Talk:Neuroimmune System
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== Neuroimmunology: ==
Role of Microglia in immune response of Brain tissue, Antigen presentation in Brain.
Microglia are specialized macrophages capable of phagocytosis that protect neurons of the CNS. Though not technically glia because they are derived from hemopoietic precursors rather than ectodermal tissue, they are commonly categorized as such because of their supportive role to neurons. These cells, comprise approximately 15% of the total cells of the CNS. They are found in all regions of the brain and spinal cord. Microglial cells are small relative to macroglial cells, with changing shapes and oblong nuclei. They are mobile within the brain and multiply when the brain is damaged. In the healthy CNS, microglia processes constantly sample all aspects of their environment (neurons, macroglia and blood vessels).Microglia are a type of glial cell that act as the immune cells of the Central nervous system(CNS). Microglia, the smallest of the glial cells, can act as phagocytes, cleaning up CNS debris. Most serve as representatives of the immune system in the brain. Microglia are close cousins of other phagocytic cells including macrophages and dendritic cells. Microglia are derived from myeloid progenitor cells (as are macrophages and dendritic cells) which come from the bone marrow. During embryonic development, however, they migrate to the CNS to differentiate into microglia. Microglia are thought to be highly mobile cells that play numerous important roles in protecting the nervous system. They are also thought to play a role in neurodegenerative disorders such as Alzhemer’s disease, dementia, multiple sclerosis and Amyotropic lateral sclerosis. Microglia are responsible for producing an inflammatory reaction to insults. Amoeboid Microglia: Amoeboid microglia are associated with the developing CNS. In rats it has been shown that amoeboid microglia appear late in gestation and disappear soon after birth. These cells exhibit a round cell body, possess pseudopodia and thin filopodia-like processes and contain numerous lysosomes; indicative of a motile phagocytic phenotype. During the post-natal period amoeboid microglia are believed to play a role in tissue histogenesis through the removal of inappropriate and superfluous axons and through the promotion of axonal migration and growth. Ultimately, amoeboid microglia grows long crenulated processes and transform into ramified microglia found in the adult CNS. Ramified Microglia: Ramified microglia are present in abundance in the brain parenchyma and constitutes approximately 10-20 % of the total population of glial cells in the adult. These small round cells comprise numerous branching processes and possess little cytoplasm. In the adult the resident population of ramified microglia is maintained through local cell division and through the recruitment of circulating peripheral blood monocytes. Classically, ramified microglia were considered to be inactive under physiological conditions, however, it is now known that microglia exhibit pinocytotic activity and localized motility particularly of their ramified protrusions. Microglial processes directly contact neuronal cell bodies, astrocytes and blood vessels, therefore it seems likely that microglia monitor the well-being of brain cells and also function to cleanse the extracellular fluid in order to maintain central homeostasis. In this respect, it has been suggested that ramified microglia contribute to metabolite removal and to the clearance of toxic factors released from injured neurons. A recent study has even demonstrated that microglia have the propensity to transform into neurons, astrocytes or oligodendrocytes . Hence, ramified microglia may represent a unique population of multi-potent stem cells in the adult CNS, which strongly implicates microglia in CNS repair. Reactive Microglia: In response to injury or pathogen invasion, quiescent ramified microglia proliferates and transform into active ‘brain macrophages’ otherwise known as reactive microglia. Microglial proliferation can be studied using antibodies raised against nuclear antigens such as ki67 or proliferating cell nuclear antigen (PCNA) or by Bromodeoxyuridine(BrdII) staining. Reactive microglia are rod-like, devoid of branching processes and contains numerous lysosomes and phagosomes. The reactive cell form represents a population of macrophages, which are associated with brain injury and neuroinflammation. Following a damaging event, reactive microglia accumulates at the site of injury where they play a neuroprotective role phagocytosing damaged cells and debris. In acute lesions the peak of microglial activation occurs 2-3 days post insult, but if the pathological stimulus persists microglial activation continues. Reactive microglia express MHC class II antigens and other surface molecules necessary for antigen presentation including CD40, B7 and ICAM-1. Consequently, microglia are considered to be the most potent antigen presenting cells in the CNS. Like macrophages, reactive microglia secrete a number of inflammatory mediators, which serve to orchestrate the cerebral immune response. Factors secreted include super oxide, nitric oxide, prostanoids, glutamate, quinolinic