Thesis (Ph. D.)--University of Missouri--Columbia, 1999. / "May 1999." Typescript. Vita. Includes bibliographical references (leaves 199-250). Also available on the Internet.

Abstract Successful pregnancy is characterized by a shift toward Th2 type immune response and suppression of adaptive immune responses to ensure acceptance of the semi-allogenic fetal graft. Also the innate immune system plays a major role during pregnancy. Recurrent miscarriage is defined as three or more consecutive pregnancy losses. About 1% of all women will suffer recurrent miscarriage. The causes of recurrent miscarriage remain unexplained in half (50%) of the cases. Susceptibility to recurrent miscarriage is probably mediated by Th1 type immune response with pronounced expression and secretion of pro-inflammatory cytokines (e.g. TNFα and IFNγ) paralleled with decreased production of anti-inflammatory cytokines (e.g. IL-10). Factors that regulate immune response during pregnancy include hormonal factors (e.g. hCG and progesterone). Immunogenetic factors also contribute to this regulation. Several functionally important polymorphisms in various immunomodulatory genes have been identified during recent years. Some of these polymorphisms may be important in regulating the Th1/Th2 balance during pregnancy. Putative immune dysregulation caused by these polymorphisms has been researched intensively. Conflicting results have been published about associations between several of these polymorphisms and recurrent miscarriage. In this study, HLA-G (exon 2 and 3), IL-10 (-1082A/G), IL-1RA (intron 2 VNTR) and CD14 (-159C/T) polymorphisms were studied in 38 Finnish women with RM. All of these polymorphisms have been associated with altered gene expression. Distribution of HLA-G*I, II, III and IV were 0.577, 0.375, 0 and 0.048 respectively in the studied Finnish population. According to the present classification the G*I allele group mostly consists of the allele 010101, while G*II covers the combination of 010102, 010401 and 0105N, as well as some other rare alleles. There were no associations between recurrent miscarriage and the HLA-G, IL-10 and CD14 polymorphisms. However, in IL-1RA polymorphism, the rare IL1RN*3 allele was increased in women with recurrent miscarriage. It is not known, if this particular allele is associated with differences in IL-1RA or IL-1 production. Although the study population was small, it may be supposed that quantitative differences in the production of single immunomodulatory molecules due to normal genetic variation may not be grossly harmful to the fetal allograft. This indicates the robustness and flexibility of the reproduction system. For survival, it is essential that minor variations are tolerated. Thus, large-scale studies focusing on the effect of a pro-inflammatory genetic profile based on the presence of several pro/anti-inflammatory genetic markers are needed to discover if immunogenetic factors predispose women to recurrent miscarriage.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 4 uppsatser.

As doenças virais têm sido importantes causas de morbidade e mortalidade nas últimas décadas, sendo que algumas delas são relacionadas com polimorfismos genéticos, que determinam a susceptibilidade do hospedeiro ou a resistência a essas infecções, influenciando na patogênese, além de desempenhar importante papel em respostas ao tratamento. Entre elas, destaca-se o HTLV-1, sendo que cerca de 10 a 20 milhões de pessoas em todo o mundo possuem esse vírus. Apenas 5% dos indivíduos infectados desenvolverão algum tipo de doença relacionada a tal infecção, entre elas destaca-se a HAM/TSP. Apesar da complexidade, o entendimento das interações hospedeiro versus HTLV-1 é de fundamental importância para avaliar prognóstico clínico dos portadores assintomáticos, visto que as opções diagnósticas e de tratamento não são adequadas, até o momento, para determinar o risco de progressão para HAM/TSP. Com isso, este trabalho