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Results for “HLA polymorphism”

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PubMed1989

The polymerase chain reaction.

The polymerase chain reaction (PCR) is a novel technique that amplifies specific sequences with remarkable efficiency. Repeated cycles of denaturation, primer annealling and extension carried out with the heat stable enzyme, Taq polymerase, leads to exponential increases in the target DNA sequences. The technique has been widely applied in immunology to define HLA polymorphism, T-cell receptor and immunoglobulin diversity, pathogen detection, quantification of lymphokines and lymphoma or leukaemia detection. In addition, it has been very widely applied in all areas of molecular biology and human genetics. Because of its simplicity and sensitivity, PCR represents a major technical development for molecular biologists and will continue to have a great impact on molecular immunology. This review by John Bell describes the basic PCR technique and some variations on it and briefly explores their uses in molecular immunology.

DNA↗
PubMed1985

Human Ia molecules carrying MT1 determinants: purification with a monoclonal antibody.

A monoclonal antibody 77.34, reactive with polymorphic HLA class II molecules, was produced. The allotype specificity of this IgG2a antibody was analyzed by cytotoxicity, flow cytometry, and cellular radioimmunoassay. Cytotoxic reactivity on a panel of B cells from 88 unrelated individuals was concordant with the MT1 (DC1) allospecificity (r = 0.83). Immunoanalysis by flow cytometry showed that cells from MT1+ homozygous cell lines were reactive, whereas MT2+ and MT3+ homozygous cells were not. A cellular radioimmunoassay performed under saturating conditions indicated that three MT1+ cell lines bound 14-45 X 10(5) molecules of antibody per cell representing 30-40% of the amount detected with monomorphic anti-DR monoclonal antibody 21w4. The subset of molecules bearing the MT1 allospecificity was purified with a 77.34 IgG immunoadsorbent. The purified molecules were antigenically reactive with several antibodies directed at DQw1 molecules but were devoid of reactivity to monomorphic anti-DR antibodies. Two-dimensional gel electrophoresis showed that the alpha subunit is composed of several acidic spots of Mr 32,000 whereas the beta subunit was seen as a single spot of Mr 25,000, corresponding to DQw1 molecules. DR molecules purified by monoclonal antibody affinity were unreactive with 77.34 antibody. All of the 77.34 reactivity was observed with the fractions depleted of DR molecules. Two-dimensional gel analysis showed marked differences between the purified DR and DQw1 molecules. The presence of the MT1 determinant on Ia molecules referred to as the DQw1 molecules and distinct from those bearing the DR epitopes was confirmed on two DR1, MT1 homozygous cell lines. Thus, DQw1 molecules can be purified away from DR1 molecules by affinity chromatography to 77.34 IgG, specifically reactive with the MT1 (DQw1) allospecificity. The binding of 77.34 IgG to MT1+ cells was not inhibited by all monoclonal antibodies reported to be correlated with the MT1 allospecificity suggesting that the latter might be comprised of more than a single epitope.

Animals↗
PubMed1995

Allogeneic lymphocyte chimerism after clinical lung transplantation.

Donor lungs contain large amounts of passenger leukocytes which are transferred to the recipient by organ transplantation. In this study we have analysed the fate of these cells and have studied the populations of donor leucocytes detectable in the blood circulation of ten lung transplanted patients during the first postoperative weeks. To this aim we have applied immunocytological as well as flow cytometric analyses using monoclonal antibodies against polymorphic HLA class I antigens that differed between donor and recipient as well as antibodies against cell differentiation markers. The results demonstrate that donor cells can be detected in the circulation of all lung transplanted patients but there is a considerable interindividual variability between 0.9% and 17.5% (mean 5.1%) on postoperative day 3. Cells were usually detectable for 2-4 weeks and had disappeared in all patients after 1 month. The circulating donor cells consisted exclusively of lymphocytes. T cells were the predominant population, most of which seemed to be CD45R0+, but B and NK (natural killer) cells were also present. Probably due to the small numbers of patients studied no correlation between clinical parameters and the extent of donor lymphocyte persistence; there were no clinical graft-versus-host reactions. The findings demonstrate the regular existence of a transient (macro)chimerism due to passenger lymphocytes in the early phase after lung transplantation. The immunological function and the relation between this phenomenon and the long-term microchimerism which frequently develops after solid organ transplantation remain unclear.

