Gene/Protein Disease Symptom Drug Enzyme Compound
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Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.
Hum Mol Genet 2001 Dec 01
PMID:Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. 1174 34

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis.
Mol Med 2001 Sep
PMID:Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children. 1177 47

Allovectin-7 is a gene transfer product consisting of the human leukocyte antigen HLA-B7 gene co-expressed with the beta2-microglobulin gene. Allovectin-7 is being developed as an immunotherapy approach for a variety of malignancies, with special focus on melanoma, and head and neck cancer. Efficacy results in the phase II setting appear to be promising; an 11% systemic response rate among the intent-to-treat population and 15% response rate in the evaluable population was observed in patients with refractory metastatic melanoma with disease limited to skin, lymph nodes and lung. Stable disease was seen in 19.2% of the intent-to-treat population and 25.9% of the evaluable population in the same group of patients. Treatment has been extremely well tolerated with the most common side effects including mild-to-moderate injection site reactions and flu-like symptoms, all of which resolved rapidly and decreased in incidence after the first injection. Current evaluation of the drug includes higher Allovectin-7 doses and injection of multiple tumors in metastatic melanoma patients. A phase III trial comparing Allovectin-7 plus dacarbazine versus dacarbazine in untreated patients with metastatic melanoma has been completed, and preliminary results are soon to be reported. Phase I/II data also indicate promising activity of Alovectin-7 in patients with advanced refractory head and neck squamous cell carcinoma, with 10% of 60 patients achieving partial response and 23% stable disease after one cycle of treatment. Trials of Allovectin-7 as an adjuvant treatment in earlier stages of disease evolution are planned.
Curr Opin Mol Ther 2002 Feb
PMID:Technology evaluation: Allovectin-7, Vical. 1188 99

During chorionic villi sampling for prenatal diagnosis with molecular biology techniques, contamination by maternal decidua frequently occurs and can lead to misinterpretation of the test results. To avoid such problems, we present a new method for appraising maternal contamination of fetal DNA, based on genomic typing of the highly variable human leukocyte antigen (HLA) locus-DRB1*, locus A* and locus B* regions by genetic amplification with sequence-specific primers and PCR. Fetal DNA samples obtained for beta-thalassemia diagnosis were analysed after artificial contamination with increasing maternal DNA concentrations ranging from 0.5 to 10% (0.5, 1, 3, 5 and 10%). The approach was found to be rapid, specific, reproducible and highly sensitive and permits recognition of 1-3% contamination by maternal DNA concentrations. The system currently used for detecting maternal DNA contamination in fetal samples is the analysis of polymorphic loci by variable number of tandem repeats and/or short tandem repeats. We propose that the analysis of HLA alleles may provide a valid alternative or complement to this system.
Mol Hum Reprod 2002 Jun
PMID:Analysis of HLA-DRB1*-A* and -B* alleles in prenatal diagnosis for determination of maternal contamination in fetal DNA. 1202 78

Preimplantation genetic diagnosis has become a method of choice in genetic practices. The present experience includes thousands of clinical cases of preimplantation genetic diagnosis, demonstrating the safety, accuracy and reliability of the technique and its clinical relevance for those at-risk couples who cannot accept traditional methods for prenatal diagnosis and termination of pregnancy. Most recently, preimplantation genetic diagnosis has been performed for late-onset disorders, such as genetic predisposition to cancers, Alzhelmer's disease and nondisease testing involving human leukocyte antigen typing, never practiced in prenatal diagnosis. The review of these developments suggests the clinical usefulness of this new approach for avoiding the birth of children with genetic predisposition to cancers and other late-onset disorders, or preimplanation human leukocyte antigen matching to provide the treatment of the affected siblings requiring bone marrow transplantation.
Expert Rev Mol Diagn 2002 Sep
PMID:Preimplantation diagnosis for diseases with genetic predisposition and nondisease testing. 1227 22

