Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) beta/A4 amyloid deposition is found in meningocortical blood vessels and in diffuse plaques in the cerebral cortex. Diffuse plaques putatively represent early stages in the formation of senile plaques. Microglia are intimately associated with congophilic plaques in Alzheimer's disease (AD), but microglial involvement in diffuse plaque formation is controversial. Therefore, we studied the relationship between microglia and diffuse plaques in the cerebral cortex of four patients with HCHWA-D using a panel of macrophage/microglia markers (mAbs LCA, LeuM5, LeuM3, LN3, KP1, OKIa, CLB54, Mac1, Ki-M6, AMC30 and the lectin RCA-1). Eight AD patients, one demented Down's syndrome (DS) patient and four non-demented controls were included for comparison. In controls and HCHWA-D patients ramified or "resting" microglia formed a reticular array in cortical gray and subcortical white matter. Microglial cells in or near HCHWA-D diffuse plaques retained their normal regular spacing and ramified morphology. In AD/DS gray matter more microglial cells were stained than in controls and HCHWA-D patients. Intensely immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic plaques. In contrast to the resting microglia, these "activated microglia" strongly expressed class II major histocompatibility complex antigen, HLA-DR, and were AMC30-immunoreactive. These findings support the view that microglia play a role in the formation of congophilic plaques but do not initiate diffuse plaque formation. Another finding in this study is the presence of strong monocyte/macrophage marker immunoreactivity in the wall of cortical congophilic blood vessels in HCHWA-D.
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PMID:Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical study. 752 4

Cerebral amyloid-beta (A beta) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D). A beta deposits are found mainly in the cerebral and cerebellar meningocortical blood vessels and as plaques throughout the cerebrocortical gray matter. A beta deposition in arteries and arterioles starts at the junction of media and adventitia and proceeds to involve the media causing degeneration of the vascular smooth muscle cells. Cerebrocortical arterioles often show one or two layers of radial A beta around a layer of homogenous A beta that replaces the media. Degenerating neurites, reactive astrocytes and microglial cells may surround cerebrocortical angiopathic arterioles and capillaries, probably in reaction to invasion of the perivascular neuropil by A beta fibrils. Furthermore, clusters of coarse extracellular matrix deposits may be found near A beta-laden cerebrocortical arterioles. The amyloid-associated proteins, cystatin C, and beta PP colocalize diffusely with Dutch vascular A beta, whereas HLA-DR immunoreactivity is found only in the periphery of the diseased vessel wall. The latter phenomenon may be related to the presence of perivascular cells. Angiopathic blood vessels frequently show structural changes. The relation of the described pathology to the development of hemorrhage, infarction and leukoencephalopathy needs further elucidation.
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PMID:Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): II--A review of histopathological aspects. 873 27

Arterial and arteriolar amyloid-beta (A beta) deposition in hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) and Alzheimer disease (AD) cerebral amyloid angiopathy (CAA) were studied as to morphology, extent, and association with mononuclear phagocyte system (MPS) cells using A beta, a-smooth muscle actin, and monocyte/macrophage marker (HLA-DR, CD68, CD11c, CD45) immunohistochemistry. The HCHWA-D/AD arterial/arteriolar media showed compact A beta deposits, first appearing at the media/adventitia junction, and concomitant smooth muscle loss. Only HCHWA-D CAA featured (a) severe involvement of larger arteries and (b) arterioles showing a single or double ring of radial A beta surrounding compact A beta. Radial A beta appeared to develop at the media/adventitia junction. Monocyte/macrophage marker-positive foci/cells co-localized with HCHWA-D arterial A beta. Focal HLA-DR/CD11c positivity was observed at the media/adventitia junction of AD/HCHWA-D arteries in the absence of local A beta, but not in controls. Monocyte/macrophage marker positivity co-localizing with radial A beta appeared continuous with perivascular cells and microglia clustering perivascularly. These results suggest that (a) MPS cells are topographically associated with HCHWA-D arterial A beta and radial arteriolar A beta, and (b) HLA-DR/CD11c immunoreactivity may appear at the media/adventitia junction prior to A beta. The latter finding and the assumed formation of radial A beta at the media/adventitia junction may relate to involvement of the abluminal basement membrane in CAA pathogenesis. The role of MPS cells in this process remains to be established.
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PMID:Association of vascular amyloid beta and cells of the mononuclear phagocyte system in hereditary cerebral hemorrhage with amyloidosis (Dutch) and Alzheimer disease. 905 41

Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of inflammatory cytokines and chemokines being upregulated by TLR agonists, CD4+ T cells were significantly less infectable by HIV after TLR4-stimulation than the unstimulated control. These data demonstrate that the inflammatory effects that occur in the presence TLR agonist stimulations do not necessarily translate to the activation of T cells. Most importantly, the finding that TLR4-stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection in this in vitro system strongly suggests that the increased chemokine and possible antiviral factor expression induced by these TLR agonists play a powerful although complex role in determining HIV infection risk.
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PMID:Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated in vitro Model. 3139 21

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.
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PMID:Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model. 3300 68