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

Epithelial cells of the human respiratory tract express human leukocyte antigen (HLA) and the costimulatory molecules B7-1 and B7-2. Little is known, however, about the constitutive expression of genes encoding for the more recently identified members of the B7 homolog family of costimulatory molecules or about the influence of cellular differentiation and cytokines on their activity or on that of HLA or B7-1 and B7-2. Human nasal epithelial (HNE) cells were grown at the air-liquid interface (ALI) for 2 or 21 days to model in vivo conditions. Expression of genes for HLA-B and HLA-DR1 increased during mucociliary differentiation during this period and became more similar to HNE cells obtained fresh by brush biopsy from nasal turbinates. Gene transcripts for B7-H3 and B7-H2 were abundantly expressed in cells cultured at the ALI, but neither their activities nor that of B7-2 was significantly altered during differentiation. IFN-gamma and TNF-alpha upregulated mRNA encoding for both HLA molecules, but not for the B7 molecules. This study describes, for the first time, the expression of B7-H3 and B7-H2 by HNE cells and thus expands the range of potential costimulatory signals through which these cells may interact with activated mucosal T lymphocytes. In addition, the results suggest that the extent of mucociliary differentiation of cultured cells may influence this capability.
Am J Physiol Lung Cell Mol Physiol 2004 Jul
PMID:Expression of genes for B7-H3 and other T cell ligands by nasal epithelial cells during differentiation and activation. 1504 68

CD94/NKG2A is an inhibitory receptor expressed by most human natural killer (NK) cells and a subset of T cells that recognizes human leukocyte antigen E (HLA-E) on potential target cells. To elucidate the cell surface dynamics of CD94/NKG2A receptors, we have expressed CD94/NKG2A-EGFP receptors in the rat basophilic leukemia (RBL) cell line. Photobleaching experiments revealed that CD94/NKG2A-EGFP receptors move freely within the plasma membrane and accumulate at the site of contact with ligand. The enriched CD94/NKG2A-EGFP is markedly less mobile than the nonligated receptor. We observed that not only are lipid rafts not required for receptor polarization, they are excluded from the site of receptor contact with the ligand. Furthermore, the lipid raft patches normally observed at the sites where FcepsilonR1 activation receptors are cross-linked were not observed when CD94/NKG2A was coengaged along with the activation receptor. These results suggest that immobilization of the CD94/NKG2A receptors at ligation sites not only promote sustenance of the inhibitory signal, but by lipid rafts exclusion prevent formation of activation signaling complexes.
Mol Biol Cell 2004 Jul
PMID:Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. 1513 25

Cervical cancer is a multifactorial disease and infection by oncogenic human papilloma viruses represents the main environmental risk factor. Only a subset of infections becomes persistent and develops into cancer, implying that genetic susceptibility factors are needed for malignant progression. Here, we use a population-based cohort of affected sib-pairs (ASPs) to examine the role of the human leukocyte antigen (HLA) class I and class II loci in cervical cancer susceptibility. Analysis of 278 ASPs revealed significant excess genetic sharing for all three HLA class II loci studied, DPB1, DQB1 and DRB1, with the strongest evidence for DQB1 and DRB1. No evidence of excess sharing was observed for the HLA class I HLA-B and HLA-A loci. When the material was stratified on the basis of the DQB1*0602/DRB1*1501 susceptibility haplotype, carriers showed significant sharing for all loci, whereas non-carriers showed no evidence of excess genetic sharing at any of the loci. However, for the DPB1 locus there was no difference in allele frequency between carriers and non-carriers indicating that the effect seen in DPB1 is not simply due to linkage disequilibrium. Our results show that the HLA class II represents a major genetic susceptibility locus to cervical cancer in contrary to the class I that do not appear to have a significant impact on predisposition to the disease. The strongest class II effects are coming from the DQB1 and DRB1 loci, but the DPB1 locus also contributes to the susceptibility to cervical cancer.
Hum Mol Genet 2004 Sep 01
PMID:Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer. 1523 5

