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1.
Tissue Antigens ; 86(6): 406-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26449183

RESUMO

Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.


Assuntos
Cadeias beta de HLA-DP/genética , Hepatite B Crônica/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Povo Asiático/genética , Portador Sadio/epidemiologia , Portador Sadio/imunologia , Criança , Progressão da Doença , Feminino , Frequência do Gene , Genes MHC da Classe II , Predisposição Genética para Doença , Genótipo , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/imunologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Genes Immun ; 16(1): 54-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25373727

RESUMO

Previous studies have suggested that the human leukocyte antigen (HLA) is involved in the etiology of Crohn's disease (CD); however, few reports are available on the association between HLA class I antigens and CD in Japan. In this study, we performed association analysis of HLA class I antigens in CD using 208 Japanese patients and 384 healthy controls. We identified novel positive associations between CD and HLA-A*02:01 (odds ratio (OR)=1.64, P=0.016) and HLA-A*02:07 (OR=2.31, P=0.0067) and confirmed previously reported positive associations between CD and HLA-Cw*14:02 (OR=2.18, P=0.0021) and HLA-B*51:01 (OR=1.70, P=0.033). We also identified novel negative associations between CD and HLA-A*24:02 (OR=0.60, P=0.0047) and HLA-B*07:02 (OR=0.38, P=0.0041). Although the associations were not significant after full Bonferroni correction, we suggested that HLA class I genes have dual functions, susceptibility and resistance in controlling the development of CD.


Assuntos
Doença de Crohn/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Povo Asiático/genética , Estudos de Casos e Controles , Genes MHC Classe I , Humanos , Japão
4.
Bone Marrow Transplant ; 45(5): 846-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20348972

RESUMO

The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports.


Assuntos
Antígenos HLA , Terminologia como Assunto , Organização Mundial da Saúde , Humanos
5.
Genes Immun ; 9(4): 302-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18418398

RESUMO

T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-gamma (IFN-gamma). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating -451 to -347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-gamma/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.


Assuntos
Proteínas de Homeodomínio/genética , Proteínas com Domínio T/genética , Células Th1/imunologia , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células COS , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Sequência Consenso , Ilhas de CpG/genética , Genes Reporter , Hemaglutininas/metabolismo , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/metabolismo , Humanos , Luciferases de Renilla/metabolismo , Dados de Sequência Molecular , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas com Domínio T/metabolismo , Células Th1/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ativação Transcricional
6.
J Hum Genet ; 53(4): 314-324, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18259684

RESUMO

To systematically evaluate genetic susceptibility to type 2 diabetes (T2D) in "candidate" regions on chromosomes 1q, 3q and 12q, we examined disease association by using a total of 2,083 SNPs in two-step screening; a screening panel comprised 473 cases and 285 controls and an extended (or combined) panel involved 658 cases and 474 controls. For the total interval screened (40.9 Mb), suggestive evidence of association was provided for several annotated gene loci. For example, in the MCF2L2 gene on 3q, a significant association (a nominal P value of 0.00009) was observed when logistic regression analysis was performed for three associated SNPs (rs684846, rs35069869 and rs35368790) that belonged to different LD groups. Also, in the SLC15A4 gene on 12q, rs3765108 showed a marginally significant association with an overall estimated odds ratio of 0.79 (P=0.001). No significant association was found for known candidate gene loci on 3q, such as ADIPOQ and IGF2BP2. Using the available samples, we have observed disease associations of SNPs derived from two novel gene loci in the Japanese population through high-density searches of diabetes susceptibility in three chromosomal regions. Independent replication will clarify the etiological relevance of these genomic loci to T2D.


