1,721,090 research outputs found
Innate inflammation in Parkinson's disease
No full textThe resident macrophages of the brain-the microglia-are morphologically activated during the progression of Parkinson's disease. Observational studies in human postmortem material and studies in animal models seek to define the contribution that this innate immune response might make to the pathogenesis and rate of progression of Parkinson's disease. We review here some of the key conceptual issues that need to be considered when performing these studies. We highlight the fact that most postmortem studies have not given due consideration to common comorbidities present in patients with Parkinson's disease and also the limitations of attempting to extrapolate from animal models to a chronic progressive neurodegenerative disease in humans that lasts for many years.</p
Persistent pathogens in the parenchyma of the brain
No full textIt has recently been shown that bacteria and viruses can be delivered to the brain parenchyma without evoking an immune response. These experiments demonstrate that there are no cells within the brain parenchyma that can initiate a primary immune response, and that the drainage of pathogens from the brain parenchyma is distinct from that documented for soluble proteins. A persistent pathogen in the brain parenchyma can become a target for the immune system following peripheral sensitisation, and this may lead to bystander tissue damage. These observations may have consequences for vaccination of persons with central nervous system HIV infection
Microglial priming in neurodegenerative disease
No full textUnder physiological conditions, the number and function of microglia-the resident macrophages of the CNS-is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state-a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration<br/
Contribution of systemic inflammation to chronic neurodegeneration
No full textSystemic infection or inflammation gives rise to signals that communicate with the brain and leads to changes in metabolism and behaviour collectively known as sickness behaviour. In healthy young individuals, these changes are normally transient with no long-term consequences. The microglia are involved in the immune to brain signalling pathways. In the aged or diseased brain, the microglia have a primed phenotype as a consequence of changes in their local microenvironment. Systemic inflammation impacts on these primed microglia and switches them from a relatively benign to an aggressive phenotype with the enhanced synthesis of pro-inflammatory mediators. Recent evidence suggests that systemic inflammation contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and may accelerate disease progression. The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention. Prompt treatment of systemic inflammation or blockade of signalling pathways from the periphery to the brain may help to slow neurodegeneration and improve the quality of life for individuals suffering from chronic neurodegenerative disease
Central nervous system involvement in Langerhans cell histiocytosis: the importance of long term follow-up
No full textInflammation and Axon Degeneration
No full textAxon injury is a significant part of multiple sclerosis (MS) pathology. Postmortem analysis shows that axon injury occurs early in the evolution of the plaque, and the degree of axon injury correlates with the intensity of the inflammatory response. Studies in animal models of MS show that axon injury also occurs in a number of these models. The transection of an axon by inflammatory cells and their products is an irreversible lesion and insights into the early stages of this process are needed. Furthermore, a spectrum of molecules secreted by inflammatory cells including T-cells, B-cells, and macrophages in an immunologically nonspecific manner may precipitate axon transection. These "molecular scissors" may act on the axon in a number of different ways. They may activate biochemical pathways, intrinsic to the axon, that lead to local auto destruction similar to programmed-cell-death, or apoptosis, of the cell body. Therapeutic interventions to target the molecules of destruction that are secreted by inflammatory cells that act as molecular scissors to precipitate axon transection are much needed.</p
Microglia
No full textMicroglia are the resident macrophages of the brain parenchyma (1). Although it has long been known that microglia are of myeloid lineage, based on immunocytochemical detection of macrophage-restricted antigens (2), it has only relatively recently been shown, by fate mapping studies, that these cells are of yolk sac origin and enter the developing neuroepithelium of the central nervous system (CNS) in the embryo (3). They are present throughout the length of the neuraxis, characterized by their fine processes emanating from a small cell body, and each cell appears to occupy its own territory. The morphology of microglia and their territorial behavior is well illustrated in retina whole mounts (Fig. 1). The density and morphology of the microglia vary between distinct functional divisions of the CNS, with the lowest density found in the cerebellum and perhaps the highest density in the substantia nigra (4). These regional differences have been well studied in rodents, the most common experimental animal models, and although similar regional differences are seen in the human brain, there are some notable differences. In the rodent brain, the microglia are denser in gray matter than in white matter, while in the human brain, the microglia are denser in the large-fiber tracts that dominate the larger brain (5).</p
Macrophages and nerve regeneration
No full textMacrophages are not only phagocytic cells but also secrete a plethora of growth factors that are potentially important for regeneration. This review will examine the emerging evidence of a likely contribution by macrophages to axonal regeneration.</p
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