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At least 469 records · Page 26Linked to original sources
PubMed1998

Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus.

The human leukocyte antigen is a crucial genetic factor that initiates or regulates immune response by presenting foreign or self antigens to T lymphocytes. The aim of this study was to investigate whether HLA polymorphism is associated with the onset or progression of liver injury in chronic hepatitis C virus (HCV) infection. We determined HLA class I antigens and class II alleles in 130 hepatitis C virus (HCV)-infected patients (33 carriers with persistently normal alanine transaminase [ALT] values and 97 patients with chronic liver disease [CLD]). HLA class I (A, B) was typed serologically, and class II (DRB1, DQB1) was typed by means of polymerase chain reaction-restriction fragment length polymorphism methods. The frequencies of DRB1*0405 and DQB1*0401 were higher in HCV-infected patients than in uninfected subjects. Among HCV-infected patients, the frequencies of B54, DRB1*0405, and DQB1*0401 were significantly higher in patients with CLD than in those carriers with persistently normal ALT values, whereas DRB1*1302, DRB1*1101, and DQB1*0604 were more frequently found in carriers with persistently normal ALT values than in patients with CLD. From extended haplotype analyses, in carriers with B54-DRB1*0405-DQB1*0401 haplotype, the risk of having liver injury was 13.2 times greater than in carriers with DRB1*0405-DQB1*0401 but without B54 [P = 0.0015, Haldane odds ratio = 13.2 (95% confidence interval, 1.7-103.8)]. In contrast, carriers with B44-DRB1*1302-DQB1*0604 had a 12.7-fold lower relative risk of developing liver injury compared to those with the haplotype containing B44 but not DRB1*1302-DQB1*0604 [P = 0.0076, Haldane odds ratio = 0.079 (0.009-0.695)]. Our findings show that extended haplotypes including class I B54 are closely associated with the progression of liver injury, whereas extended haplotypes including class II DRB1*1302-DQB1*0604 are associated with low hepatitis activity in chronic HCV infection.

Adult↗
PubMed1989

Direct HLA typing by rosetting with immunomagnetic beads coated with specific antibodies.

Paramagnetic monodisperse polymer beads were coated with purified human hybridoma antibodies specific for polymorphic HLA determinants. The mAb-coated beads bound specifically to cells from individuals with the relevant HLA type. The rosettes formed by beads and cells were isolated with a magnet. Rosette formation was evaluated microscopically and used as criterion for positive typing. By this rosette assay, fast and reliable HLA typing of whole blood was possible.

Antibodies, Monoclonal↗
PubMed1999

Low prevalence of selective human leukocyte antigen (HLA)-A and HLA-B epitope losses in early-passage tumor cell lines.

The down-regulation of human leukocyte antigen (HLA) class I molecules, especially the selective down-regulation of certain allelic products, is believed to represent a major mechanism of tumor escape from immune surveillance. In the present report, an original approach is described to precisely evaluate and classify HLA class I epitope losses in 30 cancer patients with malignant melanoma and lung, breast, endometrium, ovary, and colon carcinoma tumors. Early-passage tumor cell lines were established in culture from the corresponding metastatic tumor lesions obtained in each patient. Both the cell lines and the tumor lesions were compared, in their HLA-A and -B expression, to the peripheral blood mononuclear cells (PBMCs) obtained from the same patient (autologous PBMCs). On the basis of HLA-genotyping data, the appropriate monoclonal antibodies identifying mono- and poly-morphic HLA-A and HLA-B epitopes were selected from a panel of 34 antibodies for a total of 24 testable alleles. The selected antibodies were used not only in immunohistochemical assays on cryostatic tumor sections and cytospins of PBMCs but also in quantitative, sensitive flow cytometry assays on early-passage tumor cells and PBMC suspensions. With this latter method, a low overall HLA expression was detected in 26 tumor cell explants and a complete, generalized HLA-A, HLA-B, HLA-C loss in the remaining 4 cases. However, no complete, selective loss of any of the 45 tested HLA-A and HLA-B allomorphs was observed. Sequences from all of the HLA class I alleles could be detected at the genomic DNA level in tumor cells and tissues. At variance from the literature and the results of immunohistochemical experiments performed in parallel on the corresponding tumor lesions, the relative proportions of the various HLA epitopes were relatively preserved in each early-passage cell line/PBMC pair, and selective increases, rather than decreases, in the expression of polymorphic HLA epitopes had the highest prevalence and greatest magnitude. Our data suggest an alternative tumor stealth strategy in which up- and down-regulation are equally important. This alternative model of tumor-host interaction better fits the available models of tumor cell recognition by CTLs and natural killer cells bearing activatory and inhibitory receptors for HLA-A, HLA-B, HLA-C molecules.

