Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantigen-specific CD4+ T cells have been implicated as the causative cell type in: multiple sclerosis, rheumatoid arthritis, autoimmune uveitis, diabetes mellitus, inflammatory bowel disease and graft-versus-host disease. The pathology of a number of experimentally induced autoimmune diseases is also mediated by autoantigen-specific CD4+ T cells. Ideally, treatment of CD4+ T-cell-mediated diseases would eliminate the autoantigen-specific cells, while sparing the remainder of the T-cell repertoire. We have developed an effective therapy that deletes the autoreactive T cells at the site of autoimmune tissue destruction. This approach uses an antibody directed against a cell-surface protein (OX-40, also known as CD134) that is selectively upregulated on activated autoantigen-specific T cells within the inflamed tissue.
Mol Med Today 1998 Feb
PMID:Antibodies to OX-40 (CD134) can identify and eliminate autoreactive T cells: implications for human autoimmune disease. 954 94

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.
Hum Mol Genet 1998 Aug
PMID:Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. 966 63

Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS-predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations.
Hum Mol Genet 1998 Aug
PMID:DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. 966 64

Multiple sclerosis is characterized by myelin destruction and oligodendrocyte loss. The neuropathological hallmark of the disease is the presence of demyelinated plaques in the central nervous system. We have recently found a gliotoxic factor in MS cerebrospinal fluid which induces programmed cell death in vitro, in glial cells. Here we show DNA fragmentation and glial cell death in biopsy samples, obtained from a patient who underwent surgery with suspicion of tumor, and whose disease record, including brain autopsy, demonstrated an active multiple sclerosis. We used the in situ TUNEL technique, a method which sensitively detects the DNA fragmentation accompanying programmed cell death in tissue sections, and compatible with classical fixation techniques. We found intense DNA fragmentation in nuclei of glial cells at-or very near-to the site of demyelination. A double labeling technique showed that glial fibrillary associated protein positive astrocytes may undergo programmed cell death in multiple sclerosis.
Cell Mol Biol (Noisy-le-grand) 1998 Jun
PMID:Case report: DNA fragmentation in glial cells in a cerebral biopsy from a multiple sclerosis patient. 967 92

Retroviruses are suspected to be involved in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Here, we describe a complete cartography of a novel human endogenous retroviral sequence with a pol domain which shares a high homology with the pol sequence of the multiple sclerosis associated retrovirus (MSRV). Since this new endogenous retroviral sequence is located in the close vicinity of the locus of the human gene coding for the T-cell receptor (TcR) alpha and delta chains on chromosome 14, it could be of potential interest for the understanding of MS pathogenesis.
Cell Mol Biol (Noisy-le-grand) 1998 Sep
PMID:An endogenous retrovirus with nucleic acid sequences similar to those of the multiple sclerosis associated retrovirus at the human T-cell receptor alpha, delta gene locus. 976 96

Interactions between the immune system and the brain are a key element in the pathophysiology of diseases such as multiple sclerosis, neuroAIDS, and Alzheimer's, which affect large numbers of individuals and are associated with a high social cost. However, the neuroanatomical basis of brain-immune interactions has not been elucidated. We report that in Wistar rats of either sex bilateral electrolytic lesion of the medial forebrain bundle reduces body weight by 28% 7 days after lesioning, and causes widespread infections, aphagia, adypsia, structural damage to the lymphoid organs and heavy depression of T lymphocytes cytotoxicity. The following alterations occur in the immune system after those lesions: the weight of the thymus, spleen and lymphonodes is reduced by 77.9%, 49.1% and 48.4%, respectively. The thymus is atrophied and contains fewer lymphoid cells in the cortex than in the medulla. In the spleen the white pulp is reduced and lymphoid cells from periarteriolar zones and at the chords are almost absent. In lymph nodes cortical small lymphocytes are depleted and primary and secondary nodules and germinal centers all but disappear. Cytotoxicity of lymphocytes is reduced by 86.2% in the thymus, 77.6% in the spleen and 70.2% in lymph nodes. The critical area of lesion is at the medialmost portion of the medial forebrain bundle, at the preoptic area and rostral part of the anterior hypothalamus. We suggest that this area contains neural circuits that are crucial for keeping the structure of lymphoid organs and the functional integrity of the immune system.
Mol Psychiatry 1998 Sep
PMID:Circumscribed lesion of the medial forebrain bundle area causes structural impairment of lymphoid organs and severe depression of immune function in rats. 977 72