objetivou estudar a associação entre alguns marcadores virais, genéticos e imunológicos relacionados ao desenvolvimento de HAM/TSPem pacientes infectados por HTLV-1. O ambulatório de HTLV do Instituto de Infectologia \"Emilio Ribas\" (IIER) possui uma coorte de portadores de HTLV em seguimento há 19 anos, para o presente estudo foram selecionados 247 voluntários portadores de HTLV-1, por conveniência. Somente pacientes adultos, com seguimento ativo no ambulatório no período de junho de 2011 até julho de 2016 foram convidados a participar. Este protocolo foi aprovado pelo CEP do IIER (Nº13/2011), e o TCLE foi obtido de todos os voluntários participantes. Os indivíduos foram classificados de acordo com seu quadro clínico neurológico em dois grupos: Grupo I (160 assintomáticos) e Grupo II (87 HAM/TSP). Amostra de sangue venoso foi coletada e as células mononucleares separadas. O material foi utilizado para o ensaio de PVL e para a genotipagem de IFN-?4, HLA-C e KIR, pela técnica de qPCR . A análise estatística no modelo multivariado mostrou associação de risco para HAM/TSP com as variáveis LPA (p=0,001) e a idade (p=0,019), além disso, o polimorfismo doIFN-?4 no rs8099917 foi associado no modelo recessivo(OR=0,31, IC=0,105 - 0,961) como fator de proteção ao desfecho.:Esse modelo estudado explica 8% dos fatores de progressão e de proteção para HAM/TSP. Desse modo, estudos genéticos multicêntricos envolvendo análise de exoma e maior número de casos de HAM/TSP, deveriam ser realizados. O entendimento da patogênese da mielopatia pode oferecer marcadores de valor prognóstico importantes para o manejo clínico, além de contribuir para o achado de novas intervenções terapêuticas no futuro. / The viral diseases have been major causes of morbidity and mortality in recent decades, some of which are related to genetic polymorphisms, which determine the susceptibility or resistance to these infections, influencing the pathogenesis, besides of playing an important role in responses to treatment. Among them, it is highlighted HTLV-1, in which around 10 to 20 million people worldwide. Only 5% of infected subjects will develop some kind of disease related to such infection, including HAM/TSP. Despite the complexity, the understanding of host interactions versus HTLV-1 is fundamental importance to evaluate clinical prognosis of asymptomatic subjects, once the diagnostic options and treatment are not adequate, so far, to determine the risk of progression to HAM/TSP. Therefore, the purpose of this study was to investigate the association among some genetic polymorphisms, viral and immunological markers related to the development of HAM/TSP in HTLV-1-infected subjects. At the Institute of Infectious Diseases \"Emilio Ribas\" (IIER) has a cohort of HTLV subjects followed up for 19 years, for this study 247 volunteers with HTLV-1were selected for convenience. Only adult patients with active follow up in the period from June 2011 to July 2016 were invited to participate. This protocol was approved by the ethical committee at IIER (nº13/2011), informed consent was obtained. Subjects were classified according to their neurological status in two groups: Group I (160 asymptomatic) and Group II (87 HAM / TSP). Blood sample was collected and PBMCs The DNA was used to the PVL assay and IFN-?4, HLA-C and KIR genotyping using qPCR. It has been observed an association to HAM/TSP with LPA variables (p=0.001) and age (p=0.019) in the multivariable analysis. On the other hand, the polymorphism of IFN-?4 rs8099917 was associated in the recessive model (OR=0.31, CI=0.105-0.961) as a protective factor to HAM/TSP. This study explains 8% of progression and protective factors for HAM/TSP. Thus, multi-center studies involving genetic analysis and more cases of HAM/TSP, should be done. The understanding of the HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management and contribute to the discovery of new therapeutic interventions in the future.