Antibodies, Monoclonal↗
PubMed2001

HLA-DR4-Ala74 beta is associated with risk and poor outcome of severe aplastic anemia.

Severe aplastic anemia (SAA) is a heterogeneous hematological disorder with a high mortality. Genetic predisposition has been shown to play a role in a considerable proportion of SAA cases. For instance, the human lymphocyte antigen HLA-DR2 has been repeatedly demonstrated to be over-represented in SAA patients. In this paper, we expand on the evidence for the contribution of HLA polymorphism in the susceptibility to SAA, which was obtained using the "high-resolution" technique of HLA-DRB1 subtyping. The DRB1*1501 allele appeared to be responsible for the predominance of DR2 specificity in SAA patients and was the most significant risk factor for this disease. It was observed in 23/44 (52.3%) patients versus 22/100 (22.0%) donors [odds ratio (OR) = 3.9; 95% confidence interval (CI): 1.8-8.3; P = 0.0005, corrected P (Pc) < 0.05]. In addition, DRB1*04 alleles also displayed non-random distribution in the SAA group. In particular, DRB1*04 variants coding for alanine at position 74 of the DR beta 1 chain (HLA-DR4-Ala74 beta subtype) were detected in all 13 DR4-positive SAA patients but only in 15/24 (62.5%) controls (OR = 16.6; 95% CI: 0.9-312.0; P = 0.015). Multiple comparison analysis confirmed that the HLA-DR4-Ala74 beta subtype confers susceptibility to SAA independently from the DRB1*1501 allele. Finally, examination of the clinical records has shown that the HLA-DR4-Ala74 beta subtype is associated with poor outcome of SAA.

Adolescent↗
PubMed2002

Advances in understanding the genetic basis of rheumatoid arthritis and osteoarthritis: implications for therapy.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are polygenic diseases. Polymorphisms in candidate genes have been studied for possible association with susceptibility to disease development. Aside from HLA polymorphisms, of particular interest are those in genes encoding cytokines, signaling molecules, and enzymes involved in the production and catabolism of oxygen and nitrogen radicals. Cytokines are involved in the modulation of the pathological process and have been the target for novel therapeutic interventions. Evidence for their involvement in RA and OA has been provided from genetic analyses in patient populations as well as from animal models of disease. Intracellular signaling cascades control cellular responses and thus regulate many aspects of the pathology manifested in rheumatic diseases. Deciphering the organization and activity of such signaling pathways in disease is underway. Polymorphisms have been identified in gene promoter regions regulating efficient binding of transcription factors, and in coding regions of genes whose products are involved in signal cascades relevant to RA. Among these are the NF-kappaB pathway, steroid receptors and the p53 tumor suppressor gene. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have also been implicated in rheumatic diseases. It is thought that excess, damaging, ROS/RNS may arise from an imbalance between the production and removal of these chemical species. Polymorphisms in genes that encode enzymes involved in either generating or degrading ROS/RNS may contribute to such an imbalance. In the last few years, polymorphisms in such genes have indeed been identified as risk factors for rheumatic diseases.

Animals↗
PubMed1999

HLA class II polymorphism in a Gabonese Banzabi population.