The family of proteins called matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix proteins. These zinc and calcium dependent enzymes, which include the collagenases, stromelysins and gelatinases, are involved in normal tissue remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiological conditions, in addition to the regulated proteolyses of inactive precursors to the active form, the degradative nature of these enzymes are precisely controlled by endogenous inhibitors (TIMPs). The excess syntheses and production of these proteins lead to the accelerated matrix degradation associated with diseases such as arthritis, cancer and multiple sclerosis. The MMPs have therefore proved to be attractive targets for structure based drug design. The pursuit of low molecular weight inhibitors of these proteins have encouraged structural studies on several members of family, so that the molecular details of enzyme-inhibitor interactions of the MMPs have become available. These studies provide insights into the basic structural framework of the MMP superfamily and reveal characteristics which promote specificity between individual members. The analyses of the three dimensional structure of the MMPs in the context of their primary sequence and the design and selectivity of low molecular weight inhibitors of the superfamily is the subject of this review.
Prog Biophys Mol Biol 1998
PMID:Matrix metalloproteases: variations on a theme. 978 58

Microglial cells play important roles in brain injury and repair and are implicated in diseases such as Alzheimer's disease, Creutzfeldt-Jacob disease, multiple sclerosis, the Aids Dementia Complex and stroke. Despite their importance in neuropathology, the underlying molecular basis for the activation of microglia after brain injury is not understood. We show, using RT-PCR, in situ hybridisation, immunocytochemistry, and electrophoretic mobility shift assay, that the CCAAT-enhancer binding protein alpha (C/EBP alpha), a sequence specific DNA-binding protein, is induced in microglial cells, but not astrocytes or neurons, after hypoxic-ischemic brain injury. These results suggest that C/EBP alpha might regulate gene expression and consequentially have a role in the activation and/or proliferation of microglia following brain injury.
Brain Res Mol Brain Res 1998 Oct 30
PMID:CCAAT-enhancer binding protein alpha is expressed in activated microglial cells after brain injury. 979 5

Prostaglandin D synthetase (PGD-S; prostaglandin-H2 D-isomerase, EC 5,3,99,2), a 30 kDa glycoprotein also known as beta-trace protein that catalyzes the formation of prostaglandin D2 (PGD2) from PGH2, was purified to apparent homogeneity from human cerebrospinal fluid (CSF) using a two-step procedure involving HPLC on a Vydac C8 reversed-phase column and high performance electrophoresis chromatography (HPEC) using a 10% T SDS-polyacrylamide gel. The purity of PGD-S isolated from CSF was confirmed by silver stained SDS-polyacrylamide gel and direct protein microsequencing (NH2-APEAQVSVQPNFQ). A highly specific polyclonal antibody was prepared against this protein for immunoassay development. Using an ELISA, it was found that the concentration of PGD-S in CSF did not alter significantly in different pathological conditions of the central nervous system (CNS). These include dementia (n = 9), hydrocephalus (n = 4), neuropathy (n = 11), optic neuritis (n = 4), multiple sclerosis (n = 11), and demyelinating syndrome (n = 11), when compared to normal individuals (n = 12); however, the level of PGD-S in the CSF obtained from patients with brain tumor (n = 11), was reduced by as much as 2-fold when compared to control samples (n = 12) illustrating PGD-S is a potentially useful marker for brain tumor.
Biochem Mol Biol Int 1998 Nov
PMID:Quantification of prostaglandin D synthetase in cerebrospinal fluid: a potential marker for brain tumor. 984 24

Developments in transgenic technology have greatly enhanced our ability to understand the functions of various genes in animal models and relevant human diseases. The tetracycline (tet)-regulated transactivation system for inducing gene expression allowed us to control the expression of exogenous genes in a temporal and quantitative way. The ability to manipulate a cell-specific promoter enabled us to express one particular protein in a single type of cell. The combination of a tetracycline system and a tissue-specific promoter has led us to the development of an innovative gene expression system, which is able to express genes in a cell type-specific and time- and level-controllable fashion. An oligodendrocyte-specific myelin basic protein (MBP) gene promoter controls the reversed tet-inducible transactivator. The green fluorescent protein (GFP) gene was placed under the control of the human cytomegalovirus (CMV) basic promoter in tandem with seven tet-responsive elements (TRE), binding sites for the activated transactivator. Upon the addition of doxycycline (DOX, a tetracycline derivative), tet transactivators became activated and bound to one or more TRE, leading to the activation of the CMV promoter and the expression of GFP in oligodendrocytes. We have successfully expressed GFP and luciferase at high levels in oligodendrocytes in a time- and dose-dependent fashion. In the absence of DOX, there was almost no GFP expression in oligodendroglial cultures. Graded levels of GFP expression were observed after induction with DOX (0.5 to 12.5 microg/ml). Our data indicate that this inducible gene expression system is useful for the study of gene function in vivo and for the development of transgenic animal models relevant to human diseases such as multiple sclerosis.
Mol Med 1999 Feb
PMID:Expression of green fluorescent protein in oligodendrocytes in a time- and level-controllable fashion with a tetracycline-regulated system. 1020 78


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