Contribution to Disease

Several arguments support a key role for microglia during immunopathologies. They are potentially pha-gocytic and have a pronounced microbicide and cytotoxic potential. Upon activation, microglia can rapidly upregulate the expression of several immuno-molecules, such as MHC I and II, the CD4 antigen, and adhesion molecules. They are the most efficient and the most promptly inducible antigen presenting cells of the brain parenchyma, assuming an active immune surveillance in the CNS. Resting microglial cells stimulated with IFN-g express MHC II products and display a capacity to present protein antigens in the molecular context of MHC II to CD4-positive T lymphocytes. In the context of MHC I expression, they can also become targets of cytotoxic CD8-positive T lymphocytes. Furthermore, microglia secrete as well as respond to several cytokines.

One of the characteristic features of microglia is the rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. Mi-croglial activation occurs after injury or changes in microenvironment, even before pathological changes or in the absence of obvious neuropathic changes, as part of an early CNS immune defense system. In terms of structural changes, many intermediate morphologies of activated microglia exist. Microglial hypertrophy begins with the formation of several stout processes, but they do not become phagocytic. If neuronal degeneration occurs in the brain parenchyma, activated microglia proliferate and transform into phagocytic cells. As the primary immune effector cells of the CNS, microglia respond to traumatic insult or the presence of pathogens by migrating to the site of injury, where they may proliferate. Activated microglia at the site of inflammation express increased levels of MHC antigens and become phagocytic. Like other tissue macrophages, microglia release inflammatory cytokines and mediators that amplify the inflammatory response by recruiting effector cells to the site of injury. In addition, microglia can release neurotoxins that may potentiate damage to CNS cells. The intense secretory activity of these cells is associated with diseases such as trauma, stroke, epilepsy, AIDS, and MS, in which the microglial response is prominent and deleterious to the brain tissue. The secretory activity of microglia has also been related to the neuronal destruction seen in Alzheimer's disease (AD).

1. Acquired Immunodeficiency Syndrome

HIV-1 causes an AIDS-associated psychomotor complex in a number of patients, who eventually develop either encephalitis or leukoencephalopathy. The main target cells of HIV-1 infection in the brain are microglia and macrophages, with a very limited infection of astrocytes and endothelial cells. Infected microglial cells can be detected by the presence of HIV antigens. The two pathological hallmarks of the HIV-1 infection of the CNS are multinucleated giant cells as a result of cell-to-cell fusion and microglial nodules (Fig. 5). Although microglial cells and macrophages seem to be the only cell types productively infected by HIV-1 within the brain, the replication rate of the virus remains relatively low in CNS tissue compared to other tissues. Thus, the neuropathological alterations in AIDS are more likely due to the neurotoxicity of certain viral products, toxic factors, and cytokines released by infected microglia and macrophages. Some of these putative toxic factors, such as viral proteins, are specific to HIV-1 infection of the CNS, whereas other potentially toxic factors are also involved in other diseases in which activation of microglia plays a key role in the pathological process. Among viral proteins, the viral surface glycoprotein gp120 can be released by infected microglia and macrophages. This protein induces excitoxicity in neurons via activation of glutamate receptors, it can inhibit myelin formation in oligodendrocytes, or it can alter Na + /H + ion transport in astrocytes, leading to an increased secretion of glutamate and potassium. The infection of microglial cells and macrophages, and their subsequent activation, also results in the generation of a wide variety of secretory factors that are potentially neurotoxic, such as TNF-a, cytokines, chemokines, arachidonic acid metabolites, and nitric oxide. TNF-a released by infected microglia is particularly toxic to oligodendrocytes and can be an important factor in myelin damage. Arachidonic acid and its metabolites act mainly via potentiation of glutamate receptors on neurons, leading to an increase in intracellular calcium toW* lisp mb I %

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