The HLA class II typing of 167 unrelated Gabonese individuals from the Banzabi ethnic group was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The most frequent alleles at each locus were DRB1*1501-3 (0.31), DQA1*0102 (0.50), DQB1*0602 (0.42) and DPB1*0402 (0.29). The estimation of the haplotype frequencies as well as the observation of the segregation of several haplotypes using additional HLA typing of relatives, revealed that the three-locus haplotype DRB1*1501-3-DQA1*0102-DQB1*0602 was found at the highest frequency (0.31) among these individuals. This haplotype is not typically African and has already been described in Caucasians, but its presence at high frequency is exclusive to populations originating from Central Africa, and can thus be designated as a particular genetic marker of these populations.

Adolescent↗
PubMed2002

Human leukocyte antigen-A, -B, -C and -DR alleles and soluble human leukocyte antigen class I serum level in Ménière's disease.

Previous studies have suggested that many human leukocyte antigen (HLA)-A, -B, -C and -DR alleles are associated with Ménière's disease (MD), an inner ear disorder with a proposed autoimmune etiopathogenesis. Despite some discrepancies many reports are in agreement with a hypothesis suggesting an influence of serologically detected HLA-C products in the susceptibility to the disease. To confirm these data we investigated the distribution of HLA-A, -B, -C and -DR antigens that well define the HLA polymorphism using DNA typing. Furthermore, as autoimmune factors have been claimed to play a role in MD, we investigated the serum level of soluble HLA class I (sHLA-I). Molecular typing of HLA class I and II was performed using polymerase chain reaction sequence-specific primers in 41 patients affected by MD, 34 patients affected by other inner ear diseases (OIDs) and 101 healthy subjects. An ELISA technique was employed to investigate the serum level of sHLA-I in 17 MD patients, 10 OID patients and 83 healthy subjects. The results showed a significantly increased frequency of the Cw*07 specificities in MD patients when compared to OID patients (63.4% vs 32.3%; p = 6.9 x 10(-3); relative risk [RR] = 3.6) and healthy subjects (63.4% vs 35.6%; p = 2.28 x 10(-3); RR = 3.1). The sHLA-I concentrations detected in sera did not differ significantly between MD patients (616 +/- 271 ng/ml), OID patients (570 +/- 307 ng/ml) and healthy subjects (518 +/- 340 ng/ml).

Case-Control Studies↗
PubMed1987

Functional polymorphisms among HLA-DR4+ DR beta chains associated with limited peptide diversity.

Tryptic peptide map analysis by high-pressure liquid chromatography of DR4- associated DR beta chains revealed limited structural variation within DR beta polypeptides. Comparison of 3H-leucine-labelled tryptic peptide maps of Dw4 and Dw14 homozygous cells identified distinct peaks corresponding to Dw4 and Dw14-associated DR beta polypeptides. HPLC analysis of cell line 256, heterozygous for two DR4-related specificities, Dw4 and Dw14, displayed both peptides, corresponding to the variable Dw4 and Dw14 chromatograms. This observation was confirmed using a deletion mutant cell line derived from 256 lacking Dw4-associated class II genes. The observed peptide variation correlated precisely with predicted nucleotide-derived amino acid sequences implicating amino acids 66-71 of the DR beta chain as contributing to HLA-D structural and functional polymorphisms.

Amino Acid Sequence↗
PubMed2001

Human leukocyte antigen-DQ and DR polymorphisms predict rheumatoid arthritis outcome better than DR alone.

Conflicting data have been published on the value of the shared epitope (SE) hypothesis in predicting disease outcome in rheumatoid arthritis (RA). Recently we have proposed an alternative hypothesis, referred to as the RA protection (RAP) model. In this model, the HLA-DQ loci carry predisposition while HLA-DRB1 alleles encoding the motif DERAA provide protection against severe RA. In the present study, we have compared the respective values of the models in predicting both remission and erosions in early RA patients. We made use of an early arthritis clinic in which 158 RA patients and 138 patients with undifferentiated arthritis were enrolled. Patients were typed for HLA-DQ and -DR using high resolution DNA typing methods. Homozygosity for predisposing HLA-DQ alleles was associated with no remission and high erosion score. The presence of DERAA-bearing DRB1 alleles was negatively associated with erosions in otherwise predisposed individuals and increased the chance of being in remission. We found that the RAP model was significantly better than the SE model in predicting remission rate and erosion scores at one and two years in early RA patients. We conclude that HLA polymorphism does not only affect RA susceptibility, but also protects against severe disease at early stage.