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 imunossupressão / INTRODUCTION: 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

Introdução e Objetivos: A maior prevalência de doença celíaca (DC) em indivíduos com diabetes mellitus tipo I (DM1) já é reconhecida. Ambas as doenças tem causa autoimune, em que os genes HLA classe 2 representam o principal fator genético de risco. Porém, existe uma considerável parcela da população que não manifesta tais doenças e são portadores desses genes. Estudo de associação genômica (GWAS) identificaram polimorfismos de susceptibilidade às duas doenças em genes diferentes do sistema HLA, que poderão auxiliar na compreensão da causa e das suas variabilidades clínicas. Os objetivos desse estudo foram avaliar as frequências dos polimorfismos HLA e não HLA em pessoas como DM1 e com DC e relacionar esses dados com a ocorrência de sintomas gastrointestinais, com a idade do diagnóstico da DM1 e com história alimentar. Métodos: Delineamento transversal, com avaliações retrospectivas e prospectivas, em pessoas com DM1 com e sem DC. Foram realizadas entrevista e revisão de prontuário dos pessoas, seguido de coleta de sangue ou saliva. A pesquisa dos genes RGS1, IL2-IL21, BACH2, TLR7/TLR8 e IL18RAP foi realizada por PCR Real-Time. Os alelos DQA1* 0501 e DQB1* 0201 para DQ2.5 e o alelo DQB1*0302 para DQ8 foram identificados a partir da técnica de genotipagem de HLA Tag-single-nuleotide polymorphism (Tag SNP). Resultados: As frequências alélicas e genotípicas entre 273 pessoas com DM1 sem DC e 39 pessoas com DM1 e DC não apresentaram diferença significativa. A presença de sintoma gastrointestinal foi mais frequente nos portadores dos polimorfismos dos genes RGS1 e IL18RAP. O tempo de aleitamento materno, a idade de introdução do glúten e a idade do diagnóstico da DM1 foram semelhantes entre os grupos. A comparação dos cinco polimorfismos com a combinação dos haplótipos para DQ2.5 e DQ8 não apresentou diferença significativa. Nos 312 indivíduos, com DM1 com e sem DC e nos 66 indivíduos portadores de DC sem DM1 foi identificado alelos DQ2.5 e ou DQ8 em 97% dos casos, enquanto que nos indivíduos com DC sem DM1 identificou-se em 76% dos casos. DQ2.5 foi mais frequente entre pessoascom DC e DQ8 foi mais frequentes entre pessoas com DM1. Conclusões: A presença dos polimorfismos dos genes estudados não modificou a chance do indivíduo com DM1 ter ou não DC. Houve associação dos genes RGS1 e IL18RAP com sintomas gastrointestinais. A pesquisa dos alelos DQ2.5 e DQ8, pela técnica Tag-SNP, permitiu determinar um alto valor preditivo negativo no diagnóstico de DC na população com DM1 e com DC, semelhante ao descrito na literatura com a técnica convencional. / Introduction and Objectives: The higher prevalence of celiac disease (CD) in individuals with diabetes mellitus type I (T1D) is already recognized. Both diseases have autoimmune cause, where HLA genes class 2 represent the major genetic risk factor. However, there is a considerable portion of the population that does not manifest such diseases and are carriers of these genes. Genome-wide association studies (GWAS) have identified susceptibility polymorphisms to both diseases in different genes of the HLA system that may assist in understanding the etiology and in its clinical variabilities. The objectives of this study were to evaluate the frequencies of HLA and non-HLA polymorphisms in patients with T1D and CD, related to the occurrence of gastrointestinal symptoms, the age of diagnosis of T1D and food history. Methods: Mixed design with retrospective and prospective evaluations in patients with T1D with and without DC. They were conducted interview and review of medical records of patients, followed by collecting blood or saliva. The search for genes RGS1, IL21-IL2, BACH2, TLR7 / TLR8 and IL18RAP was performed by Real-Time PCR. The alleles DQA1 * 0501 and DQB1 * 0201 for DQ2.5 and DQB1 * 0302 for DQ8 were identified from the Tag-single-nucleotide polymorphism (tag SNP) genotyping HLA technique Results: The allelic and genotypic frequencies between 273 T1D patients without CD and 39 patients with T1D and CD showed no significant difference. The presence of gastrointestinal symptoms were more frequent in patients with polymorphisms of genes RGS1 and IL18RAP. The duration of breastfeeding, the age of introduction of gluten and the age of diagnosis of T1D were similar between the groups. The comparison of the five polymorphisms with the combination of haplotypes for DQ2.5 and DQ8 showed no significant difference. In 312 individuals with DM1 with and without CD and 66 individuals with CD without T1D was identified alleles DQ2.5 and/or DQ8 in 97% of cases, whereas in individuals with CD without T1D was identified in 76% of cases . DQ2.5 was more frequent among patients with CD and DQ8 was more frequent among patients with T1D Conclusions: The presence of polymorphisms of genes studied did not modify the chance of T1D whether or not DC. There was an association of RGS1 and IL18RAP genes with gastrointestinal symptoms. The survey of DQ2.5 and DQ8 alleles by Tag-SNP technique allowed determining a high negative predictive value in the diagnosis of CD in the population of patients with T1D and DC, similar to that described in the literature with the conventional technique.

