Dissertations / Theses on the topic 'HLA histocompatibility antigens'
To see the other types of publications on this topic, follow the link: HLA histocompatibility antigens.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'HLA histocompatibility antigens.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Talken, Beth L. "Assembly of the Lw¹⁶ and Ld class I MHC molecules." free to MU campus, to others for purchase, 1996. http://wwwlib.umi.com/cr/mo/fullcit?p9720532.
Full text
2
Pang, Ha Sang. "Identification of CD8+ T cell epitopes from HCA661 presented by HLA-A2 molecules /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202006%20PANG.
Full text
3
葉德俊 and Tak-chun Timothy Yip. "Characterization of a monoclonal antibody reactive against major histocompatibility complex class II antigens." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1992. http://hub.hku.hk/bib/B3123334X.
Full text
4
Yip, Tak-chun Timothy. "Characterization of a monoclonal antibody reactive against major histocompatibility complex class II antigens /." [Hong Kong] : University of Hong Kong, 1992. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13478771.
Full text
5
Hume, Clifford Robert. "Regulation of HLA class II expression in class II negative mutant B-cell lines /." Access full-text from WCMC, 1989. http://proquest.umi.com/pqdweb?did=745028251&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
Full text
6
Halley, Lorna Louise. "The investigation of the HLA system and wheat gluten in determining risk of schizophrenia." Thesis, University of the Highlands and Islands, 2015. https://pure.uhi.ac.uk/portal/en/studentthesis/the-investigation-of-the-hla-system-and-wheat-gluten-in-determining-risk-of-schizophrenia(60acd449-c659-4743-9dbd-4392c0fc015a).html.
Full textAbstract:
Genome-wide association (GWA) studies confirmed that the HLA genes were strongly associated with schizophrenia but the HLA variants identified by GWA studies had a lower frequency in patients with schizophrenia than control subjects. The HLA molecules have function of presenting peptide antigens to T lymphocytes in order to initiate an immune response. Environmental factors such as infection and dietary proteins have been found to be associated with schizophrenia. This PhD program has thus focused on the following objectives: (1) identification of genetic variants for schizophrenia in the HLA region and (2) investigation of circulating antibodies to linear peptide antigens derived from wheat gluten in schizophrenia. The major findings from this work are as follows: 1. The HLA-DQ2.5 variants were strongly associated with schizophrenia; this finding is consistent with that from GWA study. 2. The NOTCH4 association was replicated in our study samples, in which a CNV in exon 19 of the gene may be associated with risk of schizophrenia. 3. There was no HLA-II variant identified to be associated with a high risk of schizophrenia but a CNV present in the HLA-DQ/DR region might confer risk of the disease. 4. The levels of circulating antibodies to linear peptide antigens derived from wheat gluten were significantly lower in schizophrenia patients than controls. This finding is inconsistent with previous studies that showed elevated levels of circulating antibodies in schizophrenia across subpopulations. In conclusion, it is likely that not one but many HLA variants lead to risk of schizophrenia development. From this research it is likely that anti-gluten antibodies are not an environmental trigger for this disease. Further investigation is needed to clarify the role of the HLA region in bridging the gap between genetic make-up and environmental factors in developing schizophrenia.
7
Kosmoliaptsis, Vasilis. "Investigation into the immunogenicity of human leukocyte antigen mismatches in kidney transplantation." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609630.
Full text
8
Schulte, Kathleen Q. "Mutagenized HLA DNA Constructs: Tools for Validating Molecular HLA Typing Methodologies." Thesis, University of North Texas, 1999. https://digital.library.unt.edu/ark:/67531/metadc500888/.
Full textAbstract:
This study describes the development and validation of mutagenized cloned DNA constructs, which correspond to the polymorphic regions of the class II region of the HLA complex. The constructs were used to verify the allelic specificity of primers and probes in polymerase chain reaction (PCR)-based HLA typing assays such as Sequence Specific Primers (SSP) and Sequence Specific Oligonucleotide Probes (SSOP). The constructs consisted of the entire polymorphic region of exon 2 of class II HLA allele sequences that included primer annealing sites or probe hybridization sites. An HLA allele sequence was inserted into a plasmid, cloned, then mutagenized to match a specific HLA allele, and finally, the correct clone was verified by bidirectional sequencing of the insert. Thus, the construct created a cloned reference DNA sample for any specific allele, and can be used to validate the accuracy of various molecular methodologies.
9
Yamamoto, Masaru. "Synthesis and oxidation studies of sulfur containing inhibitors for human leukocyte elastase : (2) synthesis of cyclic peptide analogs for tissue factor pathway inhibitor (TFPI) : Part 2 synthesis and evaluation of aziridinecarboxylic acid analogs as a new family of cysteine proteinase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/25953.
Full text
10
Chang, Yea-wen. "Application of molecular genetic techniques to the study of major histocompatibility complex class II allelic associations with insulin-dependent diabetes mellitus in Chinese /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B18539919.
Full text
11
Oudshoorn, Machteld. "Investigations into the complexity and polymorphism of HLA-D loci in South Africa." Doctoral thesis, University of Cape Town, 1989. http://hdl.handle.net/11427/26581.
Full textAbstract:
The HLA complex is the most polymorphic genetic system known in man. The frequency of the HLA class II antigens have been well studied in Caucasoids but little data is available concerning HLA antigen frequencies in Negroes. In this thesis the class II antigens, excluding HLA-DP, were studied in South African (SA) Negroes (Xhosa), Cape Coloureds ( a group of mixed racial origin) and SA Caucasoids using serological, cellular ( HTC typing) and Southern blot techniques. The results obtained for the SA Negroes were compared with those previously found in Nigerians and American Negroes. Marked differences in HLA distribution occurred between these groups, which in part may be explained by Khoisan admixture in the SA Negroes. In addition, striking frequency differences were observed between the three SA populations. For example, in the Xhosa the HLA-DR1, DR4, DR7, DRw8, DQw2, DQw3, Dw1 and Dw3 specificities were found at a significantly lower frequency, whereas HLA-DR3, DRw6 and Dw' RSH' were found at a significantly higher frequency compared with the SA Caucasoids. The frequency in the Cape Coloureds was intermediate between those of the Xhosa and Caucasoids. In the SA Negroes and Cape Coloureds, several new specificities were detected such as HLA-DRw18, DR2 LUM(CT), DRwl2x6, DRw8x14, Dw' RSH', Dw' JOH' and Dw' BME'. The HLA-DR and DQ haplotypes in significant linkage disequilibrium were similar in the three groups. However, several haplotypes with unusual DR and DQ combinations such as HLA-DRw17,DQw7; DR9, DQw2 and DR4, DQw5 were present in the SA Negroes and Cape Coloured families. Al though some of these unusual haplotypes could be explained in terms of recombination between the common haplotypes, none could be typed using a panel of well defined homozygous typing cells, suggesting that the response observed in mixed lymphocyte culture arises from separate molecular determinants. The data on HLA class II antigen frequencies presented in this thesis is essential for future studies on HLA and disease associations and for establishing population relationships. Knowledge of new HLA class II antigens in the various population groups is also important in renal transplantation as matching for HLA-DR antigens is known to improve graft survival.
12
Bonfiglioli, Rubens. "Frequência dos alelos do HLA-B27 em pacientes brasileiroa com artrite psoriásica." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310633.
Full textAbstract:
Orientador: Manoel Barros BértoloTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-16T11:36:12Z (GMT). No. of bitstreams: 1 Bonfiglioli_Rubens_D.pdf: 4535259 bytes, checksum: c162b3d3293837dabf58f540050f6b46 (MD5) Previous issue date: 2009
Resumo: Este estudo prospectivo analisou a epidemiologia, clínica e perfil genético de 102 pacientes brasileiros com Artrite Psoriásica. A associação do complexo maior de histocompatibilidade (MHC) de classe I, e os alelos do HLA-B27 com aquelas variáveis foram avaliados e comparados com sadios controles, HLA-B27 positivos, compondo um grupo de 111 indivíduos. A predominância foi do sexo masculino (59,8%), raça caucasóide (89,2%) e HLA-B27 negativos (79,4%). Oligoartrite assimétrica (62,7%) foi o subgrupo de Artrite Psoriásica mais observado, seguido pela forma espondilítica (16,7%) e poliarticular (15,7%). O sexo masculino e o subgrupo dos espondilíticos foram estatisticamente mais associados ao HLA-B27, e o subgrupo oligoarticular ao HLA-B27 negativo. Entre os 21 pacientes com Artrite Psoriásica e HLA-B27 positivos existiu uma significante prevalência do HLA-B*2705 (90,5%), similar ao observado no grupo controle (80,2%); HLA-B*2703 e HLA-B*2707 foram estatisticamente associados ao grupo controle
Abstract: This prospective study analyzed the epidemiologic, clinical and genetic profile of 102 Brazilian patients with psoriatic arthritis (PsA). The association of the major histocompatibility complex (MHC) class I and the HLA-B27 alleles with these variants was outlined, and compared to a control healthy HLA-B27 positive group of 111 individuals. There was a predominance of male gender (59.8%), Caucasian race (89.2%) and negative HLA-B27 (79.4%) patients. Asymmetric oligoarthritis (62.7%) was the most frequently observed clinical PsA subgroup, followed by spondylitis (16.7%) and polyarthritis (15.7%). Male gender and the spondylitis subgroup were statistically associated to the positive HLAB27 and the oligoarthritis subgroup was associated to the negative HLA-B27. Among the 21 HLA-B27 positive PsA patients, there was a significant prevalence of the HLA-B*2705 allele (90.5 %), similar to that observed in the control group (80.2%); HLA-B*2703 and HLA-B*2707 were statistically associated to the control group. Other antigens such as HLA- B07 (14 patients), HLA-B08 (14 patients) and HLA-B44 (13 patients) among others, were found in HLA-B27-negative patients
Doutorado
Clinica Medica
Doutor em Clínica Médica
13
Odeberg, Jenny. "Human cytomegalovirus immune evasion strategies /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-126-8.