Alleles↗
PubMed2005

[Correlation between the polymorphism of HLA-A, -B, and -DRB1 alleles and susceptibility to leukemia].

AIM: To explore the correlation between the polymorphism of HLA-A, -B and -DRB1 alleles and susceptibility to leukemia in Chinese Han population, Gansu province. METHODS: The polymorphism of HLA-A, -B and -DRB1 alleles in 57 patients with leukemia and 45 normal controls were determined by PCR with sequence-specific oligonucleotide probe (PCR-SSO). RESULTS: The frequencies of allele HLA-A01, -B38, and -DR15 in patients with leukemia were higher than those in control group (P<0.05), while the frequencies of allele HLA-A11 and -DR03 notably decreased (P<0.05). CONCLUSION: HLA-A01, -B38 and -DR15 alleles in Han population, Gansu province seem to contribute to the genetic susceptibility, while HLA-A11 and -DR03 alleles to the genetic resistance, to leukemia.

Adolescent↗
PubMed2005

[The role of HLA DRB1 genetic polymorphisms in non-Hodgkin's lymphomas].

The role of tumor necrosis factor (TNF)-308A polymorphic allele on non-Hodgkin's lymphoma (NHL) outcome was documented in the previous studies, although the role of the neighboring polymorphisms was unknown. The aim of the present study was to asses the frequencies and distributions of the HLA DRB1, TNF-308 and lymphotoxin alpha (LTalpha)+252 allelic polymorphisms in NHL patients and healthy controls and their influence on NHL outcome. The HLA DRB1, TNF-308 and LTalpha +252 allelic frequencies and distributions didn't differ significantly between patients and healthy controls, thus it is unlikely that polymorphisms within the above mentioned sites confer susceptibility for lymphoma occurrence. Among the polymorphic alleles HLA DRB1*03, TNF-308A and LTalpha +252A remaining in linkage disequilibrium, TNF-308A was the only allele associated with higher TNF and its p55 and p75 receptors' plasma levels (p = 0.009, p = 0.03, and p = 0.007), lower complete remission rates (p = .006), shorter freedom from progression (FFP) and overall survival (OS) (p = 0.009 and p = 0.017, respectively). Among the polymorphic HLA DRB1 alleles, null HLA DRB1*02 was the sole allele along with the TNF-308A that remained independent factors for shorter FFP (relative risk [RR] = 1.18, p < 0.02 and RR = 1.63, p < 0.0001, respectively) and OS (RR = 1.25, p < 0.0001 and RR = 1.51, p < 0.0001, respectively). Innate immunity reflected by inherited HLA DRB1 genes repertoire and genetic propensity of the host to regulate TNF production and/or other closely linked genes influences clinical course and outcome of NHL.

Aged↗
PubMed1998

High resolution HLA class I typing by reference strand mediated conformation analysis (RSCA).

We describe the application of RSCA for the high resolution typing of alleles encoded within the highly polymorphic HLA class I system. RSCA differs from other sequence based typing methodologies in that the HLA type is assigned on the basis of differences in DNA conformation between different HLA alleles. HLA class I locus specific PCR was performed on the sample to be HLA typed and the PCR product mixed with a fluorescent labelled locus specific reference strand. DNA molecules were allowed to reanneal and the duplexes formed were separated by non-denaturing PAGE. Only duplexes which possess the fluorescent labelled reference strand were detected using an automated DNA sequencer. The mobilities of duplexes formed for 131 HLA class I alleles have been calculated and HLA type assigned. The use of a laser scanning system for accurate detection of migrating DNA, in combination with specific software for data analysis and correction of gel variablility, make RSCA sufficiently robust to detect alleles differing by as little as one nucleotide, resulting in a simple and automated technique for high resolution HLA typing.

Alleles↗
PubMed2001

[Multiple sclerosis: the recent progress of research and treatment].