Xu Xuequn. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 100-125). / Abstracts in English and Chinese. / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Epstein-Barr (EBV) Virus --- p.1 / Chapter 1.1.1 --- Virus Structure and Genome Structure --- p.1 / Chapter 1.1.2 --- Virus Types --- p.2 / Chapter 1.2 --- EBV Infection and malignancies --- p.3 / Chapter 1.2.1 --- In Vitro Infection --- p.3 / Chapter 1.2.2 --- Infection in the Natural Host --- p.8 / Chapter 1.2.3 --- Malignancies Associated with EBV --- p.11 / Chapter 1.3 --- T Cell-Mediated Immune Response to EBV --- p.16 / Chapter 1.3.1 --- The Pathway of Cell-Mediated Immune Response in Viral Infection --- p.16 / Chapter 1.3.2 --- Cell-Mediated Immune Response to EBV --- p.18 / Chapter 1.3.3 --- The Feature of CTLs Response to EBV --- p.20 / Chapter 1.4 --- CTLs to EBV Relevant MalignancieśؤApplications and Challenges --- p.21 / Chapter 1.5 --- HLA Polymorphisms and Strategy of Epitope-Based CTLs Therapy --- p.24 / Chapter 1.6 --- The Effect of HLA Polymorphism on EBV-Specific CTL Epitope Choice in Southern Chinese --- p.27 / Chapter 1.7 --- ELISPOT Assay 226}0ؤ Detection of CTLs Response --- p.32 / Chapter 1.8 --- Aim of This Study --- p.37 / Chapter Chapter 2: --- Material and Methods: --- p.39 / Chapter 2.1 --- Peptides --- p.39 / Chapter 2.2 --- PBMCs Preparations --- p.43 / Chapter 2.3 --- PBMC Counting and Cells Dilution --- p.43 / Chapter 2.4 --- Elispot Assay --- p.44 / Chapter 2.5 --- Counting the Spots --- p.45 / Chapter 2.6 --- Spots Forming Cells (SFC/106) and Positive Standard --- p.46 / Chapter Chapter 3: --- Results --- p.47 / Chapter 3.1 --- Validation of ELISPOT assay methodology --- p.47 / Chapter 3.2 --- CTLs Response to Each Epitope in the Population --- p.55 / Chapter 3.2.1 --- Positive Response to A11 Restricted and Mutant Epitopes in the Population --- p.55 / Chapter 3.2.2 --- Positive Frequencies of A2 Restricted Epitopes in the Population --- p.63 / Chapter 3.2.3 --- Positive Frequencies of Other HLA Allele Restriction Peptides --- p.70 / Chapter 3.3 --- CTLs Response Frequencies Categorized by Proteins --- p.74 / Chapter 3.3.1 --- "CTLs Response to LMP1, LMP2, EBNA1 Epitopes" --- p.74 / Chapter 3.3.2 --- "CTLs Response to EBNA2, EBNA-LP Epitopes, EBNA3 Epitopes" --- p.75 / Chapter 3.3.3 --- CTLs Response to LYTIC Epitopes --- p.79 / Chapter 3.4 --- Summary --- p.80 / Chapter Chapter 4: --- Discussion --- p.82 / Chapter 4.1 --- Discussion of A11 Restricted Epitopes --- p.82 / Chapter 4.2 --- Discussion of A2 Restricted Epitopes --- p.86 / Chapter 4.3 --- Discussion of Other HLA Restricted Epitopes --- p.89 / Chapter 4.4 --- "Discussion ofLMPl, LMP2, EBNA1 Epitopes" --- p.92 / Chapter 4.5 --- "Discussion of EBNA2, EBNA3, and EBNA-LP epitopes" --- p.96 / Chapter 4.6 --- Discussion of LYTIC Epitopes --- p.96 / Chapter 4.7 --- Discussion of Summary --- p.98 / Chapter Chapter 5 --- Conclusion --- p.99 / Chapter 6 --- Reference --- p.100 / Chapter 7 --- Appendix --- p.126 / Chapter 7.1 --- "Appendix 1, raw data of Elispot assay on CTLs response to EBV relevant epitopes m Hong Kong donors" --- p.126 / Chapter 7.2 --- "Appendix 2, frequencies from highest cell number wells of the peptides (SFC/106)" --- p.126 / Chapter 7.3 --- "Appendix 3, typical Elispot assay figure " --- p.126

