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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Posttranscriptional suppression of gene expression can be achieved by introduction of sequence-specific small interfering (si) RNA duplexes and by de novo intracellular synthesis of short sequence-specific double-stranded RNAs. However, achieving desired levels of knockdown is a barrier to successful analytic and therapeutic application. We demonstrate that increasing expression of introduced short hairpin RNA (shRNA) can markedly enhance RNA interference (RNAi) and that this approach can be used to achieve maximal target down-regulation, when the choice of optimal siRNA-binding sites is restricted or when multiple genes are simultaneously targeted and the amount of siRNA is limiting. A dose-dependent RNAi effect was accomplished by placing copies of shRNA under control of the Pol III U6 small nuclear RNA promoter in tandem in a DNA vector. Using this system, we achieved simultaneous down-regulation of expression of classical human leukocyte antigen (HLA) class I genes in cultured and primary human T cells, which might be applied to help circumvent T-cell-mediated rejection of immunogenic and/or HLA-disparate allografts.
Mol Ther 2005 May
PMID:Amplification of RNAi--targeting HLA mRNAs. 1585 Oct 19

Despite its novelty, preimplantation genetic diagnosis has become an alternative to traditional prenatal diagnosis, allowing the establishment of only unaffected pregnancies and avoiding the risk of pregnancy termination. In addition, preimplantation genetic diagnosis is presently applied for much wider indications than prenatal diagnosis, including common diseases with genetic predisposition and preimplantation human leukocyte antigen typing, with the purpose of establishing potential donor progeny for stem cell treatment of siblings. Many hundreds of apparently healthy, unaffected children have been born after preimplantation genetic diagnosis, presenting evidence of its accuracy, reliability and safety. Preimplantation genetic diagnosis appears to be of special value for avoiding age-related aneuploidies in patients of advanced reproductive age, improving reproductive outcome, particularly obvious from their reproductive history, and is presently an extremely attractive option for carriers of balanced translocations to have unaffected children of their own.
Expert Rev Mol Diagn 2005 Jul
PMID:Preimplantation genetic diagnosis in assisted reproduction. 1601 68

Identification of major histocompatibility complex (MHC)-associated peptides recognized by T-lymphocytes is a crucial prerequisite for the detection and manipulation of specific immune responses in cancer, viral infections, and autoimmune diseases. Unfortunately immunogenic peptides are less abundant species present in highly complex mixtures of MHC-extracted material. Most peptide identification strategies use microcapillary LC coupled to nano-ESI MS/MS in a challenging on-line approach. Alternatively MALDI PSD analysis has been applied for this purpose. We report here on the first off-line combination of nanoscale (nano) LC and MALDI TOF/TOF MS/MS for the identification of naturally processed MHC peptide ligands. These peptides were acid-eluted from human leukocyte antigen (HLA)-A2, HLA-A3, and HLA-B/-C complexes separately isolated from a renal cell carcinoma cell lysate using HLA allele-specific antibodies. After reversed-phase HPLC, peptides were further fractionated via nano-LC. This additional separation step provided a substantial increase in the number of detectable candidate species within the complex peptide pools. MALDI MS/MS analysis on nano-LC-separated material was then sufficiently sensitive to rapidly identify more than 30 novel HLA-presented peptide ligands. Peptide sequences contained perfect anchor amino acid residues described previously for HLA-A2, HLA-A3, and HLA-B7. The most promising candidate for a T-cell epitope is an HLA-B7-binding nonamer peptide derived from the tumor-associated gene NY-BR-16. To demonstrate the sensitivity of our approach we characterized peptides binding to HLA-C molecules that are usually expressed at the cell surface at approximately only 10% the levels of HLA-A or HLA-B. In fact, multiple renal cell carcinoma peptides were identified that contained anchor amino acid residues of HLA-Cw5 and HLA-Cw7. We conclude that the nano-LC MALDI MS/MS approach is a sensitive tool for the rapid and automated identification of MHC-associated tumor peptides.
Mol Cell Proteomics 2005 Dec
PMID:Rapid and sensitive identification of major histocompatibility complex class I-associated tumor peptides by Nano-LC MALDI MS/MS. 1611 85

The killer cell immunoglobulin-like receptors (KIR) are a recently discovered family of activating and inhibitory receptors that control natural killer (NK) cell function. KIR exist as a diverse family of receptors that have evolved rapidly by both gene duplication and recombination events. These findings were unexpected for a family of genes involved primarily in the innate immune response. These findings together with the observation that several of these genes have human leukocyte antigen (HLA) class I ligands, have led to a flurry of investigation into how KIR participate in viral infections, autoimmune diseases and malignancies. This review summarizes the major features of these genes and discusses how they may be involved in both disease pathogenesis and its amelioration.
Mol Interv 2005 Aug
PMID:Hanging in the balance. KIR and their role in disease. 1612 37

Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several genome screens have been successful in identifying susceptibility loci in celiac disease, the only genetic contributors identified so far are the human leukocyte antigen (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of celiac disease is the activation of a T-helper 1 immune response, when the antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4(+) T-cells. Recently, new insights into the activation of an innate immune response have also been described. It is generally accepted that the immune response triggers destruction of the mucosa in the small intestine of celiac disease patients. Hence, the activation of a detrimental immune response in the intestine of celiac disease patients appears to be key in the initiation and progression of the disease. This review summarizes the immunologic pathways that have been studied in celiac disease thus far, and will point to new potential candidate genes and pathways involved in the etiopathogenesis of celiac disease, which should lead to novel alternatives for diagnosis and treatment.
Expert Rev Mol Diagn 2005 Sep
PMID:Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients. 1614 72