Adult↗
PubMed2005

HLA genes in Mexican Teeneks: HLA genetic relationship with other worldwide populations.

The HLA allele frequency distribution of the Mexican Teenek Indians has been studied and compared with those of other First American Natives and worldwide populations (a total of 15694 chromosomes from 73 different populations were analyzed). This study corroborate the restricted HLA polymorphism in the Amerindian populations and demonstrate how the Amerindians show a relatively homogeneity as opposed to other First Native American groups. Finally, the present data support previous ones that state the lack of complete correlation between language and genetics in micro-environmental studies; Teenek Mayan language does not correspond with a close Mayan (Guatemala) relatedness.

Alleles↗
PubMed1999

Antigen presenting cells integrate opposing signals from CD4+ and CD8+ regulatory T lymphocytes to arbitrate the outcomes of immune responses.

An individual's set of polymorphic HLA class II and I molecules is known to select the T cell repertoire in the thymus and to present processed antigenic peptides (pAg) to mature peripheral CD4+ T helper (Th) and CD8+ T cytotoxic (Th) cells in the periphery. This review highlights new studies which address how antigen presenting cells (APC) integrate the responses of cognate Th and T suppressor (Ts) cells to determine the outcome of immune responses. Together with other findings, these studies emphasize that understanding the mechanism of immune processes requires consideration of HLA molecules in the context of the peptides they bind, the antigen presenting cells (APC) that express them and the T lymphocytes that recognize them. The activities of lymphocyte and APC surface structures are becoming integrated into a physiological understanding of the cellular interactions between regulatory and effector T cells with APC.

Animals↗
PubMed2001

[Detection of fetal cells in maternal blood: myth or reality?].

Fetal cells exist in maternal blood and can be utilized for prenatal diagnosis. These cells are present from the sixth week of gestation, with frequency increasing as gestation advances, to many years after the birth. Enrichment of trophoblast cells, erythroblasts and lymphocytes was performed with various density gradient techniques and either magnetic activated or fluorescent activated sorting techniques. The abnormalities were detected by fluorescent in-situ hybridation (FISH) with chromosome-specific DNA probes for the detection of trisomy 21, trisomy 18, Klinefelter syndrome 47 XXY, or by polymerase chain reaction (PCR) for the detection of fetal sex, certain Mendelian disorders (as beta-globin mutations), HLA polymorphisms and fetal Rhesus D blood type. However others studies were necessary to determine the sensitivity and specificity of this technique as a noninvasive alternative to conventional methods of prenatal cytogenetic diagnosis.

Blood Cells↗
PubMed1995

Isolating fetal cells in the maternal circulation.

Fetal cells exist in maternal blood and can be utilized for prenatal genetic diagnosis. The use of polymerase chain reaction (PCR) technology on maternal blood has enabled the detection of fetal sex, Mendelian disorders (e.g. beta-globin mutations), HLA polymorphisms and fetal Rhesus (D) blood type. Enrichment for erythroblasts and trophoblasts by various density gradient and flow sorting techniques followed by fluorescence in-situ hybridization (FISH) with chromosome-specific DNA probes has allowed detection of trisomy 21, trisomy 18, Klinefelter syndrome (47,XXY) and 47,XYY. The fetal cell type that has generated the most success is the nucleated erythrocyte; however, trophoblasts, lymphocytes and granulocytes are also considered to be present in maternal blood. Fetal cells circulate in maternal blood during the first and second trimesters, with frequency increasing as gestation advances. Emphasis is thus now directed toward determining the most practical and efficacious manner for this technique to be applied to prenatal genetic diagnosis. A large scale collaboration of clinical evaluations is underway in the USA, upon completion of which assessment can be made of whether this technology can serve as an alternative to conventional invasive and non-invasive methods of prenatal cytogenetic diagnosis.