Host genetic factors are known to contribute to disease susceptibility and course in sarcoidosis. They may also be important in defining the pattern of disease presentation and progression, as well as its overall prognosis. We have studied human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a cohort of Indian patients with sarcoidosis and 275 healthy control subjects from north India. Although no specific HLA class I allele association was found among sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with control subjects. Among class II alleles, positive association of DRB1*11, DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed. Clinical follow-up of the patient cohort up to a 5-yr period showed a predominant occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset, advanced disease on chest radiographs, and chronic course with frequent relapses on tapering off the prednisolone treatment. Further, multivariate logistic regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis. The present findings imply that HLA-associated genetic factors influence the risk for the development of sarcoidosis and disease progression.
Am J Respir Cell Mol Biol 2003 Aug
PMID:Human leukocyte antigen-DR alleles influence the clinical course of pulmonary sarcoidosis in Asian Indians. 1260 Aug 14

Professional antigen-presenting cells (APCs) constitute a heterogeneous leukocyte population that controls T cell induction. Experimental animal studies have delineated the principal APCs of the airway mucosa as a network of intraepithelial dendritic cells (DCs). Whether the situation is comparable in the human airways is unknown. Here we performed a detailed characterization of putative APCs residing in the normal upper airway mucosa, employing confocal microscopy of whole-mount preparations combined with immunophenotyping. A dense network of human leukocyte antigen-DR+ cells with dendritic morphology was found not only in the epithelium (median number, 573/mm2), but also in the lamina propria. In both compartments these cells could be divided into two main populations based on their phenotypic characteristics: the majority expressed a macrophage-like phenotype (CD11b+CD14+CD64+CD68+RFD7+), whereas the smaller population was predominantly constituted by CD1c+CD11c+ immature DCs intermingled with the former. These immature DCs corresponded to the lineage-negative human leukocyte antigen-DR+CD11c+ DC subset present in peripheral blood. Thus, the human upper airway mucosa, in contrast to the rodent counterpart, contains a heterogeneous dense network of dendritic APCs consisting of spatially closely related macrophages and DCs. How these two cell populations regulate the tone of the local adaptive immune system should be the focus of further studies.
Am J Respir Cell Mol Biol 2004 Jan
PMID:Human nasal mucosa contains antigen-presenting cells of strikingly different functional phenotypes. 1282 49

Eight hemochromatosis probands with HFE C282Y homozygosity had frequent, severe, or unusual infections and common variable immunodeficiency (CVID) or immunoglobulin (Ig) G subclass deficiency (IgGSD). Thus, we performed serum Ig isotyping and other characterization of 43 additional unselected probands, 5 human leukocyte antigen (HLA)-identical siblings, and 240 consecutive CVID or IgGSD index patients. C282Y allele frequencies were estimated in 58 CVID or IgGSD index patients without hemochromatosis phenotypes and in 341 controls. HLA-A and -B haplotypes and frequencies were determined in all 51 probands, 186 CVID or IgGSD index patients without hemochromatosis phenotypes, and 751 controls. Thirteen unselected probands (30%) had CVID or IgGSD. Among all 21 hemochromatosis probands with CVID (n = 4) or IgGSD (n = 17), Ig subclass deficiency patterns were IgG(1) (n = 5), IgG(1) and IgG(3) (n = 6), IgG(3) (n = 9), and IgG(1), IgG(3), and IgG(4) (n = 1). IgG(2) or IgA deficiency was not detected; one proband had IgM deficiency. Mean values of total IgG, IgG(1), and IgG(3) were significantly lower in probands with CVID or IgGSD. Mean values of age, transferrin saturation, and ferritin at diagnosis and phlebotomy units required to induce iron depletion were similar in probands with or without CVID or IgGSD; phlebotomy had no apparent effect on IgG levels. C282Y frequencies were similar in CVID or IgGSD index cases without hemochromatosis phenotypes and in controls. There was concordance of Ig and hemochromatosis phenotypes in probands and respective HLA-identical siblings. Eight of 240 CVID or IgGSD index patients had hemochromatosis phenotypes and C282Y homozygosity (3 vs 0.7% and 0.2% controls; P < 0.0001, respectively). The frequency of A*03-B*07 was greater in CVID and IgGSD index cases without hemochromatosis phenotypes than in controls (0.0968 vs 0.0546, respectively; P = 0.0032). HLA-A*03-B*07 was the predominant haplotype in probands grouped by presence or absence of CVID or IgGSD. Some probands in each group were A*03-B*07 homozygotes; group A*03-B*07 frequencies were similar. We conclude that serum IgG abnormalities characteristic of CVID or IgGSD are common in hemochromatosis probands, and that the prevalence of hemochromatosis is increased in CVID and IgGSD index cases. These observations could be explained by the increased frequencies of HLA-A*03-B*07 in C282Y homozygotes and in CVID and IgGSD, and by the common occurrence of putative CVID or IgGSD allele(s) on haplotypes bearing C282Y.
Blood Cells Mol Dis
PMID:Common variable immunodeficiency and IgG subclass deficiency in central Alabama hemochromatosis probands homozygous for HFE C282Y. 1285 Apr 93