As doenças virais têm sido importantes causas de morbidade e mortalidade nas últimas décadas, sendo que algumas delas são relacionadas com polimorfismos genéticos, que determinam a susceptibilidade do hospedeiro ou a resistência a essas infecções, influenciando na patogênese, além de desempenhar importante papel em respostas ao tratamento. Entre elas, destaca-se o HTLV-1, sendo que cerca de 10 a 20 milhões de pessoas em todo o mundo possuem esse vírus. Apenas 5% dos indivíduos infectados desenvolverão algum tipo de doença relacionada a tal infecção, entre elas destaca-se a HAM/TSP. Apesar da complexidade, o entendimento das interações hospedeiro versus HTLV-1 é de fundamental importância para avaliar prognóstico clínico dos portadores assintomáticos, visto que as opções diagnósticas e de tratamento não são adequadas, até o momento, para determinar o risco de progressão para HAM/TSP. Com isso, este trabalho objetivou estudar a associação entre alguns marcadores virais, genéticos e imunológicos relacionados ao desenvolvimento de HAM/TSPem pacientes infectados por HTLV-1. O ambulatório de HTLV do Instituto de Infectologia \"Emilio Ribas\" (IIER) possui uma coorte de portadores de HTLV em seguimento há 19 anos, para o presente estudo foram selecionados 247 voluntários portadores de HTLV-1, por conveniência. Somente pacientes adultos, com seguimento ativo no ambulatório no período de junho de 2011 até julho de 2016 foram convidados a participar. Este protocolo foi aprovado pelo CEP do IIER (Nº13/2011), e o TCLE foi obtido de todos os voluntários participantes. Os indivíduos foram classificados de acordo com seu quadro clínico neurológico em dois grupos: Grupo I (160 assintomáticos) e Grupo II (87 HAM/TSP). Amostra de sangue venoso foi coletada e as células mononucleares separadas. O material foi utilizado para o ensaio de PVL e para a genotipagem de IFN-?4, HLA-C e KIR, pela técnica de qPCR . A análise estatística no modelo multivariado mostrou associação de risco para HAM/TSP com as variáveis LPA (p=0,001) e a idade (p=0,019), além disso, o polimorfismo doIFN-?4 no rs8099917 foi associado no modelo recessivo(OR=0,31, IC=0,105 - 0,961) como fator de proteção ao desfecho.:Esse modelo estudado explica 8% dos fatores de progressão e de proteção para HAM/TSP. Desse modo, estudos genéticos multicêntricos envolvendo análise de exoma e maior número de casos de HAM/TSP, deveriam ser realizados. O entendimento da patogênese da mielopatia pode oferecer marcadores de valor prognóstico importantes para o manejo clínico, além de contribuir para o achado de novas intervenções terapêuticas no futuro. / The viral diseases have been major causes of morbidity and mortality in recent decades, some of which are related to genetic polymorphisms, which determine the susceptibility or resistance to these infections, influencing the pathogenesis, besides of playing an important role in responses to treatment. Among them, it is highlighted HTLV-1, in which around 10 to 20 million people worldwide. Only 5% of infected subjects will develop some kind of disease related to such infection, including HAM/TSP. Despite the complexity, the understanding of host interactions versus HTLV-1 is fundamental importance to evaluate clinical prognosis of asymptomatic subjects, once the diagnostic options and treatment are not adequate, so far, to determine the risk of progression to HAM/TSP. Therefore, the purpose of this study was to investigate the association among some genetic polymorphisms, viral and immunological markers related to the development of HAM/TSP in HTLV-1-infected subjects. At the Institute of Infectious Diseases \"Emilio Ribas\" (IIER) has a cohort of HTLV subjects followed up for 19 years, for this study 247 volunteers with HTLV-1were selected for convenience. Only adult patients with active follow up in the