Cell Separation↗
PubMed1993

Persistence of donor lymphocytes in liver allograft recipients.

Occasional cases of graft-versus-host disease after liver transplantation indicate a transfer of donor lymphocytes by human liver grafts. However, little is known about the usual fate and potential function of passenger lymphocytes in clinical liver transplantation. In this study, we have analyzed liver graft recipients for the presence of donor lymphocytes in the early course after transplantation. The presence of such cells in blood, the graft, and, occasionally, the skin was studied by the use of mAb to polymorphic HLA class I determinants and double-staining techniques in flow cytometry and immunocytology. The findings were compared with the clinical courses and with the results of routine graft biopsies. Within the first week after transplantation, in all 16 patients, between 1% and 24% donor lymphocytes (T, NK, and B cells) were detectable in blood, and in 14 of 22 patients (64%), between 2% and 23% donor T cells were found in the graft. After more than 2 weeks, donor cells were still present in blood in 2 of 14 patients at very low numbers. The presence of donor lymphocytes in the graft was associated with intragraft immune activation in 5 of 15 patients, but no clinical rejection occurred in these cases; mild graft-versus-host disease was observed in one patient. These findings demonstrate that donor lymphocytes regularly persist in liver-grafted patients for some time; this transient mixed lymphoid chimerism is only rarely associated with clinical graft-versus-host disease and some evidence even suggests that these donor-derived lymphocytes may exert beneficial immunomodulatory properties.

Adult↗
PubMed2003

Peptide immunotherapy for allergic disease.

The only disease-modifying treatment available for IgE-mediated disease is specific immunotherapy, but the retention of B cell epitopes in whole allergen preparations confers a risk of IgE-mediated systemic reactions to their administration. Compelling evidence for the central role of T cells in allergic disease suggests that IgE-binding epitopes could be removed from such therapy, improving safety without affecting efficacy. Short, allergen-derived peptides lack the conformational determinants required for IgE crosslinking and are, therefore, an attractive therapeutic possibility. However, human leukocyte antigen (HLA) polymorphism means that T cell peptide epitopes present a huge diversity, which makes the design of peptide-based vaccines problematic. Over the past 10 years, advances in our understanding of epitope selection and major histocompatibility complex (MHC)-peptide-T cell receptor interactions have taken this therapy forward to early clinical trials with human volunteers.

Animals↗
PubMed2000

Recombinant technology in transfusion medicine.

Recombinant technology in transfusion medicine has really only just begun to have large-scale impact. The preparation of blood products, determination of blood group phenotype, detection of blood group specific antibodies does not currently employ DNA-based methods for their preparation or detection. The detection of bloodborne viruses, production of blood grouping reagents and diagnosis of HLA polymorphism all include recombinant DNA-based technologies and are beginning to impact on routine laboratory life in Transfusion medicine. This review analyses the current use of recombinant technology in transfusion medicine, and indicates where there is likely to be significant development of this methodology (particularly in molecular diagnostics) oven the next decade or so. The impact of molecular medicine in the field of transfusion has already begun. Recent licensing of thrombopoietin for clinical use may have a profound effect on the very high current demand for platelet transfusions. Gene therapy protocols for the treatment of haemophilias and other coagulation disorders, and the production of recombinant blood products may reshape the demand for clotting factors from human plasma. I also consider the potential impact of the exciting technologies of DNA arraying and nucleic acid therapeutics in the fields of molecular diagnostics and the possible treatment of leukemia respectively.

Animals↗
PubMed2001

Use of T cell epitopes for vaccine development.

