Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus-specific CD4+ T cells could be involved in the pathogenesis of multiple sclerosis, provided they can gain entry to the intrathecal compartment. The authors have previously demonstrated that cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. They now report that CD4+ T cells specific for the Epstein-Barr virus DNA polymerase peptide EBV 627-641 were present in the cerebrospinal fluid from one of two multiple sclerosis patients, and that a high proportion of these CD4+ T cells cross-recognized an immunodominant myelin basic protein peptide, MBP 85-99. In the observed patient, the proportion of EBV 627-641-specific CD4+ T cells seemed to exceed 1/10,000 in cerebrospinal fluid, compared to approximately 1/100,000 in blood. These findings prove that Epstein-Barr-virus specific CD4+ T cells can gain access to the intrathecal compartment, and suggest that Epstein-Barr virus-specific CD4+ T cells could target myelin basic protein in the central nervous system.
 ...
PMID:Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein-Barr virus and myelin basic protein. 1538 50

Viral infections are thought to play an important role in the pathogenesis of multiple sclerosis potentially through molecular mimicry, but direct evidence from humans and animal models remains inadequate. Based on the fact that amino acid homology has been found between viral and host encephalitogenic protein, we designed four viral peptides (peptides of HBV polymerase protein, large T protein of JC virus, EB virus DNA polymerase and alkaline exonuclease of Human herpesvirus 6) with limited homology to myelin basic protein and explored their clinical, immunological and histological characteristics in Lewis rats. The immunization with JC virus peptide induced slight clinical signs of EAE in Lewis rats. Immunological examination indicated that rats immunized with JC virus peptide triggered T-cell cross-reactivity against MBP68-86, but failed to induce antibody cross-reactivity with MBP68-86. Histological staining exhibited the infiltration of inflammatory T cells and the activation of microglia in spinal cords of rats immunized with MBP68-86 and JC virus peptide. Other three peptides had negative findings in Lewis rats. These results suggested that molecular mimicry could be an important factor in the pathogenesis of EAE induced with JC virus peptide by expanding a population of reactive T cells that recognize MBP68-86 in Lewis rats inferring a possible pathogenesis for molecular mimicry in MS.
 ...
PMID:Induction of experimental autoimmune encephalomyelitis in Lewis rats by a viral peptide with limited homology to myelin basic protein. 1761 6

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active in selected cell types and provides targeted and sustained reduction of circulating T and B lymphocytes implicated in the pathogenesis of MS. The biologic activity of cladribine depends on the preferential accumulation of cladribine phosphates in cell types with a high intracellular ratio of deoxycytidine kinase to 5'-nucleotidases. Cladribine-phosphates interfere with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism, including DNA polymerase and ribonucleotide reductase. This in turn leads to DNA strand breaks and ultimately cell death. This review explores the mechanism of action of cladribine further, in the context of recent clinical data, after completion of the phase III, 96-week, placebo-controlled CLARITY study. In this study, cladribine tablets demonstrated significant efficacy on clinical and neuroimaging outcomes in relapsing-remitting MS.
 ...
PMID:Cladribine: mode of action and implications for treatment of multiple sclerosis. 2124 42