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

Both positive and negative regulatory elements responsive to the product of the adenovirus type 12 E1A gene are located in the promoter region of the gene for mouse H-2Kbm1 major histocompatibility complex (MHC) class I antigen (1). We have analyzed the negative regulatory element that is affected by E1A and identified a target CAA repeated motif, CAA(A)CAAA, within -1725 to -1705 and -1591 to -1568 in a 316-bp sequence located in the far upstream region of H-2Kb promoter (-1837 to -1522; +1 refers to the cap site). The extent of cell surface expression of the MHC class 1 antigen was significantly decreased in the case of transfectants obtained by introducing an expression plasmid that included MHC class 1 cDNA with the CAA repeated element, as compared with that of a plasmid with mutated CAA repeats. We have also characterized the nuclear proteins that bind to this motif. The analysis of the effects of mutations during competition assays of in vivo and gel retardation competition assays demonstrated that the CAA repeated element is essential not only for E1A-dependent repression of transcription but also for the cell surface expression of the product of the mouse H-2Kb class I gene, presumably through nuclear proteins that specifically bind to it.
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PMID:Negative regulation of the gene for H-2Kb class I antigen by adenovirus 12-E1A is mediated by a CAA repeated element. 826 66

Signaling through antigen presenting cells is required to activate T lymphocytes. The antigen-specific signal is given by interaction of the T-cell receptor (TCR) with the major histocompatibility complex (MHC)/peptide complex. Also essential for activation is the interaction of the coreceptor CD28 with ligands of the B7 family (CD80 and CD86) on antigen presenting cells. Coreceptor CTLA-4 is a negative regulator and binds the same B7 isoforms, contributing to immunologic homeostasis and peripheral tolerance. CD28 and CTLA4 are homologous and closely linked genes in 2q33, as are CD80 and CD86 in the 3q21 chromosomal region. Pemphigus foliaceus (PF) is a multifactorial autoimmune blistering disease characterized by keratinocyte detachment and by autoantibodies against desmoglein 1, a desmosomal protein. To investigate the involvement of CD28, CTLA4, CD80, and CD86 genes in PF pathogenesis, 18 polymorphisms in 2q33 and 3q21 chromosomal regions were analyzed in 269 patients and 395 controls subdivided according to predominant ancestry in Euro-Brazilian and Afro-Brazilian individuals. Associations were found with CD86 1057G>A, CTLA4-1722T>C, CTLA4-318C>T, CTLA4(AT)n, CD28(CAA)n, and D2S72(CA)n. There is no evidence of gene-gene interactions. We conclude that polymorphisms in the 2q33 and 3q21 chromosomal regions may influence PF disease susceptibility, most likely affecting CTLA4 and possibly inducible T-cell costimulator, (ICOS) expression, and also CD86 function.
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PMID:Polymorphisms in the 2q33 and 3q21 chromosome regions including T-cell coreceptor and ligand genes may influence susceptibility to pemphigus foliaceus. 2043 86

Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T-cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex-II presentation owing to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T-helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.
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PMID:Cystatin C regulates major histocompatibility complex-II-peptide presentation and extracellular signal-regulated kinase-dependent polarizing cytokine production by bone marrow-derived dendritic cells. 3151 6

The cysteine protease inhibitor Cystatin C (CST3) is highly expressed in the brains of multiple sclerosis (MS) patients and C57BL/6J mice with experimental autoimmune encephalomyelitis (EAE; a model of MS), but its roles in the diseases are unknown. Here, we show that CST3 plays a detrimental function in myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE but only in female animals. Female Cst3 null mice display significantly lower clinical signs of disease compared to wild-type (WT) littermates. This difference is associated with reduced interleukin-6 production and lower expression of key proteins (CD80, CD86, major histocompatibility complex [MHC] II, LC3A/B) involved in antigen processing, presentation, and co-stimulation in antigen-presenting cells (APCs). In contrast, male WT and Cst3-/- mice and cells show no differences in EAE signs or APC function. Further, the sex-dependent effect of CST3 in EAE is sensitive to gonadal hormones. Altogether, we have shown that CST3 has a sex-dependent role in MOG35-55-induced EAE.
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PMID:Cystatin C Plays a Sex-Dependent Detrimental Role in Experimental Autoimmune Encephalomyelitis. 3302 52