Full text
14
Patel, Kantibhai Motiram. "The association of the human leukocyte antigens alleles and type 2 diabetes mellitus among Mexican Americans." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2009. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
Full text
15
Wong, Hoi-hei Vera, and 王愷曦. "Isolation of human leukocyte antigen G/cytokeratin 7 positive fetal cells from transcervical samples for potential use in prenatal genetic diagnosis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208587.
Full textAbstract:
There has been an increase in rates of chromosomal abnormalities in newborns as a result of reproductive aging. For the past decades, a lot of effort has been placed on identifying pregnancies at risk of genetic defects. Conventional prenatal genetic diagnosis is achieved by invasive procedures that have been associated with an increased risk of pregnancy loss. This has led the researchers to explore the use of non-/minimally invasive techniques for prenatal diagnosis.
Trophoblasts are known to be shed from regressing chorionic villi into the lower uterine pole of pregnant women during the first trimester. These cells are trapped within cervical mucus, which can be retrieved with a cytobrush. By using human leukocyte antigen G (HLA-G) and cytokeratin-7 (CK7) as trophoblast markers, this study aims to investigate the possibility of isolating individual fetal trophoblast from transcervical samples for genetic diagnosis.
195 healthy pregnant women requesting for legal termination of pregnancy (TOP) were recruited in this study. Transcervical cells were collected from them with the use of a cytobrush before TOP. HLA-G+ or CK7+ cells were then isolated by a combination of mucolytic action, fluorescent immunohistochemistry, and micromanipulation. The origin of these cells was subsequently investigated by either fluorescent in situ hybridization (FISH) or allelic profiling by quantitative fluorescent polymerase chain reaction (QF-PCR) based on chromosome 16, chromosome X, amelogenin gene and sex determining region Y (SRY) gene.
This study first demonstrated the presence of fetal cells in transcervical samples based on the detection of chromosome Y signal by ordinary PCR. Cells expressing HLA-G and CK7 were also identified among transcervical cells. Immunopositive cells were isolated by micromanipulation under fluorescent microscopy. One isolated cell expressing CK7 was shown to inherit paternal allele at a locus on chromosome 16, suggesting the possible fetal origin of this cell. However, this study was still hampered by a number of technical factors. Further optimization of the protocol is required before transcervical trophoblasts can be retrieved in a reliable manner.published_or_final_version
Obstetrics and Gynaecology
Master
Master of Philosophy
16
Rodrigues, N. R. "The human cytochrome P-450 21-hydroxylase genes." Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:77be8950-4675-4a55-ab4f-27b788082007.
Full textAbstract:
Deficiency of the cytochrome P-450 steroid 21-hydroxylase (21-OHase) which causes Congenital Adrenal Hyperplasia (CAH) is a monogenic autosomal recessive disorder which is linked to HLA. There are two 21-OHase genes in man, A and B, and they are mapped to the HLA class III region ~ 3 kb 3' to the complement genes C4A and C4B, respectively. Two genes encoding 21-OHase were isolated, characterized and sequenced. Both 21-OHase genes are ~ 3.3 kb in length and are split into 10 exons by nine introns. Comparison of the two genes showed that although they are highly conserved, there are three deleterious mutations in the 21-OHase A gene which cause frameshifts and introduce in phase premature termination codons. Thus the 21-OHase A gene is a pseudogene. Comparison of the 21-OHase B gene to the other cytochrome P-450 sequences revealed that although the cysteine-429 was conserved in 21-OHase, there is very little homology with other cytochrome P-450, indicating it belongs to a separate family of genes within the superfamily. Clear evidence of polymorphism in 21-OHase is apparent on comparison with other 21-OHase B sequences. There is a size polymorphism of 494 and 495 amino acids. The differing severities of 21-OHase deficiency in CAH may be due to allelic variants of the 21-OHase B gene, since in most cases the defect is not due to gene deletion (Rumsby et al., 1986). A 21-OHase B gene from a patient with CAH was characterized and sequenced. There were 13 nucleotide alterations in his single 21-OHase B gene, one of which at codon 269 caused a serine to change to a threonine residue. The G → C transversion in the 21-OHase B gene from the patient at codon 269 introduced a new NcoI restriction site into the gene. This restriction fragment length polymorphism (RFLP) was used to study other patients with CAH and normal individuals. The NcoI RFLP was found not to be confined to the 21-OHase B gene but was also present in some 21-OHase A genes. It is likely therefore that the mutation occurred in the pseudogene first and then transferred to some 21-OHase B genes.
17
Schaffer, Marie. "HLA and KIR gene polymorphism in hematopoietic stem cell transplantation /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-836-3/.
Full text
18
Chiu, Angela Chen-Yen. "DNA Typing of HLA-B by PCR with Primer Mixes Utilizing Sequence-Specific Primers." Thesis, University of North Texas, 1997. https://digital.library.unt.edu/ark:/67531/metadc278947/.
Full textAbstract:
The aim of this study was to design a resolution typing system for the HLA-B gene. This technique involves a one-step PCR reaction utilizing genomic DNA and sequence-specific primers to determine the specificity of each allele and to produce a larger primer data base ideal for serological analysis. The application of this technique to serological analysis can improve serology detection which is currently hindered by antibody cross-reactivity and the unavailability of useful typing reagents.
19
Maruya, Etsuko. "Evidence that CD31, CD49b, and CD62L are immunodominant minor histocompatibility antigens in HLA identical sibling bone marrow transplants." Kyoto University, 2001. http://hdl.handle.net/2433/150586.
Full text
20
Braga, Mayara Perez. "Alorreatividade dos enxertos ósseos homólogos na reconstrução alveolar em humanos." Universidade do Estado do Rio de Janeiro, 2014. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8418.
Full textAbstract:
Enxerto ósseo homólogo é utilizado independentemente da compatibilidade HLA entre doador e receptor ou uso de drogas imunossupressoras. Considerando o volume de transplantes ósseos realizados no Brasil e o possível efeito deletério da sensibilização HLA para o transplante de órgãos sólidos, este estudo tem como objetivo avaliar a alorreatividade do enxerto ósseo homólogo fresco-congelado utilizado na reconstrução alveolar com finalidade de reabilitação oral com prótese sobre implantes. Anticorpos anti-HLA e anti-MICA foram monitorados através do teste Labscreen Mixed, nos intervalos 0, 7, 30, 90 e 180 pós transplante ósseo em 15 pacientes (6 homens e 9 mulheres, idade média 58,1, DP=10,1) que estavam em tratamento no Instituto de Odontologia da Pontifícia Universidade Católica do Rio de Janeiro. Caso resultado do teste Mixed fosse positivo (Razão de fundo normatizado, NBG>4,5) o teste Labscreen Single (tecnologia antígeno único por pérola, SABA) era realizado para verificar se os anticorpos anti-HLA eram específicos ao doador. Nenhum paciente relatou transplante prévio, 4 relataram transfusão prévia e todas as mulheres relataram gravidez. Dez pacientes não apresentaram reação positiva no dia 0 sendo considerados não sensibilizados previamente (NSP); destes, 6 pacientes permaneceram sem nenhuma evidência de sensibilização, 2 pacientes apresentaram reação positiva para Classe I e II; 2 para Classe I apenas; e 2 para MICA, sendo considerados sensibilizados pelo enxerto ósseo oral. Dois pacientes apresentaram aumento de Intensidade Média de Fluorescência (ΔMFI>1000) de anticorpos específicos ao doador para Classe I e Classe II, e 2 somente para Classe II, demonstrando uma reação específica ao doador. Os resultados sugerem uma alorreatividade HLA oscilatória ao enxerto ósseo homólogo em reconstruções alveolares, confirmada pela formação de anticorpos anti-HLA específicos ao doador em 4 pacientes (27%) da amostra.Bone allografts are used without HLA donor-receptor compatibility or imunosupressor therapy. Taking in consideration the amount of bone graft procedures performed in Brazil and the possible deleterious effect of HLA sensitization in solid organ transplantation, the aim of this study was to evaluate fresh-freeze bone graft alorreactivity used in ridge augmentation surgery before oral rehabilitation with implants supported bridges. Anti-HLA and anti-MICA antibodies were evaluated by Labscreen Mixed test, at 0, 7, 30, 90 e 180 days after bone transplantation in 15 patients (6 men e 9 women, mean age 58,1, SD=10,1) treated at the Dental Institute of the Rio de Janeiro Catholic University. If the mixed test (Normalized Background Ratio, NBG>4,5) was positive, donor specificity was evaluated by Labscreen Single test (Single Antigen Bead Assay technology, SABA). None of patients had previous transplant history, 4 had transfusion history, and all women had pregnancy history. Ten patients did not have positive results at baseline and were considered not sensitized previously; 6 patients of them did not have any sensitization evidence during 6 month follow up, 2 patients had positive reaction for anti-HLA Class I and II; 2 were positive for anti-HLA Class I only; e 2 patients were positive for anti-MICA, and were considered sensitized by oral bone graft. Two patients had increased values of Median Fluorescence Intensity (ΔMFI>1000) of anti-HLA donor specific antibodies Class I and II, 2 for Class II only, showing a donor specific alorreactivity. The results sugest an oscilatory HLA reactivity, confirmed by the donor specific antibodies formation on 4 patients (27%) of this study.
21
Pecora, Rafael Antonio Arruda. "Associações dos anticorpos anti-HLA pré-formados e da compatibilidade HLA à rejeição celular aguda precoce no transplante hepático." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-09082016-154954/.