period from June 2011 to July 2016 were invited to participate. This protocol was approved by the ethical committee at IIER (nº13/2011), informed consent was obtained. Subjects were classified according to their neurological status in two groups: Group I (160 asymptomatic) and Group II (87 HAM / TSP). Blood sample was collected and PBMCs The DNA was used to the PVL assay and IFN-?4, HLA-C and KIR genotyping using qPCR. It has been observed an association to HAM/TSP with LPA variables (p=0.001) and age (p=0.019) in the multivariable analysis. On the other hand, the polymorphism of IFN-?4 rs8099917 was associated in the recessive model (OR=0.31, CI=0.105-0.961) as a protective factor to HAM/TSP. This study explains 8% of progression and protective factors for HAM/TSP. Thus, multi-center studies involving genetic analysis and more cases of HAM/TSP, should be done. The understanding of the HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management and contribute to the discovery of new therapeutic interventions in the future.

Although early studies on HCR provided valuable information for its characterization, the functions of HCR remain unclear. / In addition, we also isolated HCR partners in keratinocyte using a yeast two-hybrid screening. Two novel HCR partners, keratin 17 and nm23-H2, were identified. Since the expression of keratin 17 in epidermis has been recognized as a hallmark of psoriatic plaques, our findings support HCR as a candidate gene for psoriasis susceptibility. We speculate that nm23-H2 is involved in endocytosis together with HCR because nm23 also participated in endocytotic pathways. / In this study, we attempted to relate the function of HCR gene to its role in the pathogenesis of psoriasis. We first examined the subcellular localization of HCR. From a series of co-localization experiments, we eventually localized HCR in early endosomes because almost completely overlapped with active Rab4 which regulates vesicle traffic from early endosomes to perinuclear recycling endosomes and to the plasma membrane indicating that HCR may regulate sorting of internalized cargo from early endosomes to the recycling endosomes or back to the cytoplasm. / Psoriasis is a common chronic skin disorder affecting approximately 1-2% of the Caucasian population. A genetic basis for psoriasis susceptibility has been determined, however, the genetic influence of psoriasis is complex. Several genetic linkage studies have been identified. PSORS1 at 6p21.3 which has been narrowed down to a few hundred kilobase intervals around the HLA-C is the most consistently observed susceptibility locus for psoriasis in both linkage analyses and genome wide scans. HCR is a candidate gene lying within the HLA region which was previously named PG8 for 'putative gene 8' and is now more commonly called HCR for 'alpha-helix coiled-coil rod homolog'. The HCR gene is highly polymorphic. SNP association analysis showed that one SNP haplotype, named HCR*WWCC (corresponding to SNPs at nucleotides 307, 325, 1723, 2327, and involving amino acids 103, 109, 575 and 776, respectively), was associated with psoriasis. Early studies showed that the protein was confined to basal keratinocytes in healthy and non-lesional skin, whereas, it was expressed above the tips of basal and suprabasal dermal papillae in psoriatic lesional skin. / Li, Chunman. / "November 2005." / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0810. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 137-149). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / School code: 1307.