T lymphocytes play a major role in the recognition and subsequent elimination of tumors and intracellular pathogens. Induction of epitope-specific T cell responses can help in the clearance of diseases for which no conventional vaccines exist. However, the lack of simple methods to identify relevant T cell epitopes, the high mutation rate of many pathogens, and HLA polymorphism have made the development of efficient T cell epitope-based, or "epitope-driven" vaccines difficult to achieve. Our research over the past several years has applied bioinformatics tools in conjunction with T cell assays to identify naturally processed putative T cell epitopes from several pathogens. This strategy will accelerate the development of new generation T cell epitope-based vaccines against various pathogens including viruses such as HIV and WNV, bacteria such as M.tb., and parasites such as plasmodium. This chapter will review the use of a bioinformatics-based approach to identify putative T cell epitopes. It will summarize the current state of knowledge regarding T cell-epitope-based vaccines and discuss several ways to improve their efficacy.

Algorithms↗
PubMed2001

Analysis of the coding and promoter regions of the autoantigen IA-2 in subjects with and without autoantibodies to IA-2.

Despite extensive studies on HLA polymorphism, there have been few, if any, studies on allelic forms or mutations in proteins that serve as autoantigens. The present experiments were designed to look for alterations in the coding and promoter regions of the autoantigen IA-2 in type one (insulin-dependent) diabetic patients with autoantibodies to IA-2 as compared with siblings without diabetes or autoantibodies to IA-2. Genomic DNA was used as a template and was amplified by polymerase chain reaction, with pairs of primers encompassing the promoter region and the 23 exons of the coding region of IA-2. A total of nine nucleotide changes were found in the coding region of the six type 1 diabetic patients; four were silent and five were missense changes, but all occurred in the extracellular domain of IA-2 to which autoantibodies are not directed. Few, if any, changes were found in the 5' upstream (-706 to +135) promoter region. The results of the experiments support the null hypothesis that differences among individuals in the nucleotide and amino acid sequences of the promoter and coding regions of IA-2, respectively, do not account for why some individuals develop autoantibodies to IA-2 and others do not.

Amino Acid Sequence↗
PubMed2003

MHC restriction in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a rare complication in patients with asthma but more common in patients with cystic fibrosis. In the presence of the fungus Aspergillus fumigatus (Af) in the lower respiratory tract, patients mount a heightened IgG and IgE humoral response specific for Af antigens. Studies on ABPA have suggested a pathogenic role for antigen specific CD4+ Th2 like T lymphocytes producing increased levels of IL-4 and IL-5. MHC class II genes coding for highly polymorphic HLA molecules have been shown to be the likely candidates for controlling immune responses to common allergens. However there has been a lack of information on the pathophysiological role of HLA genes in the development of ABPA. This review describes an association between HLA- class II alleles and the specific responses to Af antigen (Asp f 1) in ABPA. These studies focused on MHC restriction and distribution of HLA- class II alleles in two groups of unrelated North American Caucasian patients with cystic fibrosis and/or asthma. One group consisted of patients with a confirmed diagnosis of ABPA and a second group of patients with Af sensitivity but no ABPA. HLA association studies revealed that the predisposition to develop ABPA is associated with HLA-DR2 and DR5, and possibly DR4 or DR7. A strong association of HLA-DR antigens with ABPA reflects that HLA-DR molecules may present disease-causing peptides. On the other hand a significant association of HLA-DQ2 with Af sensitive nonABPA indicates the involvement of HLA-DQ molecules in protection. A combination of these genetic factors determines the outcome of ABPA in patients with cystic fibrosis and asthma.

Animals↗
PubMed2001

T cells in the pathogenesis of systemic lupus erythematosus.