Full textAbstract:
INTRODUÇÃO: As moléculas HLA são os principais alvos da rejeição nos transplantes de órgãos sólidos. A influência dos anticorpos anti-HLA pré-formados e da compatibilidade HLA no transplante de fígado ainda não está bem definida. A maioria dos transplantes é realizada sem a pesquisa de anticorpos anti-HLA pré-formados e sem pareamento HLA. OBJETIVOS: Avaliar as associações dos anticorpos anti-HLA pré-formados e da compatibilidade HLA à rejeição celular aguda (RCA) em até 90 dias após o transplante. MÉTODOS: Coorte prospectiva de transplantes de fígado ABO compatíveis/idênticos realizados entre janeiro de 2012 e dezembro de 2013. Enxertos que sobreviveram além de 4 dias foram incluídos. A pesquisa de anticorpos anti-HLA classes I e II foram realizadas por meio de ensaios de fase sólida (LABScreen® Mixed e LABScreen® Single Antigen). MFI (Mean Fluorescence Intensity) >= 1.000 foi onsiderado omo positi o para anticorpos anti-HLA. Tipificação HLA-A, B e DR, de receptores e doadores foi feita por meio de PCR (Polymerase Chain Reaction). Conforme o número de alelos HLA incompatíveis, os transplantes foram classificados em compatíveis (0-3 incompatibilidades) e incompatíveis (4-6 incompatibilidades). Apenas episódios de RCA comprovados por biópsia, associados a alterações das provas hepáticas, foram considerados. O critério Banff foi utilizado para diagnóstico e os episódios foram estratificados em leves, moderados e graves. Modelos de regressão de Cox foram realizados e as razões de risco (RR) associadas foram determinadas. Sobrevidas livres de RCA foram obtidas por meio do estimador de Kaplan Meier e comparadas entre os grupos pelo teste log-rank. RESULTADOS: Cento e vinte e nove transplantes foram analisados. Incidência global de RCA em 90 dias foi de 14,7%. A pesquisa de anticorpos anti-HLA pré-formados foi considerada positiva em 35,6% dos transplantes. Em relação à compatibilidade HLA, 91,5% dos transplantes foram classificados como incompatíveis. A sensibilização para anticorpos anti-HLA foi associada a um risco aumentado de RCA (RR=4,3; IC 95%=1,3 - 13,5; p=0,012). De acordo com a classe do anticorpo, observamos que a classe II foi associada a um risco aumentado de RCA (RR=56,4; IC 95%= 4,5 - 709,6; p=0,002). Para anticorpos classe I, foi observada associação marginalmente significante (RR=2,77; IC 95%=0,8 - 8,8; p= 0,08). Uma melhor compatibilidade HLA não foi associada a um risco reduzido de RCA (RR= 0,9; IC 95%=0,2-4; p=0,89). CONCLUSÕES: O presente estudo mostrou que a sensibilização para anticorpos anti-HLA pré-formados om I >= 1.000 está asso iada a um risco aumentado de rejeição celular aguda precoce no transplante de fígado. Anticorpos classe II foram também associados a um risco aumentado de RCA e anticorpos classe I foram tendência. A melhor compatibilidade HLA não foi associada a um risco reduzido de RCA neste estudo. A presença de sensibilização para anticorpos anti-HLA pré-formados poderia servir como marcador de imunorreatividade aumentada contra os enxertos. Isso permitiria ajustes individualizados de imunossupressãoINTRODUCTION: Human leucocyte antigens (HLA) molecules are the main targets of rejection in solid organ transplantation. Significance of anti-HLA preformed antibodies and HLA compatibility remains unclear in liver transplantation. Majority of liver transplants are performed without assessment of preformed anti-HLA antibodies and HLA-matching. OBJECTIVES: Evaluate associations of preformed anti-HLA antibodies and HLA compatibility with acute cellular rejection (ACR) in the first 90 days after transplantation. METHODS: Prospective cohort of ABO-identical/compatible liver transplants between January 2012 and December 2013. Grafts that survived more than 4 days were included. Anti-HLA class I and II antibodies were determined by solid phase assays (LABScreen® Mixed and LABScreen® ingle Antigen). A mean fluores en e intensity ( I) >= 1.000 was considered as positive for anti-HLA antibodies. Recipients and donors HLA typing for HLA-A, B and DR were performed using polymerase chain reaction (PCR) assays. According to HLA mismatches (MM), transplants were divided in compatible (0-3 MM) and incompatible (4-6 MM). Only biopsy proven ACR episodes, associated with abnormal liver tests, were considered. Banff criteria was used for diagnosis of ACR and episodes were graded as mild, moderate and severe. Cox proportional hazards models were performed and associated hazard ratios (HR) were determined. Free ACR rates were estimated with Kaplan-Meier analysis and were compared between groups with the log-tank test. RESULTS: One hundred twenty nine transplants were analyzed. Overall incidence of ACR was 14.7% in 90 days. Assessment of anti-HLA pre-formed antibodies was considered positive in 35.6% of transplants. Regarding HLA compatibility, 91.5% were considered incompatible. Anti-HLA antibodies sensitization was associated with an increased risk of ACR (HR= 4.3; CI 95%=1,3 - 13,5; p=0.012). According to class of antibody, we could observe that class II was associated with an increased risk of ACR (HR=56.4; CI 95%= 4.5 - 709.6; p=0.002). Class I antibodies were considered tendency to increased risk of ACR (HR=2.7; CI 95%= 0.8 - 8.8; p=0,08). A better HLA compatibility was not associated with a lower risk of ACR (HR=0.9; CI 95%=0.2-3.8 p=0.89). CONCLUSIONS: The present study indicates that preformed anti-HLA antibodies with I >= 1.000 are associated with an increased risk of early ACR rejection in liver transplantation. Class II antibodies were also associated with an increased risk of ACR. Class I antibodies were considered tendency. HLA matching had no influence on early acute cellular rejection on this study. Anti-HLA antibodies sensitization could serve as a marker of increased immunoreactivity to the graft. It would serve for tailored immunosuppression
22
Pina, Fabiana Pompeo de. "Artrite reumatoide em Afro-brasileiros : "O papel do HLA"." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310626.
Full textAbstract:
Orientador: Manoel Barros BertoloDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-14T03:46:59Z (GMT). No. of bitstreams: 1 Pina_FabianaPompeode_M.pdf: 947949 bytes, checksum: 7e9310579d25142d2d37758ff60f7796 (MD5) Previous issue date: 2009
Resumo: A associação de antígenos de histocompatibilidade com a Artrite Reumatóide (AR) vem sendo demonstrada em inúmeros estudos. No entanto, a avaliação em populações afro-descendentes ainda foi pouco estudada. Os propósitos deste estudo foram os de determinar a freqüência dos alelos HLA-DRB1 e as contribuições do polimorfismo desses alelos na susceptibilidade da AR na população afrobrasileira. Este estudo avaliou também, se a teoria do epitopo semelhante (SE) e o modelo de proteção da Artrite Reumatóide (RAP Model) se aplicam aos pacientes afro-brasileiros com AR. Os alelos HLA-DRB1 de 72 pacientes afro-brasileiros com AR, diagnosticados pelos critérios do American College of Rheumatology (ACR), e de 75 indivíduos saudáveis foram tipados e subtipados utilizando-se a técnica de reação em cadeia de polimerase de DNA amplificado hibridizado, com seqüência de primers específicos de alta e baixa resolução, e depois comparados. Os alelos HLADRB1 *0404 e *0405 apresentaram freqüência maior nos pacientes do que no grupo controle. Já, alelo HLA-DRB1*0102 apresentou uma freqüência aumentada no grupo controle (9,3%), quando comparada com a freqüência nos pacientes. Os alelos DRB1 considerados como pertencentes ao grupo do epitopo semelhante estavam presentes em 39 pacientes (54,2%) e em 20 controles (26,7%), indicando que teoria do epitopo semelhante se aplica à população afro-brasileira com Artrite Reumatóide. Os alelos HLA-DRB1 que apresentavam a sequência DERAA (alelos protetores) reduziram, de forma independente, o risco de desenvolver AR. Os dados obtidos apontam para uma intensa miscigenação racial presente no Brasil. Assim, como nos faz concluir que a susceptibilidade da Artrite Reumatóide em afro-brasileiros é, provavelmente, mediada pela interação de fatores genéticos e étnicos
Abstract: The association of histocompatibility antigens with Rheumatoid Arthritis (RA) comes being demonstrated in innumerable studies. However, the evaluation in afrodescendents populations still little was studied. The aim of this study has been to determine the frequency of HLA-DRB1 alleles, and the contributions of the polymorphism of these alleles in the susceptibility of RA in the Afro-Brazilian population as well. This study, also evaluated, if the theory of the shared epitope (SE) and the model of protection of the Rheumatoid Arthritis (RAP Model) can also be applied to the Afro-Brazilian patients suffering RA. The HLA-DRB1 alleles in 72 Afro-Brazilian patients suffering RA, diagnosed in accordance to the criteria of the American College of Rheumatology (ACR), and of 75 healthful volunteers had been typed and sub-typed using the technique of the polymerase chain reaction of the amplified hybridized DNA, with specific sequence of primers of high and low resolution, were then compared. The HLA-DRB1 *0404 and *0405 alleles had presented higher frequency in the patients group than in the control group. The HLADRB1 *0102 alleles presented a frequency increased (9,3%) in the control group, when compared with the patients group. The DRB1 alleles considered as pertaining to the group of shared epitope were present in 39 patients (54.2%) and in 20 members of the control group(26.7%), indicating that the theory of the shared epitope it is also applied to the Afro-Brazilian population with Rheumatoid Arthritis. The HLADRB1 alleles that presented DERAA sequence (protectors alleles), had reduced, of independent form, the risk to develop RA. The gotten data point to an intense racial miscegenation in Brazil. Thus, as in it makes them to conclude that the susceptibility of the Rheumatic Arthritis in Afro-Brazilian is, probably, determined by the interaction of genetic and ethnic factors
Mestrado
Clinica Medica
Mestre em Clinica Medica
23
Yin, Liusong. "Studies of HLA-DM in Antigen Presentation and CD4+ T Cell Epitope Selection: A Dissertation." eScholarship@UMMS, 2014. http://escholarship.umassmed.edu/gsbs_diss/700.
