this intercellular communication pathway, microglia are capable of exerting robust neuroprotective effects, contributing significantly to repair after brain injury. microglia have also been shown to contribute to proper brain development, through contacting immature, developing neurons. development for a long time it was thought that microglial cells differentiate in the bone marrow from hematopoietic stem cells, the progenitors of all blood cells. however, recent studies show that microglia originate in the yolk sac during a remarkably restricted embryonal period and populate the brain mesenchyme. yolk sac progenitor cells require activation colony stimulating factor 1 receptor (csf1r) for migration into the brain and differentiation into microglia. additionally, they continuously renew themselves and persist throughout life without replenishment from peripheral monocytic precursors. monocytes can also differentiate into myeloid dendritic cells and macrophages in the peripheral systems. like macrophages in the rest of the body, microglia use phagocytic and cytotoxic mechanisms to destroy foreign materials. microglia and macrophages both contribute to the immune response by acting as antigen presenting cells, as well as promoting inflammation and homeostatic mechanisms within the body by secreting cytokines and other signaling molecules. in their downregulated form, microglia lack the mhc class i/mhc class ii proteins, ifn-γ cytokines, cd45 antigens, and many other surface receptors required to act in the antigen-presenting, phagocytic, and cytotoxic roles that distinguish normal macrophages. microglia also differ from macrophages in that they are much more tightly regulated spatially and temporally in order to maintain a precise immune response. another difference between microglia and other cells that differentiate from myeloid progenitor cells is the turnover rate. macrophages and dendritic cells 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 for the body to constantly replace 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, 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. aging microglia undergo a burst of mitotic activity during injury; this proliferation is followed by apoptosis to reduce the cell numbers back to baseline. activation of microglia places a load on the anabolic and catabolic machinery of the cells causing activated microglia to die sooner than non-activated cells. to compensate for microglial loss over time, microglia undergo mitosis and bone marrow derived progenitor cells migrate into the brain via the meninges and vasculature. accumulation of minor neuronal damage that occurs during normal aging can transform microglia into enlarged and activated cells. these chronic, age-associated increases in microglial activation and il-1 expression may contribute to increased risk of alzheimer's disease with advancing age through favoring neuritic plaque formation in susceptible patients. dna damage might contribute to age-associated microglial activation. another factor might be the accumulation of advanced glycation endproducts, which accumulate with aging. these proteins are strongly resistant to proteolytic processes and promote protein cross-linking. research has discovered dystrophic (defective development) human microglia. "these cells are characterized by abnormalities in their cytoplasmic structure, such as deramified, atrophic, fragmented or unusually tortuous processes, frequently bearing spheroidal or bulbous swellings." the incidence of dystrophic microglia increases with aging. microglial degeneration and death have been reported in research on prion disease, schizophrenia and alzheimer's disease, indicating that microglial deterioration might be involved in neurodegenerative diseases. a complication of this theory is the fact that it is difficult to distinguish between "activated" and "dystrophic" microglia in the human brain. in mice, it has been shown that cd22 blockade restores homeostatic microglial phagocytosis in aging brains. image of microglia clinical significance main article: role of microglia in diseasestep-by-step guide for analyzing microglia phenotypesmicroglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. they respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells. as part of their response they secrete cytokines, chemokines, prostaglandins, and reactive oxygen species, which help to direct the immune response. additionally, they are instrumental in the resolution of the inflammatory response, through the production of anti-inflammatory cytokines. microglia have also been extensively studied for their harmful roles in neurodegenerative diseases, such as alzheimer’s disease, parkinson’s disease, multiple sclerosis, as well as cardiac diseases, glaucoma, and viral and bacterial infections. there is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (ocd), tourette syndrome, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (pandas). since microglia rapidly react to even subtle alterations in central nervous system homeostasis, they can be seen as sensors for neurological dysfunctions or disorders. in the event of brain pathologies, the microglial phenotype is certainly altered. therefore, analyzing microglia can be a sensitive tool to diagnose and characterize central nervous system disorders in any given tissue specimen. in particular, the microglial cell density, cell shape, distribution pattern, distinct microglial phenotypes and interactions with other cell types should be evaluated. sensome genetics the microglial sensome is a relatively new biological concept that appears to be playing a large role in neurodevelopment and neurodegeneration. the sensome refers to the unique grouping of protein transcripts used for sensing ligands and microbes. in other words, the sensome represents the genes required for the proteins used to sense molecules within the body. the sensome can be analyzed with a variety of methods including qpcr, rna-seq, microarray analysis, and direct rna sequencing. genes included in the sensome code for receptors and transmembrane proteins on the plasma membrane that are more highly expressed in microglia compared to neurons. it does not include secreted proteins or transmembrane proteins specific to membrane bound organelles, such as the nucleus, mitochondria, and endoplasmic reticulum. the plurality of identified sensome genes code for pattern recognition receptors, however, there are a large variety of included genes. microglial share a similar sensome to other macrophages, however they contain 22 unique genes, 16 of which are used for interaction with endogenous ligands. these differences create a unique microglial biomarker that includes over 40 genes including p2ry12 and hexb. dap12 (tyrobp) appears to play an important role in sensome protein interaction, acting as a signalling adaptor and a regulatory protein. the regulation of genes within the sensome must be able to change in order to respond to potential harm. microglia can take on the role of neuroprotection or neurotoxicity in order to face these dangers. for these reasons, it is suspected that the sensome may be playing a role in neurodegeneration. sensome genes that are upregulated with aging are mostly involved in sensing infectious microbial ligands while those that are downregulated are mostly involved in sensing endogenous ligands. this analysis suggests a glial-specific regulation favoring neuroprotection in natural neurodegeneration. this is in contrast to the shift towards neurotoxicity seen in neurodegenerative diseases. the sensome can also play a role in neurodevelopment. early-life brain infection results in microglia that are hypersensitive to later immune stimuli. when exposed to infection, there is an upregulation of sensome genes involved in neuroinflammation and a downregulation of genes that are involved with neuroplasticity. the sensome’s ability to alter neurodevelopment may however be able to combat disease. the deletion of cx3cl1, a highly expressed sensome gene, in rodent models of rett syndrome resulted in improved health and longer lifespan. the downregulation of cx3cr1 in humans without rett syndrome is associated with symptoms similar to schizophrenia. this suggests that the sensome not only plays a role in various developmental disorders, but also requires tight regulation in order to maintain a disease-free state.