The major histocompatibility complex (MHC) harbours genes whose primary function in regulating immune responsiveness to infection is to present foreign antigens to cytotoxic T lymphocytes (CTLs) and T helper cells. In the case of infection by human immunodeficiency virus (HIV), defining the optimal HIV epitopes that are recognised by CTLs is important for vaccine design, and this in turn will depend on the characteristics of the predominant infecting virus. Moreover, the particular MHC human leukocyte antigens (HLAs) expressed by a geographical population is important since these are likely to determine which HIV epitopes are immunodominant in the anti-HIV immune response. Consideration of these aspects has lead to the dawn of a new era of MHC-based vaccine design, in which the CTL epitopes are selected on the basis of the frequency of restricting MHC alleles. This article reviews data on the distribution patterns of molecular subtypes of HLA class I and class II extended haplotypes, discussing distribution among Asian Indians but with reference to global distributions. These data provide a genetic basis for the possible predisposition and fast progression of HIV infections in the Indian population. Since there is selective predominance of different HLA alleles and haplotypes in different populations, a dedicated screening effort is required at the global level to develop MHC-based vaccines against infectious diseases. It is hoped that this might lead to the development of multivalent, poly-epitope, subtype-specific HIV vaccines that are specific for the target geographical location.
Expert Rev Mol Med 2003 Feb 24
PMID:MHC-based vaccination approaches: progress and perspectives. 1498 10

Spondyloarthropathies (SpA) are a group of chronic rheumatic diseases, which show a strong asoociation with human leukocyte antigen (HLA)-B27. Although the association between HLA-B27 and the susceptibility to SpA was discovered thirty years ago, the exact mechanism by which HLA-B27 predisposes to disease development remains unclear. The classical role of MHC class I molecules is to present peptides for CD8+ T cells. Therefore, it has been proposed that the antigen presenting function of HLA-B27 is somehow altered in the patients developing SpA. However, despite extensive research, the attempts to create a comprehensive theory that would explain the role of HLA-B27 as an antigen presenting molecule in the development of SpA have been unsuccessful. Reactive arthritis (ReA) belongs to the group of SpA. It is a joint inflammation developing after certain bacterial infections e.g. Salmonella, Yersinia, and Chlamydia. Several unrelated observations indicate that HLA-B27 modulates the interaction between ReA-triggering bacteria and host cell. These findings suggest that HLA-B27 may possess functions, which are unrelated to antigen presentation. In this paper, we summarize these findings and discuss their potential impact in the development of SpA.
Curr Mol Med 2004 Feb
PMID:Non-antigen presenting effects of HLA-B27. 1501 58


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