Full textAbstract:
Antigen presented to CD4+ T cells by major histocompatibility complex class II molecules (MHCII) plays a key role in adaptive immunity. Antigen presentation is initiated by the proteolytic cleavage of pathogenic or self proteins and loading of resultant peptides to MHCII. The loading and exchange of peptides to MHCII is catalyzed by a nonclassical MHCII molecule, HLA-DM (DM). It is well established that DM promotes peptide exchange in vitro and in vivo. However, the mechanism of DM-catalyzed peptide association and dissociation, and how this would affect epitope selection in human responses to infectious disease remain unclear. The work presented in this thesis was directed towards the understanding of mechanism of DM-mediated peptide exchange and its role in epitope selection.
In Chapter II, I measured the binding affinity, intrinsic dissociation half-life and DM-mediated dissociation half-life for a large set of peptides derived from vaccinia virus and compared these properties to the peptide-specific CD4+ T cell responses. These data indicated that DM shapes the peptide repertoire during epitope selection by favoring the presentation of peptides with greater DM-mediated kinetic stability, and DM-susceptibility is a strong and independent factor governing peptide immunogenicity.
In Chapter III, I computationally simulated peptide binding competition reactions and found that DM influences the IC50 (50% inhibition concentration) of peptides based on their susceptibility to DM, which was confirmed by experimental data. Therefore, I developed a novel fluorescence polarization-based method to measure DM-susceptibility, reported as a IC50 (change in IC50 in the absence and presence of DM). Traditional assays to measure DM-susceptibility based on differential peptide dissociation rates are cumbersome because each test peptide has to be individually labeled and multiple time point samples have to be collected. However, in this method developed here only single probe peptide has to be labeled and only single reading have to be done, which allows for fast and high throughput measure of DM-susceptibility for a large set of peptides.
In Chapter IV, we generated a series of peptide and MHCII mutants, and investigated their interactions with DM. We found that peptides with non-optimal P1 pocket residues exhibit low MHCII affinity, low kinetic stability and high DM-susceptibility. These changes were accompanied with conformational alterations detected by surface plasmon resonance, gel filtration, dynamic light scattering, small-angle X-ray light scattering, antibody-binding, and nuclear magnetic resonance assays. Surprisingly, all these kinetic and conformational changes could be reversed by reconstitution with a more optimal P9 pocket residue. Taken together, our data demonstrated that conformation of MHCII-peptide complex constrained by interactions throughout the peptide binding groove is a key determinant of DM-susceptibility.
B cells recognizing cognate antigen on the virion can internalize and process the whole virion for antigen presentation to CD4+ T cells specific for an epitope from any of the virion proteins. In turn, the epitope-specific CD4+ T cells provide intermolecular (also known as noncognate or heterotypic) help to B cells to generate antibody responses against any protein from the whole virion. This viral intermolecular help model in which CD4+ T cells provide help to B cells with different protein specificities was established in small size influenza virus, hepatitis B virus and viral particle systems. For large and complex pathogens such as vaccinia virus and bacteria, the CD4+ T cell-B cell interaction model may be complicated because B cells might not be able to internalize the large whole pathogen. Recently, a study in mice observed that CD4+ T cell help is preferentially provided to B cells with the same protein specificity to generate antibody responses against vaccinia virus. However, for larger pathogens such as vaccinia virus and bacteria the CD4+ T cell-B cell interaction model has yet to be tested in humans. In Chapter V, I measured in 90 recently vaccinated and 7 long-term vaccinia-immunized human donors the CD4+ T cell responses and antibody responses against four vaccinia viral proteins (A27L, A33R, B5R and L1R) known to be strongly targeted by cellular and humoral responses. We found that there is no direct linkage between antibody and CD4+ T cell responses against each protein. However, the presence of immune responses against these four proteins is linked together within donors. Taken together, our data indicated that individual viral proteins are not the primary recognition unit and CD4+ T cells provide intermolecular help to B cells to generate robust antibody responses against large and complicated vaccinia virus in humans.
24
Scott, Carol Elizabeth DeWeese. "Molecular modeling and experimental characterization of HLA-DQ proteins and protein/peptide complexes : correlation with insulin-dependent diabetes mellitus (IDDM) /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8089.
Full text
25
Wavamunno, Moses Dennis. "The role of pre-transplant antibodies in predicting chronic renal allograft injury." Thesis, The University of Sydney, 2009. https://hdl.handle.net/2123/28207.
Full textAbstract:
Continued rise in the incidence of late graft loss despite better
immunosuppression and improvement in acute rejection rates has led to
renewed interest in the effect of HLA antibodies on long term graft
outcomes. The significance of pre—transplant HLA antibodies detected
by the widely used CDC assay on early graft outcomes is well studied.
However, a lot remains unknown about effects of pre—transplant
antibodies detected by sensitive solid phase assays on early and late
graft outcomes. This is due to increased use of these assays resulting in
better detection of HLA and non HLA antibodies. Such antibodies are
thought to be of low affinity and avidity. In addition, low sensitivity of
conventional techniques for diagnosis of antibody mediated graft injury
results in late diagnosis when interventions are unlikely to reverse
graft failure.
This thesis examines 3 aspects of antibody mediated graft injury,
1) effects of pre-transplant antibodies detected by Luminex (a solid
phase assay) on histology and graft function outcomes,
2) use of electron microscopy in early diagnosis of chronic antibody
mediated injury, and
3) the potential role of mycophenolate mofetil in amelioration of
chronic graft injury.
26
Lemy, Anne. "Do MICA antibodies impact on renal graft outcomes?" Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209617.
Full textAbstract:
La transplantation rénale représente le traitement de choix de l’insuffisance rénale terminale parce qu’il offre une espérance de vie plus longue et une meilleure qualité de vie.Néanmoins, l’accès à la transplantation est limité par la pénurie d’organes et dans certains cas, par la présence d’anticorps anti-HLA avant la greffe.
Bien que la présence d’anticorps anti-HLA spécifiques du donneur avant ou après la greffe ait été associée au rejet aigu et à la perte chronique d’allogreffe, un rejet humoral tant aigu que chronique peut survenir sans que ces anticorps soient détectables dans le sérum, suggérant que des réponses autologues ou allo-immunes contre des antigènes dits « mineurs » pourraient jouer un rôle dans le rejet et la perte de greffe.
MICA, en raison de son polymorphisme important, est considéré aujourd’hui comme un des systèmes antigéniques mineurs les plus robustes par sa capacité à induire des allo-anticorps. Cependant, un effet pathogène des anticorps anti-MICA sur le greffon rénal demeure à ce jour, non formellement établi.
Le but de la présente recherche a été d’étudier l’épidémiologie des anticorps anti-MICA à partir d’une large cohorte de volontaires sains et de patients atteints d’insuffisance rénale chronique terminale, de déterminer les facteurs de risque d’immunisation contre MICA, de spécifier la nature autologue ou allogénique de ces anticorps et d’évaluer au sein des patients ultérieurement transplantés, l’impact de ces anticorps sur le rejet et la survie de greffe.
La méthode utilisée pour l’identification des anticorps anti-MICA est la technique Luminex, consistant à faire réagir du sérum avec des billes de polystyrène tapissées par un seul antigène MICA recombinant, l’intensité de la liaison antigène-anticorps étant révélée par un fluorocytomètre suite à l’adjonction d’un second anticorps anti-IgG couplé à une substance fluorescente.
Nous avons identifié la grossesse, les transfusions sanguines, la greffe préalable et également l’urémie comme étant des facteurs de risque indépendants d’immunisation contre MICA.
Nous n’avons pas observé d’effet délétère des anticorps anti-MICA sur la survie à long terme du greffon rénal alors que les anticorps anti-MICA ont été plus fréquents chez les patients dits «à haut risque immunologique» et en particulier chez les patients immunisés contre le HLA.
Nos résultats suggèrent que plutôt d’être pathogènes, les anticorps anti-MICA pourraient être simplement des marqueurs de haut risque immunologique. Ceci remet donc en question l’utilité d’un monitoring des anticorps anti-MICA par la technologie Luminex.
Renal transplantation represents the treatment of choice of stage V chronic kidney disease by offering a longer life expectancy and a better quality of life than dialysis. Nevertheless, the access to transplantation is limited by the shortage of organs and, in some cases, by the presence of HLA antibodies before transplantation.
While the presence of either preformed or post-transplant donor specific anti-HLA antibodies has been associated with acute rejection or chronic graft loss, acute or chronic antibody-mediated injury may also occur in the absence of detectable anti-HLA antibodies, suggesting that autologuous or allo-immune response to other relevant minor or non-HLA antigenic determinants might play a role in rejection and subsequent graft loss. Especially, MHC class I-related chain A (MICA), a highly polymorphic minor antigenic system, is now considered to be the most robust minor antigenic system capable of inducing allo-antibodies. However, the possible deleterious effect of MICA antibodies has not been formerly established yet.
The goal of the following work was to determine the risk factors for MICA sensitization, to specify the autologuous or allogeneic nature of MICA antibodies and to assess the impact of preformed and 1 yr post-transplant MICA antibodies on defined renal graft outcomes in large cohorts of patients. The method employed for the identification of MICA antibodies was a Luminex single antigen beads assay. We found that pregnancy, previous blood transfusion, previous graft as well as chronic kidney disease were independent risk factors for MICA sensitization.