In this review, we summarized the recent progress of research and treatment of multiple sclerosis (MS). The immunogenetic study including analyses of HLA polymorphism revealed that there are two distinct subtypes of MS: Asian-type and Western-type. Since MS is a polygenic disease, there must be several susceptible genes other than HLA. A large number of candidate genes are being searched and analyzed for polymorphism. Autoantigens responsible for MS are of great interest. Screening peptide library which bind to MS susceptible genes are expected to provide with new autoantigens. Advance in treatment is also remarkable. Since interferon (IFN)-beta 1b became available, great deal of data concerning IFN beta are accumulated. IFN beta not only reduced clinical exacerbation and MRI brain lesions but also slowed the development of brain atrophy. New treatments include altered peptide ligand therapy and oral tolerization with myelin antigens, which are on the clinical trial. Vaccination with myelin reactive T cells or T cell receptor peptide also attracts a great deal of attention.

Autoantigens↗
PubMed1991

Application of silver staining to the rapid typing of the polymorphism of HLA-DQ alleles by enzymatic amplification and allele-specific restriction fragment length polymorphism.

A rapid and highly sensitive silver staining method, originally developed for the detection of proteins, was slightly modified to detect nucleic acids in polyacrylamide gels. The second exons of the histocompatibility antigen HLA-DQA 1 and DQB 1 genes were selectively amplified from genomic DNA by the polymerase chain reaction (PCR). Digestion of the PCR products by endonucleases, followed by their size-separation on polyacrylamide gels and visualization by silver staining, allowed us to define the HLA-DQ alleles of the genomic DNA. The intensity of staining of digested PCR-amplified DNA is linear from at least 8 to 18 ng for fragments of lengths ranging from approximately 40 to 200 bp. Thus, silver staining in combination with PCR and allele-specific restriction fragment length polymorphism provides a simple, safe, and rapid method for accurate definition of HLA-DQ alleles at the nucleotide level in the clinical typing laboratory.

Base Sequence↗
PubMedDate not supplied

Cell lines producing human T-cell lymphoma virus show altered HLA expression.

Human T-cell leukaemia/lymphoma virus (HTLV) can be identified in fresh and cultured T-lymphocytes from patients with adult T-cell malignancies. HLA typing of the peripheral blood lymphocytes and cultured cell lines from the patient from which the virus was originally isolated suggested the expression of additional HLA-A and -B locus antigens on the HTLV positive cultured T-cells that were not present on the EBV transformed B-cell line or on the peripheral blood lymphocytes. Peripheral blood lymphocytes (PBLs) and T-cell lines established from patients and cord blood lymphocytes, infected with virus by co-culture with T-cell lines, were typed for HLA antigens with alloantisera and in addition tested for reactivity with a monoclonal antibody (4D12) which recognizes a polymorphic HLA class-I antigen. In all HTLV positive cells, with demonstrable provirus replication, altered HLA alloantigen expression was observed. This may be explained by the observations reported in the accompanying paper which shows homology between the envelope gene region of HTLV and the region of an HLA-B locus gene which codes for the extracellular portion of a class I histocompatibility antigen.

Antigens, Surface↗
PubMed1988

Oligonucleotide probing. Applications to HLA typing.

Human leukocyte antigen typing is currently being done by both serologic and cellular techniques. It is this methodology that forms the basis for organ transplantation, since HLA antigens are the major proteins involved in graft rejection. Matching organ graft donors with recipients at these polymorphic HLA loci clearly increases graft survival in most transplant systems. However, the serologic and cellular techniques have shortcomings, including the problem of standardizing antisera, the need for technologists with expertise in T-cell cloning, and the failure to work successfully with some cells (eg, leukemic blasts). We have begun to develop a more rapid, sensitive typing method using molecular biological techniques to tissue-type cells. Using oligonucleotide probes, we can now identify HLA-D region alleles (which may differ by only a single nucleotide) that can only be differentiated by a highly technical, lengthy cellular technique. Oligonucleotide probing not only provides the basis for a rapid method of HLA typing, which in all likelihood will become generally applicable as additional sequence information becomes available, but also allows definition of a gene transcript from an individual locus rather than the phenotypic results provided by current HLA typing techniques.

Alleles↗