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Marcadores genéticos e auto-imunes do diabetes melito tipo 1: da teoria para a prática; Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice

SILVA, Maria Elizabeth Rossi da; MORY, Denise; DAVINI, Elaine
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica
Português
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O diabetes melito tipo 1 auto-imune (DM1A) resulta da destruição auto-imune seletiva das células-beta pancreáticas produtoras de insulina. O principal determinante genético de suscetibilidade para o DM1A está em genes do complexo principal de histocompatibilidade, no cromossomo 6p211.3 (locus IDDM1), responsável por 40% ou mais da agregação familiar dessa doença. O maior risco é conferido pelo genótipo do antígeno leucocitário humano HLA-DR3-DQA1* 0501-DQB1*0201/DR4-DQA1*0301-QB1*0302, e o haplótipo HLA-DR15-DQA1* 0102-DQB1*0602 é associado à proteção. Três outros loci relacionados à predisposição a DM1A são o número variável de freqüências repetidas (VNTR) do gene da insulina (IDDM2), que confere 10% da suscetibilidade genética, o antígeno-4 associado ao linfócito T citotóxico (CTLA-4) e o protein tyrosine phosphatasis nonreceptor-type 22 (PTPN22). Muitos outros genes suspeitos de predispor à auto-imunidade estão sendo investigados. O DM1A é freqüentemente associado com doença auto-imune tiroidiana, doença celíaca, doença de Addison e várias outras doenças auto-imunes, caracterizadas por auto-anticorpos órgãos-específicos, relacionados aos mesmos determinantes genéticos. Esses anticorpos são úteis na detecção de auto-imunidade órgão-específica antes do aparecimento da doença clínica...

Primary immunodeficiencies unravel critical aspects of the pathophysiology of autoimmunity and of the genetics of autoimmune disease

COUTINHO, Antonio; CARNEIRO-SAMPAIO, Magda
Fonte: SPRINGER/PLENUM PUBLISHERS Publicador: SPRINGER/PLENUM PUBLISHERS
Tipo: Artigo de Revista Científica
Português
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Background Primary Immunodeficiencies (PIDs) represent unique opportunities to understand the operation of the human immune system. Accordingly, PIDs associated with autoimmune manifestations provide insights into the pathophysiology of autoimmunity as well as into the genetics of autoimmune diseases (AID). Epidemiological data show that there are PIDs systematically associated with AID, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), Omenn syndrome, autoinunune polyendocrinopathy-candidiasis-ectodertnal dystrophy (APECED), autoinumine lymphoproliferative syndrome (ALPS), and C1q deficiency, while strong associations are seen with a handful of other deficits. Conclusion We interpret such stringent disease associations, together with a wealth of observations in experimental systems, as indicating first of all that natural tolerance to body components is an active, dominant process involving many of the components that ensure responsiveness, rather than, as previously believed, the result of the mere purge of autoreactivities. More precisely, it seems that deficits of Treg cell development, functions, numbers, and T cell receptor repertoire are among the main factors for autoimmunity pathogenesis in many (if not all) PIDs most frequently presenting with autoimmune features. Clearly...

Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: A link to autoimmunity?

GENRE, J.; ERRANTE, P. R.; KOKRON, C. M.; TOLEDO-BARROS, M.; CAMARA, N. O. S.; RIZZO, L. V.
Fonte: ACADEMIC PRESS INC ELSEVIER SCIENCE Publicador: ACADEMIC PRESS INC ELSEVIER SCIENCE
Tipo: Artigo de Revista Científica
Português
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Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease characterized by defective immunoglobulin production and often associated with autoimmunity. We used flow cytometry to analyze CD4(+)CD25(HIGH)FOXP3(+) T regulatory (Treg) cells and ask whether perturbations in their frequency in peripheral blood could underlie the high incidence of autoimmune disorders in CVID patients. In this study, we report for the first time that CVID patients with autoimmune disease have a significantly reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells in their peripheral blood accompanied by a decreased intensity of FOXP3 expression. Notably, although CVID patients in whom autoimmunity was not diagnosed had a reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells, FOXP3 expression levels did not differ from those in healthy controls. In conclusion, these data suggest compromised homeostasis of CD4(+)CD25(HIGH)FOXP3(+) cells in a subset of CVID patients with autoimmunity, and may implicate Treg cells in pathological mechanisms of CVID. (C) 2009 Elsevier Inc. All rights reserved.; The Foundation for Support of Research in the State of Sao Paulo (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP)[04/15887-1]; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); The Foundation for Support of Research in the State of Sao Paulo (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP)[07/07139-3]; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); The National Council for Scientific and Technologic Development (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico -CNPq); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); The Brazilian Ministry of Science and Technology (MCT); Ministério da Ciência...