Even if we had found a higher frequency of MICA antibodies in patients at higher immunological risk and especially, MICA antibodies had been closely associated with HLA sensitization, we showed a lack of a deleterious effect of MICA antibodies on long-term renal graft outcomes.
Our findings suggest that MICA antibodies are merely surrogate markers of high immunological risk and really question the monitoring of MICA antibodies by the presently available MICA single antigen flow beads assays.
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished
27
Chang, Yea-wen, and 張雅雯. "Application of molecular genetic techniques to the study of major histocompatibility complex class II allelic associations with insulin-dependent diabetes mellitus in Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31213960.
Full text
28
Felício, Leandro Prado. "Variabilidade e história evolutiva do gene HLA-E." Universidade Federal de Goiás, 2013. http://repositorio.bc.ufg.br/tede/handle/tede/3597.
Full textAbstract:
Submitted by Erika Demachki (erikademachki@gmail.com) on 2014-11-11T20:37:41Z
No. of bitstreams: 2
Dissertação - Leandro Prado Felício - 2013.pdf: 4839350 bytes, checksum: 07898140311917429ab55aa63ad5324e (MD5)
license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)Approved for entry into archive by Erika Demachki (erikademachki@gmail.com) on 2014-11-11T20:38:05Z (GMT) No. of bitstreams: 2 Dissertação - Leandro Prado Felício - 2013.pdf: 4839350 bytes, checksum: 07898140311917429ab55aa63ad5324e (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)
Made available in DSpace on 2014-11-11T20:38:05Z (GMT). No. of bitstreams: 2 Dissertação - Leandro Prado Felício - 2013.pdf: 4839350 bytes, checksum: 07898140311917429ab55aa63ad5324e (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-01-31
Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
The HLA-E locus is a Human Major Histocompatibility Complex (MHC) gene associated with immune-modulation and suppression of the immune response by the interaction with specific NK and T cell receptors. The HLA-E gene is considered the most conserved locus in the human HLA; however, this low variability might be a consequence of the scarce number of studies focusing this subject. In this mastering thesis we assessed the HLA-E coding and 3’ untranslated region variability in a group of individuals from Brazil and the results were evaluated together with data from the 1000Genomes Consortium. Altogether, only 28 variation sites were found in approximately 2724 bp evaluated. These variation sites were arranged into 33 haplotypes, most of them (98.2%) encoding one of the two HLA-E molecules found worldwide, i.e., the molecules associated with the allele groups E*01:01 and E*01:03. Interestingly, 85% of all haplotypes were represented by only three different sequences, each of them associated with one of the main known HLA-E coding alleles, E*01:01:01, E*01:03:01 and E*01:03:02, all of them found worldwide. This phenomenon, together with the comparisons with other primate sequences, reveals that these two main allele groups (and molecules) arose early before human speciation, and indicates that E*01:03:01 might be the oldest allele. In addition, the low nucleotide diversity found for the HLA-E coding and 3’UTR in worldwide populations suggests that the HLA-E gene is in fact a conserved gene, which might be a consequence of its key role in the modulation of the immune system.
O loco HLA-E é um gene do Complexo Principal de Histocompatibilidade Humano (MHC), cujo produto está relacionado com a modulação e supressão da resposta imunitária por meio da interação com receptores específicos das células NK e linfócitos T. O gene HLA-E é considerado o loco menos polimórfico dos genes do complexo HLA, no entanto, esta baixa variabilidade pode ser uma consequência do pequeno número de estudos realizados sobre esse tema. No presente trabalho, a variabilidade das regiões codificadoras e 3’ não traduzida do gene HLA-E foi analisada em amostras brasileiras e os resultados foram comparados com dados obtidos pelo projeto 1000Genomes. Considerando todas as populações avaliadas, apenas 28 pontos de variação foram encontrados em uma região de aproximadamente 2724-pb. Estes pontos de variação estão arranjados em 33 haplótipos diferentes, a maioria deles (98%) codificando uma das duas moléculas HLA-E frequentemente encontradas, E*01:01 e E*01:03. Ainda, 85% dos haplótipos encontrados foram representados por apenas três sequências diferentes, cada uma deles associada a um dos principais alelos da região codificadora do gene HLA-E, E*01:01:01, E*01:03:01 e E*01:03:02. Todas essas sequências foram encontradas em todas as populações avaliadas. Este fenômeno, em conjunto com as comparações envolvendo sequências de primatas, sugere que estes dois grupos de alelos principais (e moléculas) surgiram antes da especiação e dispersão humana, além de indicar que o alelo E*01:03:01 pode ser o mais antigo dentre os demais. Ainda, a baixa diversidade nucleotídica encontrada para a região codificadora e 3' NT do gene HLA-E em populações de todo o mundo sugere que este gene é, de fato, bastante conservado, provavelmente devido ao seu papel chave na modulação das respostas imunes.
29
Foley, Bree Amanda. "The immunogenetics of natural killer cell alloreactivity." University of Western Australia. School of Pathology and Laboratory Medicine, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0242.
Full textAbstract:
[Truncated abstract] Natural killer (NK) cell alloreactivity can be exploited in haploidentical haematopoietic stem cell transplantation (HSCT) to improve graft survival, reduce graft versus host disease and decrease leukaemic relapse. NK cells lyse cells that have reduced expression of class I HLA molecules. In an allogeneic setting, donor NK cells may be activated by the absence of donor (self) class I HLA molecules on recipient cells; the absence of self-epitopes being detected by inhibitory KIR receptors on donor NK cells. The way in which genetic polymorphism of the receptors and ligands affects NK allorecognition of missing self, has not been fully elucidated. HLA-C molecules are divided into two groups, C1 and C2, with KIR2DL1 recognising cells expressing C2 and KIR2DL2 and KIR2DL3 recognising cells expressing C1. Donor NK cells expressing KIR2DL2 or KIR2DL3 can be alloreactive towards a recipient if they lack the C1 epitope and donor NK cells expressing KIR2DL1 can be alloreactive towards a recipient if they lack the C2 epitope. KIR3DL1 recognises the Bw4 epitope present on one-third of HLA-B alleles and certain HLA-A alleles. NK cells from donors expressing KIR3DL1 can be alloreactive towards recipients whose cells lack Bw4. Mismatches of KIR related HLA epitopes does not always results in NK alloreactivity. Therefore it is not possible to reliably predict NK alloreactivity based solely on the donor's HLA type and KIR repertoire and the recipient's HLA type. ... All Bw4-positive HLA-B alleles, with the exception of HLA-B*1301 and B*1302, protected targets from lysis. HLA-A*2402 and HLA-A*3201 unequivocally protected target cells from lysis whereas HLA-A*2501 and HLA-A*2301 provided only weak protection from lysis. KIR3DL1-dependent alloreactive NK clones were identified in donors whose only Bw4 positive allele was HLA-A*2402 but not in donors whose only Bw4 positive HLA allele was HLA-B*1301 or B*1302. Finally this thesis demonstrated that an activating KIR can control NK cell alloreactivity. Donors who are C2 negative and KIR2DS1 positive had NK cells that expressed the activating receptor KIR2DS1 and were capable of lysing cells expressing the C2 epitope. More so, KIR2DS1 dependent NK clones were shown to override inhibitory signals generated by NKG2A interacting with its ligand, HLA-E. The identification of these NK clones has important implications for haploidentical HSCT in that recipient expressing all three NK epitopes, C1, C2 and Bw4 were previously thought to be resistant to alloreactive NK cells controlled by inhibitory receptors. Such patients may be amenable to haploidentical HSCT from C2 negative, KIR2DS1 positive donors. These results will improve the ability to predict NK cell alloreactivity based on a donor's HLA type and KIR repertoire and the recipient?s HLA type.
30
Yap, Cheng-Hon. "Factors influencing cryopreserved allograft heart valve degeneration." Connect to thesis, 2006. http://repository.unimelb.edu.au/10187/2120.
Full textAbstract:
Heart valve replacement is becoming more commonplace in developed nations. Despite this the ideal valve prosthesis has not been found. The allograft valve has been used for over 40 years and remains an important prosthesis with many advantages. However, like other biological valve prosthesis, they have a finite durability. The causes of allograft valve degeneration are still unknown. The study aims to identify factors associated with cryopreserved allograft valve degeneration. Knowledge of such factors will improve our understanding of the potential causes and mechanisms of allograft heart valve degeneration. (For complete abstract open document)
31
Aly, Theresa Ann. "Novel MHC analyses allow prediction of extreme genetic risk for type 1A diabetes /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007. http://proquest.umi.com/pqdweb?did=1400957021&sid=1&Fmt=6&clientId=18952&RQT=309&VName=PQD.
Full textAbstract:
Thesis (Ph.D. in Human Medical Genetics) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 94-108). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
32
Lie, Hanne Cathrine. "The role of genetic diversity in human sexual selection : is the MHC special?" University of Western Australia. School of Psychology, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0053.