Several genetic loci appear to be involved in susceptibility to autoimmune disease. Some loci are disease specific, whereas others appear to exert a general effect on the autoimmune disease process. Despite a large number of studies of many different diseases, consistent associations with multiple autoimmune disorders have been restricted to three gene regions: the human leukocyte antigen (HLA) class II region on chromosome 6p21, the gene encoding cytotoxic T lymphocyte-associated 4 (CTLA-4) on chromosome 2q33, and the PTPN22 gene encoding lymphoid tyrosine phosphatase (LYP) on chromosome 1p13. Each of these loci is likely to encode molecules that are crucial in the immune cascade and are actively involved in T-cell activation. Moreover, gene polymorphisms that affect function might contribute to the triggering of autoimmune disease by as-yet-unknown mechanisms. This review summarises recent developments and current understanding of the way in which molecules encoded by these susceptibility loci contribute to T-cell activation, and hypothesises how aberrant function of these molecules might trigger autoimmunity.
Expert Rev Mol Med 2005 Oct 17
PMID:HLA , CTLA-4 and PTPN22 : the shared genetic master-key to autoimmunity? 1622 50

Fanconi anemia (FA) is a genetic disease characterized by progressive, fatal bone marrow failure, congenital anomalies and predisposition to cancer. Although stem cell transplantation is therapeutic, human leukocyte antigen-identical sibling donors are available to a minority of patients. In murine models and human cells in vitro, gene transfer corrects the FA cellular phenotype of chromosomal breakage in response to DNA-damaging agents, suggesting therapeutic use of gene transfer is possible. However, disease-specific characteristics make application of viral vector technology difficult. Multiple studies are currently underway to develop a gene therapy approach for treating this disease, including phase I trials.
Curr Opin Mol Ther 2005 Oct
PMID:Gene therapy in the treatment of Fanconi anemia, a progressive bone marrow failure syndrome. 1624 81

The major histocompatibility complex human leukocyte antigen (HLA)-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis (MS). The primary susceptibility has been localized to only approximately 200 kb encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated inflammatory condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and myelin oligodendrocyte glycoprotein, an autoantigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to MS, we genotyped 1136 well-characterized MS families from the UK and the USA, as well as an African-American case-control data set, making this among the largest genetic studies in MS. Family-based and case-control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family data sets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined data sets: global P=2.4x10(-11)). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15-negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association.
Hum Mol Genet 2006 Jan 01
PMID:Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15. 1632 88

An ab initio structure prediction approach adapted to the peptide-major histocompatibility complex (MHC) class I system is presented. Based on structure comparisons of a large set of peptide-MHC class I complexes, a molecular dynamics protocol is proposed using simulated annealing (SA) cycles to sample the conformational space of the peptide in its fixed MHC environment. A set of 14 peptide-human leukocyte antigen (HLA) A0201 and 27 peptide-non-HLA A0201 complexes for which X-ray structures are available is used to test the accuracy of the prediction method. For each complex, 1000 peptide conformers are obtained from the SA sampling. A graph theory clustering algorithm based on heavy atom root-mean-square deviation (RMSD) values is applied to the sampled conformers. The clusters are ranked using cluster size, mean effective or conformational free energies, with solvation free energies computed using Generalized Born MV 2 (GB-MV2) and Poisson-Boltzmann (PB) continuum models. The final conformation is chosen as the center of the best-ranked cluster. With conformational free energies, the overall prediction success is 83% using a 1.00 Angstroms crystal RMSD criterion for main-chain atoms, and 76% using a 1.50 Angstroms RMSD criterion for heavy atoms. The prediction success is even higher for the set of 14 peptide-HLA A0201 complexes: 100% of the peptides have main-chain RMSD values < or =1.00 Angstroms and 93% of the peptides have heavy atom RMSD values < or =1.50 Angstroms. This structure prediction method can be applied to complexes of natural or modified antigenic peptides in their MHC environment with the aim to perform rational structure-based optimizations of tumor vaccines.
J Mol Biol 2006 Feb 17
PMID:Structural prediction of peptides bound to MHC class I. 1636 8

Identification of peptides presented in major histocompatibility complex (MHC) class I molecules after viral infection is of strategic importance for vaccine development. Until recently, mass spectrometric identification of virus-induced peptides was based on comparative analysis of peptide pools isolated from uninfected and virus-infected cells. Here we report on a powerful strategy aiming at the rapid, unambiguous identification of naturally processed MHC class I-associated peptides, which are induced by viral infection. The methodology, stable isotope tagging of epitopes (SITE), is based on metabolic labeling of endogenously synthesized proteins during infection. This is accomplished by culturing virus-infected cells with stable isotope-labeled amino acids that are expected to be anchor residues (i.e. residues of the peptide that have amino acid side chains that bind into pockets lining the peptide-binding groove of the MHC class I molecule) for the human leukocyte antigen allele of interest. Subsequently these cells are mixed with an equal number of non-infected cells, which are cultured in normal medium. Finally peptides are acid-eluted from immunoprecipitated MHC molecules and subjected to two-dimensional nanoscale LC-MS analysis. Virus-induced peptides are identified through computer-assisted detection of characteristic, binomially distributed ratios of labeled and unlabeled molecules. Using this approach we identified novel measles virus and respiratory syncytial virus epitopes as well as infection-induced self-peptides in several cell types, showing that SITE is a unique and versatile method for unequivocal identification of disease-related MHC class I epitopes.
Mol Cell Proteomics 2006 May
PMID:Stable isotope tagging of epitopes: a highly selective strategy for the identification of major histocompatibility complex class I-associated peptides induced upon viral infection. 1643 54


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