The role of T cells in the pathogenesis of systemic lupus erythematosus (SLE) is reviewed with a focus on autoantigen-specific T cells in SLE. The initial clue to a role for T cells in SLE was histopathologic studies demonstrating extensive infiltration of T cells at the sites of inflammation. Later studies, showing association between HLA polymorphisms and specific autoantibodies, directly implicated a role for T cells in autoantibody production. More recently, we and others have identified and characterized autoantigen-specific T cells in SLE. We review these studies on the role of autoantigen-specific T cells in SLE and present new findings on the molecular characterization of T cell immunity to Sm-B, Sm-D and U1-70kD small nuclear ribonucleoprotein (snRNP) autoantigens.

Autoantigens↗
PubMed2005

Immunopathogenesis of HIV infection.

Progression of HIV infection is largely dependent on the interaction between the viral factors and host factors. HIV primarily infects the CD4 lymphocytes in the body. It brings about the destruction of CD4 cells through multiple mechanisms including apoptosis. The loss of CD4 cell population ultimately leads to the inability of infected person to deal with opportunistic organisms. Host genetic factors such as HLA polymorphism and HIV co-receptor polymorphism may influence either susceptibility to infection or disease progression. Innate immune mechanisms may play a role in disease progression. However, adaptive immune response is the most critical component of immune system for control of HIV infection. HIV-specific CD4 helper response and HIV-specific CTL responses have clearly emerged as the most important host factors that may decide the rate of disease progression. However, the role of neutralizing antibodies still remains to be understood in context with the disease progression. One of the gray areas is the role of mucosal immune response in HIV infection. However, it is clear that it is not a single component but orchestrated action of different immune mechanisms will decide the outcome of HIV infection. The studies in persons exposed to HIV infection but who are uninfected and the long term non-progressors will be critical for understanding the immunopathogenesis of HIV infection.

Disease Progression↗
PubMed1987

Expression of MHC class I determinants on erythrocytes of SLE patients.

Strong expression of MHC Class I determinants had been observed on the erythrocytes of three genetically C4 deficient patients who all had SLE. In a study of 35 other SLE patients who were not C4 deficient, 30 showed a marked increase in the expression of MHC Class I on their erythrocytes. There was a correlation between the expression of erythrocyte Class I and disease activity. The polymorphic HLA determinants were detected by haemagglutination with human cytotoxic antisera from untransfused pregnant women. A shared monomorphic epitope of HLA-A, -B and -C, and beta 2-microglobulin were detected by haemagglutination with monoclonal antibodies. A monoclonal antibody for a monomorphic epitope on MHC Class II alpha and beta chains did not react. Erythrocytes from a group of RA patients and a group of normal controls had moderate and low expression respectively. We suggest that MHC Class I may be induced on erythrocytes maturing in a milieu containing mediators derived from activated cells of the immune system. Aberrant tissue expression of MHC antigens may be more widespread than has been previously recognized in diseases mediated by immune mechanisms.

Arthritis, Rheumatoid↗
PubMedDate not supplied

[Detection of fetal cells in maternal blood: towards a noninvasive prenatal diagnosis].

Fetal cells exist in maternal blood and can be utilized for prenatal genetic diagnosis. These cells are present during the first and second trimesters, with frequency increasing as gestation advances. Enrichment of erythroblasts by various density gradient techniques and either magnetic activated or flow sorting techniques can be followed by FISH with chromosome-specific DNA probes. This approach has allowed detection of trisomy 21, trisomy 18, Klinefelter syndrome 47,XXY and 47,XYY. Polymerase chain reaction (PCR) analysis of maternal blood has enabled the detection of fetal sex, certain Mendelian disorders (e.g. beta-globin mutations), HLA polymorphisms, and fetal Rhesus (D) blood type. The fetal cell types receiving the most attention has been nucleated erythrocyte (erythroblast) and the trophoblast. Lymphocytes and granulocytes are also present in maternal blood; however, lymphocytes are considered the cell type most likely to persist after pregnancy. A large scale collaborative is now underway in the U.S. that will allow determine whether sensitivity and specificity of this technique provide a noninvasive alternative to conventional methods of prenatal cytogenetic diagnosis.

Cell Separation↗