Full textAbstract:
[Truncated abstract] The assumption that facial attractiveness signals mate quality is central to current evolutionary theories of human sexual selection. Evidence for direct links between attractiveness and mate quality is, however, scarce, and the exact nature of mate quality remains the subject of debate. Mate quality may include genetic diversity, because genome-wide diversity has been linked to individual fitness, and diversity within the Major Histocompatibility Complex (MHC) has been associated with immunocompetence and health in many species. This thesis investigates whether individual genetic diversity plays a role in human sexual selection. The main aim is to examine whether MHC diversity, compared to genetic diversity in general, is especially important for mate preferences, health and mating success. The four studies herein are based on data collected from a large sample of heterosexual, Caucasian males and females. Participants were photographed, provided a DNA sample, and completed questionnaires regarding sexual history and health. Genetic diversity was calculated as both mean heterozygosity (H) and standardised mean-d2 (d2), separately for 12 MHC microsatellite loci and 11 nonMHC loci. The photographs were rated for various attractive features by opposite-sex raters. The first study investigated whether MHC diversity influences preferences for facial appearance in a potential mate, and if so, are they specific to the MHC and are they mediated by specific facial characteristics? I found that MHC-H, but not nonMHCH, positively predicted male facial attractiveness, and that this relationship was mediated by facial averageness. For females, nonMHC-d2 predicted facial symmetry, and potentially attractiveness. These findings indicate that faces contain visual cues to mate quality in both males and females, providing support for evolutionary theories that our preferences are adaptations for identifying mates of high quality. ... Measuring them both allowed me to tease apart their effects on mate preferences, and on health and mating success. Indeed, the MHC appears to be especially important in sexual selection as MHC diversity predicted female mate preferences after controlling for nonMHC diversity, and MHC dissimilarity predicted male mate preferences after controlling for nonMHC dissimilarity. Moreover, although MHC diversity did not appear to influence males preference for females, it did predict female mating success, suggesting that males also attend to MHC-related cues, although perhaps non-facial cues, when seeking mates. Additionally, nonMHC diversity predicted both male preferences for female faces and health, suggesting that such preferences are adaptive. Importantly, by providing direct links between facial attractiveness and biological markers of individual quality, genetic diversity, these results support the commonly held assumption that facial attractiveness signals mate quality.
33
Gupta, Manu. "Autoimmune markers in autoimmune diabetes /." Stockholm, 2003. http://diss.kib.ki.se/2004/91-7349-756-8/.
Full text
34
Santos, Kaisson Ernane dos. "Avaliação da história evolutiva do gene HLA-G por meio de polimorfismos de base única e da inserção AluyHG." Universidade Federal de Goiás, 2013. http://repositorio.bc.ufg.br/tede/handle/tede/6686.
Full textAbstract:
Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-04T13:00:39Z
No. of bitstreams: 2
Dissertação - Kaisson Ernane dos Santos - 2013.pdf: 2738475 bytes, checksum: 6c79ab9177dd126fa5cb677127debc2c (MD5)
license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-04T13:01:13Z (GMT) No. of bitstreams: 2 Dissertação - Kaisson Ernane dos Santos - 2013.pdf: 2738475 bytes, checksum: 6c79ab9177dd126fa5cb677127debc2c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)
Made available in DSpace on 2017-01-04T13:01:13Z (GMT). No. of bitstreams: 2 Dissertação - Kaisson Ernane dos Santos - 2013.pdf: 2738475 bytes, checksum: 6c79ab9177dd126fa5cb677127debc2c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2013-11-25
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The Major Histocompatibility Complex is mainly composed by genes of the adaptive immune response. In humans, part of this complex is known as the Human Leukocyte Antigens (HLA), whose genes are responsible for specific antigen presentation to effector immune cells. The classical class I HLA genes (HLA-A, -B and -C) are responsible for antigen presentation to T CD8+ cells and they constitute the most polymorphic genes in the human genome. This variability is maintained by selection mediated by microorganisms. In contrast to their classical counterparts, the non classical class I genes (HLA-G, -E and -F) present low variability and are associated with immune tolerance due to the interaction with NK and T cells inhibitor receptors. HLA-G is the most studied non classical gene, which is associated with immune response modulation, mainly during pregnancy. Considering that natural selection is acting on the HLA-G regulatory regions maintaining high heterozigosity in this region, we evaluated a nearby Alu insertion (AluyHG) correlating this Alu element with coding and 3’UTR HLA-G polymorphisms. The AluyHG insertion was particularly associated with the HLA-G haplotype known as G*01:01:01:01/UTR-1, considered a high-expressing HLA-G haplotype. The G*01:01:01:01/UTR-1/AluyHG haplotype would be the most recent HLA-G haplotypes, in spite of its high frequency in worldwide populations.
O Complexo Principal de Histocompatibilidade (MHC) é formado principalmente por genes que participam da resposta imunológica adaptativa. Entre esses genes encontramos o grupo denominado de Antígenos Leucocitários Humanos (HLA), que são responsáveis pela apresentação de antígenos específicos às células efetoras do sistema imunológico. Os genes HLA de classe I clássicos (HLA-A, -B e -C), responsáveis pela apresentação antigênica aos linfócitos T citotóxicos, são considerado como os mais polimórficos do genoma humano e de outros vertebrados. A variabilidade desses genes e elevada heterozigose é mantida por seleção mediada por microrganismos. Diferentemente dos genes clássicos, os genes HLA de classe I não clássicos (HLA-G, -E e -F) apresentam variabilidade reduzida e como função principal a tolerância imunológica, por meio de sua interação com receptores inibitórios presentes nas células NK e T. O HLA-G é o mais estudado entre esses genes e, devido sua importância como molécula imunomoduladora e sua importância em situações como gestação, e considerando evidências anteriores de seleção natural mantendo uma elevada heterozigose nas regiões regulatórias do HLA-G, avaliamos a presença de uma inserção Alu (AluyHG) próxima a este gene correlacionando os achados com a variabilidade contida nas suas regiões codificadora e 3’ não traduzida. A inserção AluyHG mostrou-se em desequilíbrio de ligação (LD) com os polimorfismos do gene HLA-G. Especificamente, o elemento inserido apresentou-se em LD com um haplótipo denominado G*01:01:01:01/UTR-1, considerado como um haplótipo de alta produção da molécula de HLA-G. Esse haplótipo aparentemente é o mais jovem entre humanos, apesar de sua elevada frequência nas populações estudadas até o momento.
35
Néel, Dominique. "Caracterisation des oligosaccharides n-lies d'antigenes hla-dr et de leurs cellules vectrices : contribution a l'etude des facteurs influencant la n-glycosylation." Paris 7, 1987. http://www.theses.fr/1987PA077138.
Full text
36
Layet, Corine. "Approche des bases structurales de l'antigenicite des antigenes hla de classe i." Aix-Marseille 2, 1986. http://www.theses.fr/1986AIX22046.
Full text
37
Garban, Frédéric. "Les molécules HLA de classe II dans les lymphocytes B de sang de cordon : présentation de l'antigène - transmission de signaux." Paris 7, 1997. http://www.theses.fr/1997PA077218.
Full textAbstract:
Les lymphocytes b de sang de cordon sont des cellules matures mais protegees des rencontresantigeniques exogenes. Les molecules hla de classe ii sont le support de la presentation antigenique et de la transmission de signaux intracellulaires d'activation ou de mort cellulaire programmee. Les cellules b de sang de cordon presentent de grandes quantites de molecules hla de classe ii vides mais la capacite d'allostimulation est preservee. Ces molecules hla de classe ii se presentent comme chez l'adulte sous forme de dimeres de dimeres, mais a la surface des lymphocytes b adultes la quantite de molecules vides est faible. En revanche, plusieurs milliers de sites vides existent a la surface des monocytes. L'etude de la signalisation via les molecules hla-dr montre un deficit de la mobilisation du calcium intracellulairedans les lymphocytes b de cordon avec deficit de l'agregation homotypique et de l'induction de l'apoptose. Ce deficit de l'apoptose est relie a l'absence de flux calcique. Des similitudes existent entre la signalisation via hla dr des cellules b de cordon et de certaines hemopathies lymphoides bchroniques (leucemie lymphoide chronique) et lymphome du manteau) avec une difference importante en ce qui concerne l'activation de la proteine kinase c. Ces donnees permettent d'approfondir nos connaissances sur les premiers stades de l'ontogenie des lymphocytes b apres la sortie de la moelle en apportant des elements sur la fonction des molecules hla de classe ii au cours de l'ontogenie.
38
Zeliszewski, Dominique. "Etude du polymorphisme et du role des molecules hla de classe 2 a l'aide de clones de lymphocytes t restreints et specifiques d'antigenes viraux." Paris 7, 1987. http://www.theses.fr/1987PA077248.
Full text
39
Quillet, Anne. "Role des antigenes hla classe i dans la susceptibilite a la cytotoxine naturelle nk/lak." Paris 7, 1988. http://www.theses.fr/1988PA077142.
Full text
40
Heldt, Christian. "Differentielle Expression von HLA-DRB-Genen." Doctoral thesis, [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964994917.
Full text
41
Amadou, Claire. "Structure et évolution du bras court du chromosome 6 humain : la région de classe I du complexe majeur d'histocompatibilité et sa partie distale." Toulouse 3, 1996. http://www.theses.fr/1996TOU30039.
Full textAbstract:
Le principe de cartographie comparative a ete suivi pour etudier l'evolution de la region de classe i du complexe majeur d'histocompatibilite (cmh). L'auteur a identifie et localise de nouveaux marqueurs conserves entre l'homme et la souris, qui ont permis une comparaison de la moitie distale du cmh entre les deux especes. Cette carte comparative met en evidence une structure conservee de la region de classe i, malgre l'absence d'orthologie entre les genes de classe i. L'auteur postule que les sequences non apparentees aux sequences de classe i sont representatives d'une structure ancestrale, dans laquelle les sequences de classe i auraient evolue independamment. Parmi les sequences conservees, un regroupement de genes de recepteurs olfactifs a ete identifie. Plusieurs hypotheses sont proposees quant a la fonction et l'evolution de ces genes
42
Krief, Patricia. "Modulation de l'expression des antigenes d'histocompatibilite induite par l'interferon gamma : role d'un inhibiteur endogene et de la differenciation." Paris 6, 1987. http://www.theses.fr/1987PA066459.
Full text
43
Meneghini, Maria Antonia Emilia. "Tracking preformed serological and T-cell alloimmune memory together with donor/recipient Molecular Human Leukocyte Antigen (HLA) disparity to improve immune-risk stratification in Kidney Transplantation." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673464.