Aterosclerose na artrite reumatóide e sua associação com auto-imunidade humoral; Atherosclerosis in rheumatoid arthritis and its relationship with humoral autoimmunity

Pereira, Ivânio Alves
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 28/02/2007 Português
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Objetivos: Muitas questões permanecem sobre as causas da aterosclerose acelerada nos pacientes com doenças inflamatórias sistêmicas como a artrite reumatóide (AR). Estudos na população geral sugeriram que além da inflamação existe uma participação patogênica da auto-imunidade na aterosclerose e discutem a possível associação dos anticorpos contra fosfolípides e proteínas de choque térmico (Hsp). O objetivo deste estudo foi investigar a presença de anticorpos contra fosfolípides, beta2-glicoproteína 1 (beta2-gp1), lipoproteína lipase (LPL) e Hsp em pacientes com AR e avaliar a associação entre estes anticorpos com a presença de aterosclerose subclínica de carótidas. Métodos: Anticorpos contra cardiolipina (aCL) IgG e IgM, beta2-gp1 IgG, IgM e IgA , Hsp 60 e Hsp 65 foram testados por ELISA em um grupo de 71 pacientes com AR comparado com 53 indívíduos controles não portadores de AR, de idade e sexo similar. Foram excluídos os pacientes com HAS, diabetes melitos e os fumantes em ambos os grupos. Níveis de lipoproteínas, parâmetros clínicos da AR, questionário de avaliação de saúde (HAQ), escore de atividade da doença (DAS) 28, velocidade de hemossedimentação (VHS) e proteína C reativa (PCR) foram avaliadas. A associação entre a presença dos anticorpos aCL...

Imunorregulação central e periférica em pacientes com Síndrome de Down e autoimunidade; Central and peripheral immunoregulation in patients with Down syndrome and autoimmunity

Ribeiro, Luciana Maria de Andrade
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 24/11/2011 Português
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Introdução: A Síndrome de Down (SD) é uma doença genética de alta prevalência, com várias alterações imunológicas decorrentes da disfunção tímica associada à doença. Neste estudo, avaliou-se a associação entre presença de autoimunidade e disfunção do timo em pacientes com SD. Métodos: Foram avaliados 22 pacientes com SD (11 com autoimunidade e 11 sem), que preenchiam os critérios de inclusão: diagnóstico clinico e genético, idade > a 10 anos e sem uso de drogas imunossupressoras. Estes pacientes foram comparados a um grupo controle formado por adolescentes saudáveis (n=11) e outro de pacientes com doenças autoimunes, caracterizados por manifestações clínicas e presença de autoanticorpos (n=11). Todos os grupos foram pareados por idade e sexo. Os parâmetros laboratoriais avaliados foram: número de leucócitos, linfócitos CD3+, CD4+, CD8+, CD19+, CD21+, CD4+CD28null , células T reguladoras (CD4+CD25+Foxp3+), linfócitos T naive (CD4+CD45RA+CD62L+) e linfócitos T de memória (CD4+CD45RO+CD62L- ) e célula NK (CD3-CD16+, CD56+) por citometria de fluxo, Foi também avaliada a concentração de sjTREC (T receptor excision circles) em sangue total por qRT-PCR .Resultados: Nos pacientes com SD, observou-se redução das concentrações séricas de sjTREC...

Autoimunidade em trabalhadores expostos à sílica; Autoimmunity in silica-exposed workers