INTRODUÇÃO: O objetivo deste estudo foi avaliar prospectivamente os anticorpos anti-HLA após o transplante renal e associar estes achados com episódios de rejeição aguda, marcação por C4d e sobrevida do enxerto. MÉTODOS: Foram avaliados 926 soros de 111 pacientes no primeiro ano pós-transplante ou até a perda do enxerto. Os anticorpos foram analisados por PRA-ELISA (Panel Reactive Antibodies by Enzyme Linked Immuno Sorbent Assay). Anticorpos anti-HLA doador-específicos foram detectados por provas-cruzadas e caracterizados pelo método de microesferas marcadas com antígenos HLA. Episódios de rejeição aguda foram classificados conforme os Critérios de Banff 97, atualizados em 2003. RESULTADOS: Conforme o PRA-ELISA pós-transplante os pacientes foram classificados em 5 Grupos: Grupo A (n=80): sem evidência de anticorpos pré e pós-transplante; Grupo B (n=8): pacientes com anticorpos de novo; Grupo C (n=5): pacientes sensibilizados que permaneceram com mesmo nível de PRA-ELISA; Grupo D (n=4): pacientes sensibilizados que elevaram o nível de PRA-ELISA e Grupo E (n=14): pacientes sensibilizados que diminuíram o nível de PRA-ELISA durante o primeiro ano pós-transplante. A incidência de rejeição aguda foi de 23,4%. Pacientes dos Grupos B, C e D apresentaram mais episódios de rejeição aguda (respectivamente, 57%; 60% e 100%) que os dos Grupos A (18%) e E (7%), (p<0,001). Rejeições ocorridas no Grupo A foram histologicamente menos severas do que as dos outros Grupos (p=0,03) e com menor incidência de C4d+ (p<0,001). Entre os pacientes com rejeição aguda, 44% deles apresentaram anticorpos no momento da rejeição, sendo que em 90% dos casos esses anticorpos foram doadorespecíficos. Rejeição mediada por células, ou seja, sem anticorpos e com C4d-, ocorreu em 56% dos casos. A incidência global de rejeição mediada por anticorpos (RMA) foi de 11%. A sobrevida do enxerto censurada para óbito foi menor em pacientes com rejeição aguda (p<0,001), especialmente naqueles com anticorpos anti-HLA doador-específicos (p<0,001), com C4d+ (p=0,003) e nos casos de RMA (p<0,003). CONCLUSÃO: Nossos dados sugerem que a monitorização dos anticorpos anti-HLA após o transplante renal pode ser útil no diagnóstico das respostas mediadas por anticorpos e tem implicações em termos de sobrevida do enxerto. / INTRODUCTION: The aim was to follow prospectively anti-HLA antibodies (Abs) after kidney transplantation and to evaluate their association with acute rejection episodes, C4d staining and graft survival. METHODS: We analyzed 926 sera from 111 transplanted patients until graft lost or during 1 year posttransplant. The antibodies were analyzed using Panel Reactive Antibodies by Enzyme Linked Immuno Sorbent Assay (PRA-ELISA). Donor-specific antibodies (DSA) were detected by crossmatch tests and characterized by single antigen beads. Acute rejections (AR) were classified by Banff 97 criteria, updated in 2003. RESULTS: According to post-transplant PRAELISA the patients were classified in 5 groups: Group A (n=80): no evidence of Abs pre and post-transplant; Group B (n=8): patients with Abs de novo; Group C (n=5): sensitized patients who sustained the same PRA-ELISA levels; Group D (n=4): sensitized patients who increased PRA-ELISA levels and Group E (n=14): sensitized patients who decreased PRA-ELISA levels during the first year. The overall incidence of acute rejection was 23,4%. Patients from Groups B, C and D had more AR (respectively, 57%; 60% and 100%) than patients from Groups A (18%) and E (7%), (p<0.001). Patients from Group A had lower Banff scores than other groups (p=0.03) and lower rates of C4d positivity on AR biopsies (p<0.001). Among patients with AR, 44% of them had antibodies which appeared/increased during the AR episodes, and 90% were DSA. AR were pure cell-mediated (C4d-/Abs-) in 56% of the cases. The overall incidence of antibody-mediated rejection (AMR) was 11%. One-year censored graft survival was lower in patients with AR (p<0.001), specially in those with DSA (p<0.001), C4d+ (p=0.003), and AMR (p<0.003). CONCLUSION: Our data suggest that monitoring of anti- HLA antibodies post-transplantation is an useful tool for the diagnosis of antibody-mediated responses, and has prognostic implications in terms of graft survival.