Assuntos
Povo Asiático/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Proteínas de Transporte/genética , Humanos , Japão , Desequilíbrio de Ligação , Escore Lod , Modelos Logísticos , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único
7.
Oncogene ; 27(26): 3729-38, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18223682

RESUMO

Antiangiogenic therapies are promising approaches to cancer control, but the details of their effects on subsequent tumor progression are not fully understood. Such therapies have the potential to eventually generate extensive amounts of tumor ischemia, and we previously demonstrated that ischemic conditions induce K-ras mutations in cells with deficient mismatch repair (MMR) mechanisms. This suggested that similar effects on oncogene mutagenesis may accompany antiangiogenic therapy. To test this, MMR-deficient colorectal cancer cells (Dks-8) were xenografted into immune-deficient mice and treated with the antiangiogenic regimen of low-dose/metronomic cyclophosphamide for 2 weeks followed by a 2-week recovery period without therapy. This treatment resulted in transient tumor growth inhibition, increased hypoxia, and decreased microvessel density, and cancer cells from treated tumors acquired activating mutations of the K-ras oncogene (K-ras(G13D)). In vitro exposure of Dks-8 cells to the active metabolite of cyclophosphamide (4-hydroxycyclophosphamide) had no effect on the K-ras status, indicating that there was no direct action of this alkylating agent on K-ras mutagenesis. In addition, cells sorted from hypoxic regions of Dks-8 tumors were enriched in K-ras(G13D) mutants. Collectively, our studies suggest that increases in tumor hypoxia induced by antiangiogenic treatment may lead to K-ras mutation and consequently tumor progression, especially in susceptible individuals.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Hipóxia Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Ciclofosfamida/uso terapêutico , Genes ras , Mutação , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Ciclofosfamida/análogos & derivados , Humanos , Camundongos , Transplante de Neoplasias , Transplante Heterólogo
8.
Tissue Antigens ; 71(2): 127-34, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18086267

RESUMO

Allele and haplotype frequencies of the human leukocyte antigens (HLA) were studied in the Kinh Vietnamese population. We analyzed 170 unrelated healthy individuals. DNA-based HLA typing was performed using a microsphere-based array genotyping platform with sequence-specific oligonucleotide probes to distinguish HLA-A, -B, -C, -DRB1 and -DQB1 alleles. A total of 21 HLA-A, 37 HLA-B, 18 HLA-C, 25 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. HLA-A*1101, A*2402, A*3303, B*1502, B*4601, Cw*0102, Cw*0702, Cw*0801, DRB1*1202, DQB1*0301, DQB1*0303, and DQB1*0501 were found with frequencies higher than 10%. Two representative haplotypes bearing two to five HLA loci were A*1101-B*1502 and A*3303-B*5801 for HLA-A-B; Cw*0801-B*1502 and Cw*0102-B*4601 for HLA-C-B; B*1502-DRB1*1202 and B*4601-DRB1*0901 for HLA-B-DRB1; DRB1*1202-DQB1*0301 and DRB1*0901-DQB1*0303 for HLA-DRB1-DQB1; A*1101-Cw*0801-B*1502 and A*3303-Cw*0302-B*5801 for HLA-A-C-B; A*1101-B*1502-DRB1*1202 and A*2901-B*0705-DRB1*1001 for HLA-A-B-DRB1, A*1101-Cw*0801-B*1502-DRB1*1202-DQB1*0301 and A*2901-Cw*1505-B*0705-DRB1*1001-DQB1*0501 for HLA-A-C-B-DRB1-DQB1. Allele distribution and haplotype analysis demonstrated that the Vietnamese population shares HLA patterns with southern Chinese, Thai, Javanese and Micronesians, while it also retains unique characteristics.


Assuntos
Povo Asiático/etnologia , Povo Asiático/genética , Antígenos HLA/genética , Alelos , Feminino , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Haplótipos , Humanos , Masculino , Vietnã/etnologia
9.
Biochem Biophys Res Commun ; 357(4): 1100-6, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17466274

RESUMO

Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4alpha (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30-2.31) (P=0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study.


