Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using synthetic peptides, we have defined the major linear antibody epitopes of Theiler's murine encephalomyelitis virus (TMEV), i.e., A1A (VP1(12-25)), A1Ba (VP1(146-160)), A1Cb (VP1(262-276)), A2A (VP2(2-16)), A2B (VP2(165-179)), and A3A (VP3(24-37)). A time course study with either pooled or individual sera indicates that susceptible SJL mice intracerebrally infected with TMEV strongly and selectively recognize the A1Cb epitope of VP1, compared with resistant BALB/c or C57BL/6 mice, which broadly recognize most of the epitopes on the different capsid proteins. However, antibodies from SJL mice subcutaneously immunized with TMEV recognize primarily A1Ba, A1Cb, and A2A epitopes. A similar predominant recognition of the A1Cb epitope was found with antibodies from the cerebrospinal fluid of intracerebrally virus-infected SJL mice. Interestingly, a substantial level of antibodies against the A1Cb epitope in virus-infected SJL mice is of the immunoglobulin G2a subclass, in contrast to an undetectable level of this immunoglobulin G subclass in virus-immunized SJL mice. The level of in vitro viral neutralization by antibodies did not correlate with the clinical signs. Antibodies to A1Cb, A2A, and A2B were able to neutralize viral plaque formation in vitro, while antibodies to A3A, A1A, and A1Ba were not.
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PMID:Analysis of antibody responses to predominant linear epitopes of Theiler's murine encephalomyelitis virus. 751 62

The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood-brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin beta1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.
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PMID:Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. 1658 65

The integrity of all organ systems requires faithful interaction between its component cells and the extracellular matrix (ECM). In the central nervous system (CNS), matrix adhesion receptors are uniquely expressed by the cells comprising the microvascular compartment, and by neurons and their supporting glial cells. Cells within the cerebral microvasculature express both the integrin and dystroglycan families of matrix adhesion receptors. However, the functional significance of these receptors is only now being explored. Capillaries of the cerebral microvasculature consist of the luminal endothelium, which is separated from circumferential astrocyte end-feet by the intervening ECM of the basal lamina. Endothelial cells and astrocytes cooperate to generate and maintain the basal lamina and the unique barrier functions of the endothelium. Integrins and the dystroglycan complex are found on the matrix-proximate faces of both endothelial cells and astrocyte end-feet. Pericytes rest against the basal lamina. In the extravascular compartment, select integrins are expressed on neurons, microglial cells, and oligodendroglia. Significant alterations in both cellular adhesion receptors and their ligands occur under the conditions of focal cerebral ischemia, multiple sclerosis (MS) and the modeled condition experimental autoimmune encephalomyelitis (EAE), certain tumors of the CNS, and arteriovenous malformations (AVMs). The changes in matrix adhesion receptor expression in these conditions support their functional significance in the normal state. We propose that matrix adhesion receptors are essential for the maintenance of the integrity of the blood-brain permeability barrier, and that modulation of these receptors contribute to alterations in the barrier during brain injury. This review examines current information about cell adhesion receptor expression within the cerebral microvasculature and surrounding tissue, and their potential roles during the vascular responses to local injury.
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PMID:Integrin-matrix interactions in the cerebral microvasculature. 1677 20

In multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), dysfunction of the blood-brain barrier (BBB) leads to edema formation within the central nervous system. The molecular mechanisms of edema formation in EAE/MS are poorly understood. We hypothesized that edema formation is due to imbalanced water transport across the BBB caused by a disturbed crosstalk between BBB endothelium and astrocytes. Here, we demonstrate at the light microscopic and ultrastructural level, the loss of polarized localization of the water channel protein aquaporin-4 (AQP4) in astrocytic endfeet surrounding microvessels during EAE. AQP4 was found to be redistributed over the entire astrocytic cell surface and lost its arrangement in orthogonal arrays of intramembranous particles as seen in the freeze-fracture replica. In addition, immunostaining for the astrocytic extracellular matrix receptor beta-dystroglycan disappeared from astroglial membranes in the vicinity of inflammatory cuffs, whereas immunostaining for the dystroglycan ligands agrin and laminin in the perivascular basement membrane remained unchanged. Our data suggest that during EAE, loss of beta-dystroglycan-mediated astrocyte foot process anchoring to the basement membrane leads to loss of polarized AQP4 localization in astrocytic endfeet, and thus to edema formation in EAE.
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PMID:Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. 1953 55

The blood-brain barrier (BBB) is a specific structure that is composed of two basement membranes (BMs) and that contributes to the control of neuroinflammation. As long as the BBB is intact, extravasated leukocytes may accumulate between two BMs, generating vascular cuffs. Specific matrix metalloproteinases, MMP-2 and MMP-9, have been shown to cleave BBB beta-dystroglycan and to disintegrate thereby the parenchymal BM, resulting in encephalomyelitis. This knowledge has been added to the molecular basis of the REGA model to understand the pathogenesis of multiple sclerosis, and it gives further ground for the use of MMP inhibitors for the treatment of acute neuroinflammation. MMP-9 is associated with central nervous system inflammation and occurs in various forms: monomers and multimers. None of the various neurological and neuropathologic functions of MMP-9 have been associated with either molecular structure or molecular form, and therefore, in-depth structure-function studies are needed before medical intervention with MMP-9-specific inhibitors is initiated.
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PMID:On the structure and functions of gelatinase B/matrix metalloproteinase-9 in neuroinflammation. 2541 Mar 59