acid, cathepsins, matrix metalloproteinases, interleukins, monocytic chemotactic protien-1, tumor nacrosis factor, interferon-gamma, tissue plasmogen activator and soluble FAS ligand. A number of neurological disorders including Alzheimer’s disease and delayed neuronal death occurring after ischaemia are associated with chronic microglial activation. In these instances the persistent activation of microglia accompanied by the sustained secretion of inflammatory mediators is thought to have a deleterious effect on neuronal function and survival, thereby exacerbating disease processes. Features of Microglia:The unique and fascinating point about microglia is that they are both supportative glia and immunocompetent defense cells.Functionally speaking microglia are a hybrid between White cells and Glial cells and, as such, there role is to protect and to support Neurons within the CNS. At the same time, however, it need to stated that the immunological competence of microglia is not on the same scale as that of Peripheral Leukocytes.And that microglia immune functions are controlled by inhibitory factors intrinsic to the CNS.Major observations that have contributed to the idea that microglia represented the brains internal immune system include the detection of MHC antigens, T & B- Lymphocytes, and other immune cells antigens on miroglia, as well as the fact that microglia, in general, have properties similar to those of Monocytes and other cells of Macrophages lineage. Microglia are weak APC’S in CNS.Microglia are extremely sessile.Only a subtype, the Perivascular microglia are regularly replaced from the bone marrow in adult animals.Upon activation microglia and macrophages share most phonotypical markers and can exert similar effecter function. Location of Microglia:Microglia are located in close vicinity to neurons in the Gray matter and between fibers tracts in the White matter of the CNS. Identification and Origin of Microglia:Del Rio Hortega (1932) was the first to describe the Microglia in the CNS, by Silver impregnation technique.He characterized a unique cell type in the CNS with an elongated soma bearing processes extending from both poles of the cell, the Ramified Microglia.The origin of Ramified microglia has been a long controversial issue. Bone marrow derived cell, that is Mesodermal elements, or alternatively, Neuroectodermal matrix cell which also serves as precursor cells for Astrocytes and Oligodendrocytes, have been suggested as developmental sources of Microglia.It was thought that microglia were derived from the neuroectoderm, similar to the other “Glial" cells. We now know however, that they are of mesodermal origin similar to other immunological cells. The resting microglia migrate into the CNS during embryological development. They can also be derived from circulating blood monocytes which migrate into the CNS later in life. Once they migrate into the CNS, the monocytes take on the morphology and staining characteristics of the resident microglia. After brain injury they become phagocytic and develop into the macrophages which we can more easily see microscopically. Astroglial cultures initiated from newborn Mouse, eopalium contained bipotential progenitor cells, that could give rise to both Astrocytes and Micriglia.Parenchymal Microglia are of Neuroectodermal origin as all other Glia.Despite there uncertainty about there origin, Microglia share most surface molecules with bone marrow derived Macrophages.Resting Microglia express a Keratin Sulphate Proteoglycan (KSPG) that is not present on Macrophages in other tissues.Interestingly, constitutive Major Histocompatibility Complex (MHC) Class-2 expression was inversely related to KSPG expression.Perivascular Microglia, a subset of microglia, which have also been termed Perivascular Cells, can be distinguished by their unique association with Blood Vessels.Perivascular Microglia are regularly replaced from the Bone Marrow.Perivascular Microglia constitutively express immune activation markers such as CD4 and MHC Class-2 molecules. Functions of Microglia:Similar to Macrophages, activated Microglia synthesize a variety of potentially harmful soluble factors.These include reactive Oxygen and Nitrogen intermediates, Proteolytic enzymes, Arachidonic acid metabolites and Proinflammatory, Potentially cytotoxic cytokines like Tumor Necrosis Factor-alpha (TNF-alpha) and Interlukin(IL-1).Microglia are able to transform into large phagocytes and there by remove debris. Microglia play an important role as immune cells in the central nervous system (CNS). Microglia are activated in threatened physiological homeostasis, including CNS trauma, apoptosis, ischemia, inflammation, and infection. Activated microglia show a stereotypic, progressive series of changes in morphology, gene expression, function, and number and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and can also act on neurons to alter their function. Antigen Presentation in Brain Tissue:Since CNS also harbors other macrophages that, although not part of the parenchyma, populate the critical interface between the CNS-parenchyma, and the blood.These cells are known as “Perivascular cells” because they reside in the perivascular spaces. They may be considered “Professional’’ macrophages and APC’S because they