Accessory cell function of airway epithelial cells. We previously demonstrated that airway epithelial cells (AECs) have many features of accessory cells, including expression of class II molecules CD80 and CD86 and functional Fcgamma receptors. We have extended these studies to show that freshly isolated AECs have mRNA for cathepsins S, V, and H [proteases important in antigen (Ag) presentation], invariant chain, human leukocyte antigen (HLA)-DM-alpha and HLA-DM-beta, and CLIP, an invariant chain breakdown product. A physiologically relevant Ag, ragweed, was colocalized with HLA-DR in AECs, and its uptake was increased by granulocyte-macrophage colony-stimulating factor and IFN-gamma treatments, which had no effect on CD80 and CD86 expression. We demonstrate the presence of other costimulatory molecules, including B7h and B7-H1, on AECs and the increased expression of B7-H1 on AECs after treatment with granulocyte-macrophage colony-stimulating factor and IFN-gamma. Finally, we compared T cell proliferation after allostimulation with AECs and dendritic cells (DCs). The precursor frequency of peripheral blood T cells responding to AECs was 0.264% compared with 0.55% for DCs. DCs stimulated CD45RO(+), CD45RA(+), CCR7(+) and CCR7(-)CD4(+), and CD8(+) T cells, whereas AECs stimulated only CD45RO(+), CD45RA(-), CCR7(-), CD4(+), and CD8(+) T cells. There was no difference in cytokine production, type of memory T cells stimulated (effector vs. long-term memory), or apoptosis by T cells cocultured with AECs and DCs. The localization of AECs exposed to the external environment may make them important in the regulation of local immune responses.
Am J Physiol Lung Cell Mol Physiol 2004 Aug
PMID:Accessory cell function of airway epithelial cells. 1524 82

It has been previously found that the nonapeptide fragment of human leukocyte antigen (HLA)-DQ molecule, located in the beta chain 164-172 with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence, suppresses the immune response. The hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr was the shortest fragment of HLA-DQ showing both cellular and humoral immunosuppressive activity, while the analog deprived of the last amino acid (Arg-Gly-Asp-Val-Tyr) showed very weak stimulatory activity with respect to the humoral immune response. This suggested that the threonine residue in the hexapeptide plays an essential role in immunosuppression. In this study, the role of the side chain of threonine residue was scrutinized in a series of synthetic analogs in which the Thr residue was substituted by various amino acids, amides and methyl ester. The synthesized peptides were evaluated for their immunosuppressive activity. Our results indicate that the substitutions did not significantly affect the immunomodulatory properties, revealing that the threonine side chain is not critical for the immunosuppressive potency of the peptides. Interestingly, a simple analogue, pentapeptide amide H-Arg-Gly-Asp-Val-Tyr-NH2 possessed high immunosuppressive potency, comparable to that of cyclosporine.
Mol Immunol 2004 Jul
PMID:Threonine at position 6 is not essential for the immunosuppressive activity of HLA-DQ(beta164-172)-hexapeptide. 1526 63

Natural killer (NK) cell-mediated, donor-vs.-recipient alloresponses occur following transplantation of human leukocyte antigen (HLA) haplotype-mismatched hematopoietic stem cells (HSCs). NK cell alloreactivity reduced the risk of relapse in acute myeloid leukemia patients while improving engraftment and protecting against graft-vs.-host disease (GvHD). NK cells are primed to kill by several activating receptors. NK killing of autologous cells is prevented because NK cells co-express inhibitory receptors (killer cell Ig-like receptors, KIR) that recognize groups of (self) MHC class I alleles. As KIRs are clonally distributed, the NK population in any individual is constituted of a repertoire with different allospecificities. NK cells in the repertoire mediate alloreactions when the allogeneic targets do not express class I alleles that block them. High resolution molecular HLA typing of recipient and donor, positive identification of donor KIR genes, and in some cases, functional assessment of donor NK clones will identify haploidentical donors who are able to mount donor-vs.-recipient NK alloreactions.
Blood Cells Mol Dis
PMID:Alloreactive natural killer cells in mismatched hematopoietic stem cell transplantation. 1552 34

Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning regimen, and benefit from advances in post-transplant immunological reconstitution. All these factors contribute to markedly reduce transplant-related mortality. Overall, event-free survival and transplant-related mortality compare favorably with reports from unrelated matched transplants. T-cell-depleted megadose stem cell transplant from a mismatched family member, who is immediately available, can be offered as a viable option to candidates with high-risk acute leukemias.
Blood Cells Mol Dis
PMID:Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia. 1552 48

Reprogramming T-cell populations by T-cell receptor (TCR) gene transfer is a new therapeutic tool for adoptive tumor immunotherapy. Gene transfer of human leukocyte antigen (HLA)-transgenic mice-derived TCR into human T-cells allows the circumvention of tolerance to tumor-associated (self) antigens (TAA). This chapter reports on the identification of the alpha and beta chains of the heterodimeric TCR derived from a mouse T-cell clone. The related DNA fragments are inserted into a retroviral vector for heterologous expression of the TAA-specific TCR in human T-cells. Polymerase chain reaction (PCR)-based cloning protocols are provided for the tailor-made customization of murine TCR. We describe the humanization and chimerization of such TCR as well as their expression in human T-cells.
Methods Mol Med 2005
PMID:Designing TCR for cancer immunotherapy. 1558 25

Before the discovery of HFE, reports suggested that hemochromatosis patients with the ancestral haplotype (or some element thereof) have more severe iron overload than those without the haplotype. We performed univariate and multivariate analyses of the relationships of human leukocyte antigen (HLA)-A*03 and HLA haplotype A*03-B*07 to iron measures (serum iron concentration, transferrin saturation, and serum ferritin concentration at diagnosis and units of phlebotomy to achieve iron depletion) in hemochromatosis probands homozygous for HFE C282Y diagnosed in medical care. Iron overload was defined by demonstration of hepatic iron index of > or =1.9 or removal of > or =2.0 g Fe by therapeutic phlebotomy. We tabulated the phenotype frequencies of HLA-A*03 and the frequencies of common HLA haplotypes A*01-B*08, A*02-B*44, A*03-B*07, and A*03-B*14 in three groups of white adults: (1) 141 hemochromatosis probands with C282Y homozygosity; (2) 195 index cases with IgG subclass deficiency (IgGSD) or common variable immunodeficiency (CVID), disorders typically linked to Ch6p, and (3) 750 control subjects. Among probands, 86 men and 42 women had iron overload. Frequencies of HLA-A and -B alleles in probands did not depart significantly from Hardy-Weinberg equilibrium. The phenotype frequency of A*03 did not differ significantly between men and women in the each of the respective three groups. The frequency of haplotype A*03-B*07 was greater in men than women with hemochromatosis (0.3081 vs. 0.1455; P = 0.0019). The frequency of A*03-B*014 was significantly greater in women than men with hemochromatosis (0.1182 vs. 0.0407, respectively; P = 0.0134). Mean values of most iron measures were not affected by numbers of copies of A*03 or by presence of A*03-B*07 in either men or women in univariate analysis. ANOVA models of sex, age at diagnosis, and all HLA alleles and haplotypes in probands were used to determine effects of these variables on iron measures. ANOVA models revealed that (1) there were no significant predictors for serum iron concentration; (2) B*14 is associated with higher transferrin saturation in women and lower transferrin saturation in men; (3) A*01-B*08 is associated with a trend of higher serum ferritin levels; and (4) A*03-B*14 is associated with exaggeration of the age-associated upward trend in units of phlebotomy to achieve iron depletion. In hemochromatosis probands with HFE C282Y homozygosity, we conclude that (1) disparate frequencies of HLA haplotypes A*03-B*07 and A*03-B*14 occur in men and women and (2) HLA-A*03 and HLA-A*03-B*07 are not independent variables associated with iron overload severity.
Blood Cells Mol Dis
PMID:HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. 1560 98

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.
J Mol Med (Berl) 2005 May
PMID:Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease. 1575 Aug 22


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>