Assuntos
Proteínas de Fase Aguda/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 20/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Fator 4 Nuclear de Hepatócito/genética , Glicoproteínas de Membrana/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prevalência
10.
Oncogene ; 26(14): 2071-81, 2007 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-17016440

RESUMO

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon gamma (IFNgamma) inhibits the expression of COX-2 protein in intestinal epithelial cells (IECs) through a pathway that requires Janus-activated kinase (JAK) activity. In contrast, we demonstrated that transcriptional inhibition of COX-2 by IFNbeta or IFNgamma occurs in cells with silenced signal transducer and activator of transcription 1 (STAT1) expression and that IFNs retained the ability to inhibit COX-2 transcription in cells with activated RasV12, in which IFNgamma failed to induce STAT1. Thus, unlike the activity of JAK, STAT1 is not required for the inhibition of COX-2 expression by IFNgamma. In contrast to COX-2, the activation of genes in response to IFNgamma, such as interferon regulatory factor-1, was severely impaired by both STAT1 silencing and by constitutive Ras signaling. To determine whether there is a general differential requirement for STAT1 in gene activation and gene repression in response to IFNgamma in intestinal cells, we performed genome-wide analysis of IFNgamma target genes in an IEC line in which STAT1 expression was silenced by small interfering RNA. The results confirmed that the activation of the majority of genes by IFNgamma required STAT1. In contrast, the repression of several genes, as we showed for COX-2 specifically, was largely unaffected in cells with silenced STAT1. Our results therefore demonstrate that in general gene activation by IFNgamma is more sensitive to STAT1 deficiency than gene repression, and suggest that IFNgamma activates and represses gene expression via distinct pathways that can be distinguished, at least in part, by their requirement for STAT1.


Assuntos
Ciclo-Oxigenase 2/genética , Regulação para Baixo , Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Fator de Transcrição STAT1/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Inativação Gênica , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Janus Quinases/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/genética , Ativação Transcricional
11.
Oncogene ; 25(59): 7680-90, 2006 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-16799641

RESUMO

Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro- and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachment-dependent activation of the transcription factor nuclear factor-kappaB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.


Assuntos
Anoikis , Proteínas Inibidoras de Apoptose/fisiologia , Mucosa Intestinal/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/fisiologia , Proteína 3 com Repetições IAP de Baculovírus , Células Cultivadas , Matriz Extracelular/fisiologia , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , NF-kappa B/fisiologia , Ubiquitina-Proteína Ligases , Regulação para Cima , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteína bcl-X/genética , Proteína bcl-X/fisiologia
15.
Tissue Antigens ; 64(5): 600-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15496204

RESUMO

In order to determine highly immunogenic severe acute respiratory syndrome coronavirus (SARS-CoV) epitope peptides capable of inducing long-lasting immunity, we first screened immunoglobulin-G (IgG) antibodies reactive to 197 different overlapping 15-mers from the SARS-CoV proteins in the sera of three infected patients. Forty-two peptides among them were reactive to the sera from all three patients. Consequently, we tested for the reactivity of these 42 peptides to patients' sera (n = 45) at 6-month post-infection. The significantly higher levels of IgG antibodies specific to three (S791, M207 and N161) of 42 peptides were detectable in the post-infection sera from 23 (51%), 27 (60%) and 19 (42%) of 45 patients, respectively. These three peptides, recognized by their long-lasting immunity, may provide a better understanding of the immunogenicity of SARS-CoV.


Assuntos
Sistema Imunitário/imunologia , Imunidade/imunologia , Peptídeos/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/sangue , Reologia , Soro/imunologia
16.
J Med Genet ; 41(10): 763-7, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15466010

RESUMO

BACKGROUND: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. OBJECTIVE: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients METHODS: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. RESULTS: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. CONCLUSIONS: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.


Assuntos
Histiocitose de Células não Langerhans/genética , Mutação/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Idade de Início , Análise Mutacional de DNA , Éxons/genética , Feminino , Histiocitose de Células não Langerhans/imunologia , Histiocitose de Células não Langerhans/fisiopatologia , Humanos , Lactente , Íntrons/genética , Japão , Masculino , Dados de Sequência Molecular , Linhagem
18.
Bone Marrow Transplant ; 29(7): 569-75, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11979305