Full textAbstract:
INTRODUCTION: The presence of a donor-specific alloimmune response negatively impacts allograft outcomes, being associated to risk of rejection and premature graft loss. Alloimmunity can be both preformed (memory) or can develop de novo after transplantation. The immune assays currently used in clinical practice to evaluate alloimmunity have several limitations and do not allow a complete and precise assessment of those two responses at time of transplantation.
The hypothesis of this doctoral thesis is that at the time of kidney transplantation, an accurate characterization of pretransplant anti-donor alloimmune sensitization using highly sensitive assays tracking both serological memory and circulating donor-reactive memory T cells together with the assessment of the susceptibility to de novo alloimmune activation assessing the degree of donor/recipient HLA matching at the molecular level, would improve current immune-risk stratification and ultimately guide transplant physicians individualizing immunosuppressive therapies.
OBJECTIVES:
- To compare the accuracy of different immune-assays evaluating the preformed serological immunity (circulating donor(HLA)-specific antibodies), either individually or in combination and their value predicting distinct kidney graft outcomes.
- To investigate the development and kinetics of primary T-cell alloreactivity after transplantation by detection of alloreactive IFN-γ producing T cells using an Enzyme-link ImmunoSpot (ELISPOT) assay and evaluate their predominant antigen presenting pathways.
- To analyze the impact of donor/recipient HLA molecular mismatching on the generation of de novo donor-specific alloimmunity both at humoral and T-cell level after transplantation using distinct bioinformatic algorithms.
- To evaluate the value of assessing preformed donor-reactive IFN-γ-producing T cells and donor/recipient Molecular HLA mismatching to identify kidney transplant recipients at low risk of rejection when receiving reduced immunosuppression based on tacrolimus monotherapy.
METHODS: we performed two retrospective clinical studies and one prospective multicenter biomarker-guided study (CELLIMIN). The predictive capacity of different assays to detect pretransplant donor-specific antibodies (DSA) has been evaluated: flow cytometry crossmatch, solid phase assays and complement activating (C3d) capacity of DSA in vitro. Furthermore, the presence of alloreactive T cells in vitro has been assessed by Interferon-γ ELISPOT before and after transplantation. Donor/recipient HLA incompatibility has been evaluated with different informatic algorithms: Amino acid mismatch score, HLA-Matchmaker eplet mismatches and PIRCHE-II scores. It has been assessed the impact of the results of those algorithms on the prediction of primary alloimmunity both at the serological and T-cell level. Last, in a prospective study guided by biomarkers assessing both pretransplant serological and T-cell alloimmunity we randomized low-risk patients to receive either immunosuppression based on tacrolimus monotherapy or standard of care (steroids, Mycophenolate mofetil and tacrolimus).
MAIN RESULTS: DSA with high mean fluorescence intensity (MFI) and those fixing complement in vitro predict higher rejection risk. The most accurate serological assays to predict transplant outcomes were a combination of DSA detected by solid phase assay and flow cytometry crossmatch. All the informatic HLA molecular mismatch algorithms precisely predicted risk of humoral primary alloimmunity. Similarly, a higher molecular incompatibility (especially by PIRCHE-II score) predicted risk of de novo T-cell activation. Finally, in the CELLIMIN trial, we observed that patients without preformed alloreactivity (neither serological or T cell-mediated) displayed significantly lower risk of acute rejection as compared to patients with preformed cellular alloreactivity and receiving the same standard of care immunosuppression. However, patients without serological/T cell preformed alloreactivity receiving minimized immunosuppression with tacrolimus monotherapy showed significantly higher incidence of acute rejection especially those with high molecular HLA mismatch at the DQ level.
CONCLUSIONS: A complete and accurate study of the donor-specific preformed immune responses both at the serological and T-cell level, together with the assessment of the molecular HLA incompatibility, could improve stratification of the alloimmune risk in a more precise way, finally allowing adapted individualization of immunosuppression.Las respuestas inmunológicas donante-especificas impactan negativamente en la evolución del aloinjerto renal. Estas pueden ser preformadas o activarse de novo tras el trasplante. Las técnicas inmunológicas disponibles en la clínica presentan limitaciones que no permiten una evaluación completa y precisa de esas respuestas. La hipótesis de esta tesis doctoral es que una evaluación de la memoria inmunológica mediante nuevas herramientas diagnosticas junto con estudios de compatibilidad HLA donante/receptor a nivel molecular para predecir el riesgo de aloinmunidad de novo, mejorarían la estratificación del riesgo inmunológico y permitirían personalizar la terapia inmunosupresora. Se han usado diferentes metódicas de detección de anticuerpos donante-específicos (DSA) pre-trasplante: cross-match por citometría de flujo, técnicas de fase solida y capacidad de los DSA de fijar complemento (C3d) in vitro y se ha medido la presencia de células T aloreactivas in vitro mediante ELISPOT Interferon(IFN)-y antes y después del trasplante. La incompatibilidad molecular HLA se ha valorado mediante algoritmos informáticos: incompatibilidad de aminoácidos, HLAMatchmaker y PIRCHE-II. Por ultimo, en un ensayo clínico prospectivo, guiado por biomarcadores de alorespuesta pre-trasplante (serológica y celular T) se han aleatorizado pacientes de bajo riesgo a recibir monoterapia con tacrolimus o tratamiento inmunosupresor convencional y comparado el riesgo de rechazo. La combinación de DSA (por fase solida) y cross-match por citometría son las técnicas que mejor se asocian el riesgo de pérdida del injerto, mientras que los DSA con elevado índice de fluorescencia y los que fijan complemento se asocian al riesgo de rechazo. Todos los algoritmos de incompatibilidad molecular HLA se asocian al riesgo de aloreactividad humoral primaria post-trasplante. De forma parecida, la incompatibilidad molecular (sobretodo por PIRCHE-II) se relaciona al riesgo de generar respuesta T donante-especifica de novo. En el ensayo CELLIMIN, los pacientes sin aloreactividad pre-trasplante (DSA/aloractividad T) presentaron inferior riesgo de rechazo. Sin embrago, aquellos pacientes que recibieron tacrolimus monoterapia presentaron una mayor incidencia de rechazo, especialmente en presencia de elevada incompatibilidad de epletos HLA-DQ. Un estudio completo de las respuestas de memoria tanto serológica como celular T donante-específica, junto con la evaluación de la incompatibilidad HLA a nivel molecular, podrían estratificar más precisamente el riesgo inmunológico de cada receptor frente a su donante y permitir adaptar el tratamiento inmunosupresor de una forma personalizada.
44
Cayrol, Corinne. "Les molécules HLA de classe II : production d'anticorps monoclonaux pour la caractérisation de nouveaux épitopes polymorphes et étude du trafic intracellulaire des molécules DR et DQ." Toulouse 3, 1992. http://www.theses.fr/1992TOU30121.
Full textAbstract:
La region hla-d du complexe majeur d'histocompatibilite (cmh) humain, situe sur le bras court du chromosome 6, contient des genes codant les chaines alpha et beta des molecules hla de classe ii (dr, dq, dp). Ces molecules sont des glycoproteines membranaires a distribution tissulaire restreinte, qui presentent les fragments d'antigenes aux lymphocytes t auxiliaires. Elles ont une influence determinante sur la regulation de la reponse immunitaire, la susceptibilite a certaines maladies et la reponse aux allogreffes. Une particularite des molecules hla est leur tres grand polymorphisme. Bien que des anticorps monoclonaux reconnaissant des epitopes polymorphes des molecules hla de classe ii aient ete obtenus en immunisant des souris avec des cellules humaines, cette approche s'est averee souvent inefficace car les cellules humaines expriment de nombreux antigenes de surface non-hla, immunogenes pour la souris. Afin de cibler la reponse immunitaire de la souris sur les molecules hla-dr, en particulier sur les regions polymorphes de ces molecules, nous avons utilise des cellules murines transfectees exprimant des molecules hla-drbon (dr103). Cette strategie nous a permis d'obtenir des anticorps monoclonaux reconnaissant de nouveaux epitopes polymorphes des molecules hla-dr: l'un des anticorps reconnait un epitope commun aux molecules dr1, drbon, dr9 et dr10; un second anticorps reconnait un epitope present sur ces memes molecules mais aussi sur les molecules dr8; enfin, un autre anticorps se lie a toutes les molecules hla-dr sauf dr3, dr7 et dr52. De facon etonnante, l'anticorps oha tm901 reconnait les molecules hla-dr9 exprimees a la surface des lignees lymphoblastoides humaines mais ne reconnait pas ces molecules lorsqu'elles sont exprimees a la surface des lymphocytes du sang peripherique. De plus, il ne reconnait pas non plus les molecules dr9 intracellulaires nouvellement synthetisees des lignees lymphoblastoides humaines. Ces resultats suggerent que l'epitope reconnu par cet anticorps, bien que present sur les molecules hla-dr9, peut-etre absent ou masque dans certains cas. Un modele est propose pour expliquer le profil de reactivite de cet anticorps avec les molecules hla-dr9. D'autres anticorps ont ete egalement caracterises: un anticorps a reactivite monomorphe anti-dr mais reconnaissant un epitope polymorphe sur les molecules dq et dp ainsi qu'un anticorps anti-dq4+5+6. La reconnaissance des proteines antigeniques exogenes par les lymphocytes t auxiliaires necessite leur degradation en peptides et l'association de ces peptides avec les molecules hla de classe ii dans des endosomes tardifs. Les molecules de classe ii sont transportees dans ce compartiment par une proteine appelee chaine invariante (ii). Nous etudions l'hypothese d'un cotransport des molecules hla-dr et dq dependant de la chaine invariante. Notre approche consiste a obtenir des cellules hela (ii#, classe ii-) qui expriment de maniere stable des molecules hla-drbon et dq5 et d'etudier le trafic intracellulaire de ces molecules en presence ou en absence de la chaine invariante. Des experiences preliminaires montrent que, dans des cellules hela exprimant de facon stable les molecules hla-drbon, la chaine invariante modifie le trajet intracellulaire de ces molecules en les dirigeant dans des vesicules endosomales
45
Saglibene, Hélène. "Prévention du rejet de greffe de cornée et complexe majeur d'histocompatibilité." Bordeaux 2, 1992. http://www.theses.fr/1992BOR23061.