are bone marrow derived and capable of presenting antigens strongly.These so called “Other CNS macrophages’’.Other CNS macrophages represents a subset that is phenotypically distinct (CD11b\c+ and CD45high) from parenchymal microglia (which are CD 11b\c and CD45low), and they have immunological properties of peripheral accessory cells.Because of their location in the perivascular spaces, these cells are likely to come into contact with and process CNS antigens that may seep from the parenchyma into the perivascular spaces, and they may present these CNS antigens to T-lymphocytes.In contrast Microglia reside in the CNS parenchyma, where they do not usually encounter T-cells. Hence they may not be a need or an opportunity for microglia to present antigens with in the CNS. Micriglia as regulators of T-cell mediated immune response: Antigen Presentation:Antigen presentation is the critical event involved in the generation of protective T-cell responses against infectious agents or tumoral cells, and of pathogenic,autoreactive T-cell responses against self-components. It requires interaction between the T-cell receptor and processed antigenic peptides bound to major histocompatibility complex (MHC) molecules on the surface of APC. MHC class I and MHC class II molecules stimulate CD8+ cytotoxic T cells and CD4+ T-helper cells, respectively. Similar to other immune markers, in the normal CNS expression of MHC class I and class II molecules is mainly confined to dendritic cells and macrophages of the meninges, choroid plexuses and perivascular spaces. Within the normal CNS parenchyma, MHC expression is generally minimal or absent and, when present, it is restricted to some microglia.These observations and more recent studies examining the T-cell stimulatory capacity of microglia isolated from normal rodent brains indicate that, in their resting condition, microglia behave as poor APC.Ample evidence has been provided that microglia readily up regulate MHC class II expression in virtually all inflammatory and neurodegenerative conditions.MHC class II1 astrocytes have been detected only occasionally and exclusively under strong inflammatory conditions. Evidence is also accumulating that during CNS inflammation activated microglia express adhesion/costimulatory molecules, like CD11a, CD40,CD54, CD58, CD80 and CD86, which are essential for optimal APC function. In particular, interaction of CD80 and CD86 molecules with CD28 expressed on T cells is required for inducing T-cell cytokine secretion, growth and survival.CD40 ligation by CD40L on T cells enhances MHC class II and CD80/CD86 expression as well as cytokine secretion by APC, which in turn promotes T-cell activation. Although the above findings suggest that acquisition of APC function is an intrinsic feature of the microglial activation program, the actual capacity of MHC class II expressing microglia to activate intracerebrally recruited T cells most probably depends on their ability to endocytose and process the relevant antigens (the whole machinery being induced during the transformation of microglia into phagocytic cells) as well as on the pathologic context. CONCLUSIONS:Several lines of evidence indicate that microglia represent a highly responsive population of cells with the potential to engage in functions that are unique to innate immune cells, such as recognition and elimination of invading pathogens, regulation of adaptive immunity, and participation in homeostatic anti inflammatory mechanisms. Despite advances in our comprehension of the molecular and functional repertoires of microglia, important unanswered questions remain. How do diverse and multiple receptors interact to determine the phenotypes and functions of reactive microglia? Could activation of microglia (e.g., by stressed/damaged cells or infectious agents) initiate the cascade of inflammatory events leading to recruitment of hematogenous immune cells and stimulation of adaptive immune responses? What is the contribution of microglia to CNS intraparenchymal inflammation and local regulation/polarization of effecter T cells, relative to blood-derived phagocytes and APC? Does the CNS benefit from microglia activation? Is inappropriate or protracted activation of microglia proinflammatory and cytotoxic functions responsible for neuronal or myelin damage? Can microglia be activated to adopt an anti-inflammatory phenotype, and how?Because of the relevance that elucidation of the above issues may have for a better understanding of CNS disease pathogenesis and for the design of therapeutic strategies to suppress CNS inflammation, the fine mechanisms governing microglia reactivity and the involvement of these cells in the development of neurodegenerative and neuroinflammatory disorders remain the objects of intense investigation.
Research Reviews:
Wolfgang J. Striet-“Microglia as Neuroprotective, Immunocompetent cells of the CNS.’’
Patrick L. McGeer, Edith G. McGeer- The inflammatory response system of brain: implication for therapy of Alzheimer and other neurodegenerative diseases.
Guido Stollg & Sebastian Jander: The role of microglia and Macropgages in the pathophysiology of the CNS.
Immune Function Of Microglia.: Francesca Aloisi.
- Fixed typo: neurogenisis -> neurogenesis LucidWay 14:28, 25 July 2007 (UTC)