RESUMO

Effects of polymorphisms in TNFA and TNFR2 on the outcome of 462 cases of unrelated bone marrow transplantation (uBMT) were studied retrospectively. Four alleles of TNFA (U01-U04) distinguished by polymorphism in the upstream region, -1031 (T/C), -863 (C/A) and -857 (C/T), and two alleles of TNFR2 (196M/196R) distinguished by polymorphism at codon 196 were determined. Transplantation involving TNFA-U02- and/or U03-positive donors and/or recipients resulted in a higher incidence of graft-versus-host disease (GVHD) of grade III-IV (P < 0.05 for donor type, P < 0.01 for recipient type) and a lower relapse rate than that involving TNFA-U01 homozygous recipients and/or donors (P < 0.025 for donor type, P < 0.01 for recipient type). These results include the HLA mismatching effect due to linkage disequilibirium of TNFA with HLA loci. However, the effects were also observed in HLA-A, -B and -DRB1 allele-matched transplantation. Transplantation from TNFR2-196R-positive donors exhibited a higher incidence of severe GVHD (P < 0.05) and tendency for a lower relapse rate than that from TNFR2-196M homozygous donors. TNFR2-196R of recipient origin had no effect on GVHD but increased the relapse rate (P < 0.025). These results suggest that TNFA and TNFR2 typings are helpful for predicting uBMT outcome and for preventing severe complications at an early stage.


Assuntos
Antígenos CD/genética , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/genética , Polimorfismo Genético , Receptores do Fator de Necrose Tumoral/genética , Transplante Homólogo , Fator de Necrose Tumoral alfa/genética , Adulto , Anemia Aplástica/terapia , Códon/genética , Feminino , Doenças Genéticas Inatas/terapia , Genótipo , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Incidência , Desequilíbrio de Ligação , Masculino , Modelos de Riscos Proporcionais , Receptores Tipo II do Fator de Necrose Tumoral , Recidiva , Estudos Retrospectivos , Resultado do Tratamento
19.
J Clin Invest ; 108(11): 1589-96, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11733554

RESUMO

Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-A(b) molecule that presents only a single peptide (E alpha 52-68) spontaneously develops peripheral nervous system-specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow-derived cells determined disease susceptibility. While the expression of the I-A(b)-E alpha 52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4(+) T cells that can be activated by the I-A(b)-E alpha 52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4(+) T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-A(b)-E alpha 52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A(b)-E alpha 52-68 complex, probably caused by incomplete negative thymocyte selection.


Assuntos
Antígenos de Superfície/imunologia , Doenças Autoimunes/etiologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Fragmentos de Peptídeos , Doenças do Sistema Nervoso Periférico/etiologia , Receptores de Antígenos de Linfócitos T , Animais , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos
20.
Bone Marrow Transplant ; 28(6): 603-7, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11607774

RESUMO

The entire protein-coding region was divided into 45 fragments, separately amplified and analyzed for polymorphism by the PCR-SSCP (single-strand conformation polymorphism) method. The effect of polymorphism mismatching on the clinical outcome of unrelated bone marrow transplantation was studied to clarify whether products from mtDNA become minor antigens. Variability in PCR-SSCP pattern combinations of the 45 fragments suggests that each individual has a different polymorphism combination in the protein-coding region if all the coding regions were compared at the nucleotide sequence level. Nonsynonymous polymorphisms were found at relatively high frequency in MTATP8 and MTND3. Both the polymorphisms with and without substitution matched the peptide-binding motifs of HLA-A*0201. The effects of the polymorphism matching were retrospectively analyzed in 340 recipients transplanted with HLA-A, -B, -DRB1 allele-matched bone marrow from unrelated donors. There were no effects of polymorphism matching on the incidence of acute GVHD and cumulative disease-free survival. These results suggest that polymorphisms which generate peptides, with and without substitutions, that bind the same HLA molecule hardly influence GVHD because the difference between the HLA-peptide complexes is minute.


Assuntos
Transplante de Medula Óssea/imunologia , DNA Mitocondrial/genética , Polimorfismo Genético , Imunologia de Transplantes/genética , Grupo dos Citocromos b/genética , Intervalo Livre de Doença , Éxons/genética , Frequência do Gene , Doença Enxerto-Hospedeiro/genética , Teste de Histocompatibilidade/métodos , Humanos , Antígenos de Histocompatibilidade Menor/genética , ATPases Mitocondriais Próton-Translocadoras/genética , NADH Desidrogenase/genética , Polimorfismo Conformacional de Fita Simples , Transplante Homólogo/imunologia , Resultado do Tratamento
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