Full text
46
Triebel, Frédéric. "Analyse fonctionnelle et structurale des antigènes membranaires ayant un rôle dans la réponse proliférative de clones lymphocytaires T humains spécifiques de l'anatoxine diphtérique." Paris 6, 1986. http://www.theses.fr/1986PA066147.
Full text
47
Poizot-Martin, Isabelle. "Signalisation induite par les molécules HLA de classe II dans les cellules B lymphoïdes normales et malignes folliculaires." Université Joseph Fourier (Grenoble), 2000. http://www.theses.fr/2000GRE10170.
Full textAbstract:
Les lymphomes b non-hodgkiniens font partie des rares tumeurs a exprimer des molecules hla de classe ii. Ceci leur permet d'interagir directement avec les lymphocytes t cd4+ qui infiltrent la tumeur (til-t). La signalisation induite par les molecules hla-dr peut induire soit l'apoptose, soit la proliferation. La premiere partie de ce travail a ete d'etudier le role joue par les molecules hla de classe ii dans l'interaction entre les til-t cd4+ et les lymphocytes b malins de lymphome folliculaire. Par l'intermediaire des molecules hla de classe ii, des clones de til-t cd4+ sont capables d'induire l'activation des lymphocytes b malins et leur entree en phase g1 du cycle cellulaire (induction du ki-67). Afin de determiner si les lymphocytes b malins presentent des anomalies intrinseques les empechant de progresser dans le cycle cellulaire, nous avons etudie dans une deuxieme partie l'effet d'une signalisation induite par les molecules hla-dr dans des lymphocytes b normaux. Nous avons d'abord montre que l'orientation vers une voie apoptotique ou proliferative ne depend pas de l'etat d'activation du lymphocyte b, mais de la capacite du ligand a regrouper les molecules hla-dr a la surface de la cellule. En effet, un ac anti-hla-dr couple a des billes de sepharose (qui mime la relation avec un lymphocyte t cd4+) induit la proliferation des lymphocytes b normaux alors qu'un ac anti-hla-dr couple a un ac secondaire, induit l'apoptose, sans entree prealable dans le cycle cellulaire. Ces resultats montrent que dans les lymphocytes b tumoraux, l'entree en cycle correspond bien a un debut de proliferation et non a un prelude a l'apoptose. Nous avons replace la signalisation hla-dr dans un contexte physiologique : les lymphocytes b recoivent d'abord un signal induit par l'interaction d'un antigene sur le recepteur a l'ag du lymphocyte b, ce qui induit une proliferation. Ensuite, ils interagissent avec des lymphocytes t cd4+, entrainant une signalisation par les molecules hla-dr dans le lymphocyte b. La proliferation induite par la stimulation du recepteur a l'ag est regulee negativement par co-stimulation avec un ac anti-hla-dr lie a un ac secondaire. Ceci se traduit au niveau du cycle cellulaire, par une diminution de la phosphorylation de la proteine prb due a une diminution d'expression des cdk2, 4 et 6 et des cyclines e et a, et a un retard d'expression de la cycline d2. Les cdkis p21 et p27 ne sont pas impliques. Nos resultats montrent qu'un signal induit par hla-dr est suffisant pour induire une proliferation. L'absence de proliferation dans les lymphocytes b tumoraux suggerent fortement la presence d'une (ou plusieurs) anomalie(s) intrinseque(s) empechant la progression dans le cycle cellulaire. Ce blocage semble etre general puisqu'il n'affecte pas que la voie hla de classe ii mais egalement la voie il4/cd40.
48
Jeanmougin, Marc. "Imputation HLA et analyse génomique de la coinfection VIH/VHC." Thesis, Paris, CNAM, 2017. http://www.theses.fr/2017CNAM1164/document.
Full textAbstract:
La génomique d'association cherche à déterminer des liens entre le génome et des traits ou phénotypes, notamment dans le contexte de maladies. Aujourd'hui, les études les plus fréquentes en génomique d’association sont les études génome entier, qui analysent autant de variants du génomes (SNPs) que possible, sans avoir de préjugé a priori sur leur fonction biologique. Cependant, les méthodes de génotypage utilisées pour ces études ne permettent pas toujours d'obtenir des informations précises dans une région hypervariable comme la région HLA, qui joue un rôle crucial dans l'immunité, et les variants génétiques de ces régions sont souvent prédits par des approches bioinformatiques. J'ai durant ma thèse créé un nouvel outil, HLA-Check, permettant d'évaluer, à partir des génotypes obtenus par puce de génotypage, la plausibilité de données d'allèles HLA d'un même individu, et démontré que cette technique permettait d'identifier plus précisément les individus dont les allèles HLA avaient été mal caractérisés afin de les retyper ou de les écarter de l'étude. Un article documentant cet outil a été publié dans BMC Bioinformatics. J'ai également effectué une étude d'association génome entier sur le déclenchement de la cirrhose chez les patients co-infectés par le VIH (virus de l'immunodéficience humaine) et le VHC (virus de l'hépatite C). La coinfection par ces deux maladies est fréquente en raison de modes d’infection similaires, et l'infection par le VIH stimule l'activité du VHC et accélère la fibrose du foie puis sa cirrhose, causant la mort des patients co-infectés. Mon étude porte sur 306 patients co-infectés issus de la cohorte ANRS CO-13 HEPAVIH. J'ai ainsi pu mettre en évidence trois signaux associés avec le déclenchement de la cirrhose, dont deux ont un lien pertinent avec les maladies hépatiques (gene CTNND2 et gene MIR7-3HG). L'identification de ces nouveaux variants devrait permettre une meilleure compréhension des mécanismes moléculaires de la cirrhose, et contribuer au développement de nouvelles stratégies diagnostiques ou thérapeutiques. L’article documentant cette étude est en cours de publicationAssociation genomics aims at finding links between the genome and some traits or illnesses. Today, the most frequent studies in this field are genome wide association studies (GWAS), which analyze as many genome variants (mainly Single Nucleotide Polymorphisms) as possible, without any a priori on their biological function. However, genotyping methods used in these studies may be insufficient to get reliable information in higly variable regions such as the HLA which plays a crucial role in immunity, and the genetic variants of such regions are often predicted using bioinformatics approaches. During my PhD, I have created a new tool, HLA-Check, that allows to rate the plausibility of HLA alleles from the genotypes obtained from genotyping chips. I also assesses its performances and showed that it was able to point out individuals with a wrong HLA typing, in order to retype them or remove them from the study. An article documenting this tool was published in BMC Bioinformatics. I have also performed a genome-wide association study on cirrhosis outbreak in individuals coinfected with HIV (human immunodeficiency virus) and HCV (hepatitis C virus). Because of similar infection routes (blood-related), co-infection with those two viruses are frequent, and the infection by HIV enhances HCV activity and increases liver fibrosis leading to cirrhosis and death of co-infected patients. Our study has dealt with 306 co-infected patients from the ANRS CO-13 HEPAVIH cohort. I could point out three statistically significant signals, two of them being highly relevant for their involvement in liver diseases (gene CTNND2 and gene MIR7-3HG). The identification of these new variants should lead to a better understanding of the molecular mechanisms involved in cirrhosis, and should contribute to the rational developement of new diagnostic or therapeutic strategies. A publication is under way
49
Dilthey, Alexander Tilo. "Statistical HLA type imputation from large and heterogeneous datasets." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:1bca18bf-b9d5-4777-b58e-a0dca4c9dbea.
Full textAbstract:
An individual's Human Leukocyte Antigen (HLA) type is an essential immunogenetic parameter, influencing susceptibility to a variety of autoimmune and infectious diseases, to certain types of cancer and the likelihood of adverse drug reactions. I present and evaluate two models for the accurate statistical determination of HLA types for single-population and multi-population studies, based on SNP genotypes. Importantly, SNP genotypes are already available for many studies, so that the application of the statistical methods presented here does not incur any extra cost besides computing time. HLA*IMP:01 is based on a parallelized and modified version of LDMhc (Leslie et al., 2008), enabling the processing of large reference panels and improving call rates. In a homogeneous single-population imputation scenario on a mainly British dataset, it achieves accuracies (posterior predictive values) and call rates >=88% at all classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1) at 4-digit HLA type resolution. HLA*IMP:02 is specifically designed to deal with multi-population heterogeneous reference panels and based on a new algorithm to construct haplotype graph models that takes into account haplotype estimate uncertainty, allows for missing data and enables the inclusion of prior knowledge on linkage disequilibrium. It works as well as HLA*IMP:01 on homogeneous panels and substantially outperforms it in more heterogeneous scenarios. In a cross-European validation experiment, even without setting a call threshold, HLA*IMP:02 achieves an average accuracy of 96% at 4-digit resolution (>=91% for all loci, which is achieved at HLA-DRB1). HLA*IMP:02 can accurately predict structural variation (DRB paralogs), can (to an extent) detect errors in the reference panel and is highly tolerant of missing data. I demonstrate that a good match between imputation and reference panels in terms of principal components and reference panel size are essential determinants of high imputation accuracy under HLA*IMP:02.
50
Ciarlariello, Paul David. "IFN-Gamma-Mediated Immunoevasive Strategies in Multiple Myeloma." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460656019.
Full text