Michelle Corrêa da Rocha
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 26/01/2012 Português
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A sílica cristalina, ou quartzo, é um mineral abundante na areia, rochas e solo, cuja exposição crônica predispõe a lesões pulmonares, proliferação de fibroblastos e produção excessiva de colágeno no pulmão causando silicose, uma forma de fibrose pulmonar. A exposição ocupacional à sílica cristalina também tem sido considerada um fator predisponente a doenças autoimunes como artrite reumatóide, esclerodermia e lúpus eritematoso sistêmico. Neste sentido, a sílica tem mostrado agir como adjuvante, aumentando os níveis de imunocomplexos e imunoglobulinas de forma inespecífica, podendo estar relacionado ao desenvolvimento de doença autoimune. Porém, a relação entre exposição à sílica e o desenvolvimento de autoimunidade não está clara devido à falta de conhecimento dos mecanismos envolvidos. Não se sabe se a silicose constitui apenas um marcador de exposição a altos níveis de sílica em pó ou se é uma patologia que pode predispor à doença autoimune. Assim, uma investigação mais acurada de indicadores de autoimunidade em indivíduos com silicose é necessária. Nossos resultados apresentam evidências de alterações compatíveis com autoimunidade nos indivíduos expostos à sílica comparado com a população controle ao demonstrar ativação da resposta imune humoral e celular...

Thyroid function, autoimmunity and nodules in hematological malignancies

Mondello,Patrizia; Sindoni,Alessandro; Pitini,Vincenzo; Scisca,Claudio; Altavilla,Giuseppe; Benvenga,Salvatore
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2015 Português
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Objective Hematological malignancies encompass a large spectrum of disease entities whose treatment by chemo/radiotherapy could lead to thyroid complications. To the best of our knowledge, no study has simultaneously addressed thyroid function, autoimmunity and nodularity. Therefore, we decided to conduct one.Materials and methods We evaluated 82 Caucasian patients (36 women and 46 men), who were treated at our Oncology division for hematological malignancies (multiple myeloma, chronic myeloid leukemia, chronic lymphatic leukemia, non-Hodgkin lymphoma and polycythemia vera) and compared them with a control group of 104 patients. Patients who had received or were receiving external head/neck radiotherapy were excluded. All oncological patients and control individuals underwent thyroid ultrasonography and thyroid function and autoimmunity tests.Results A lower prevalence of enlarged thyroid and nodules were found in patients with respect to controls. The rate of thyroid nodules was the highest in multiple myeloma and polycythemia vera, and the lowest in chronic lymphatic leukemia. Non-Hodgkin lymphoma patients had the smallest thyroid nodules while men with multiple myeloma the biggest ones. No patient had hypothyroidism, while 5.6% of patients had subclinical hyperthyroidism. In contrast...

Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Vaarala, Outi; ; Knip, Mikael; Koski, K
Fonte: AAI Publicador: AAI
Tipo: Artigo de Revista Científica
Português
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Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions.

Adaptive Autoimmunity and Foxp3-Based Immunoregulation in Zebrafish

Iglesias, Antonio H.; Farez, Mauricio F.; Caccamo, Mario; Burns, Evan J.; Kassam, Nasim; Quintana, Francisco Javier; Oukka, Mohamed; Weiner, Howard Lee
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Background: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3+ regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage. Methods/Principal Findings: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos. Conclusions/Significance: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity.

Developing connections amongst key cytokines and dysregulated germinal centers in autoimmunity

Sweet, Rebecca A; Lee, Sau K; Vinuesa, Carola G
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica Formato: 7 pages
Português
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Systemic autoimmunity owing to overactivity of Tfh and dysregulated germinal centers has been described in mice and humans. Cytokines such as IL-21, IFN-γ, IL-6 and IL-17 are elevated in the plasma of mouse models of lupus, arthritis, and multiple sclerosis, and in subsets of patients with autoimmune disease. Monoclonal antibodies targeting these cytokines are entering clinical trials. While these cytokines exert pleiotropic effects on immune cells and organs, it is becoming clear that each and all of them can profoundly regulate Tfh numbers and/or function and induce or maintain the aberrant germinal center reactions that lead to pathogenic autoantibody formation. Here we review recent discoveries into the roles of IL-21, IFN-γ, IL-6, and IL-17 in germinal center responses and antibody-driven autoimmunity. These new insights used in conjunction with biomarkers of an overactive Tfh pathway may help stratify patients to rationalize the use of emerging monoclonal anti-cytokine antibody therapies.; R.A.S. is a Sir Keith Murdoch Fellow of the American Australian Association. C.G.V. is supported by an Elizabeth Blackburn NHMRC Fellowship. The Vinuesa Lab is supported by NHMRC program and project grants.

Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes

Honeyman, B.; Coulson, B.; Stone, N.; Gellert, S.; Goldwater, P.; Steele, C.; Couper, J.; Tait, B.; Coleman, P.; Harrison, L.
Fonte: Amer Diabetes Assoc Publicador: Amer Diabetes Assoc
Tipo: Artigo de Revista Científica
Publicado em //2000 Português
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Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.

Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes

Penno, M.; Couper, J.; Craig, M.; Colman, P.; Rawlinson, W.; Cotterill, A.; Jones, T.; Harrison, L.; Baghurst, P.; Barry, S.; Cameron, F.; Dodd, J.; Duran, C.; Forbes, J.; Makrides, M.; Morahan, G.; Nelson, K.; Nankervis, A.; Sinnott, R.; Wentworth, J.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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BACKGROUND The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. METHODS/DESIGN ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome...

Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22)

Chew, G.; Sinha, U.; Gatenby, P.; Demalmanche, T.; Adelstein, S.; Garsia, R.; Hissaria, P.; French, M.; Wilson, A.; Whittle, B.; Kirkpatrick, P.; Riminton, D.; Fulcher, D.; Cook, M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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BACKGROUND: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. OBJECTIVE: We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. METHODS: We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. RESULTS: C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity...

Die Regulationsdynamik auf Niveau der T-Zell-Signaltransduktion bei Multipler Sklerose als ein möglicher Mechanismus der Entstehung von Autoimmunität; The regulatory dynamic of the T-cell signalling transduction in multiple sclerosis implicates a possible mechanism of autoimmunity

Renninger, Markus Bruno
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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In der Immunmodulation der T-Zelle spielen die Moleküle der T-Zell- Signaltransduktion eine zentrale Rolle. Kommt es zu quantitativen oder qualitativen Störungen auf diesem Niveau kann dies die Entstehung von Autoimmunität begünstigen. Diesbezüglich wurden hier mittels rt-PCR-Analysen und interspezifischem Primerdesign die Genexpression von frühen, zentralen Komponenten der T-Zell-Signaltransduktion untersucht. Die mRNAExpressionsniveaus von LAT, Nck, Grb2, Crk und c-Cbl wurden in CD4+ TLymphozyten von Patienten, welche an Multipler Sklerose erkrankten (n=10) waren, mit denen einer gesunden Kontrollgruppe (n=10) vor und nach Stimulation verglichen. Im Vergleich beider Gruppen ergaben sich, mit Ausnahme von c-Cbl, eine durchschnittlich ähnliche basale Genexpression der Signaltransduktionsmoleküle. Im Falle von c-Cbl ließ sich eine auffallend geringere Expression dieses Moleküls in der Gruppe der MS-Patienten beobachten. Nach Stimulation zeigten die vergleichende Genexpressionsanalyse der Signaltransduktionsmoleküle in den PBMCs der MS-Patienten eine geringere Hochbzw. eine Runterregulation, worin sich ein mögliches Stadium der Anergie in den untersuchten Zellpopulationen zwischen den Schüben einer MS ableiten lassen kann. Bei der Untersuchung der Regulationsdynamik im Einzelnen zeigte LAT die stärkste Hochregulation...

Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22)

Chew, Gary Y J; Sinha, Umang; Gatenby, Paul A; DeMalmanche, Theo; Adelstein, Stephen; Garsia, Roger; Hissaria, Pravin; French, Martyn A; Wilson, Anastasia; Whittle, Belinda; Kikpatrick, Philippa; Riminton, D Sean; Fulcher, David A; Cook, Matthew C
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica Formato: 7 pages
Português
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Background The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. Objective We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. Methods We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. Results C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity...

Autoimmunity in Chagas' heart disease

Cunha-Neto,Edécio; Kalil,Jorge
Fonte: Associação Paulista de Medicina - APM Publicador: Associação Paulista de Medicina - APM
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/04/1995 Português
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The time scale dissociation between high parasitemia and tissue pathology, allied to the absence of parasites in the heart lesions of chronic Chagas' disease cardiopathy, casted doubt on the direct participation of Trypanosoma cruzi in tissue lesions. Moreover, the heart tissue lesions in chronic Chagas' disease cardiopathy are associated to an inflammatory mononuclear cell infiltrate, presumably the ultimate effectors of tissue damage. It has been hypothesized that the inflammatory cell infiltrate could mediate a delayed hypersensitivity process directed to the heart tissue components, an autoimmune response triggered by immunological cross-reactivity in the course of a protective immune response against some T.cruzi antigen homologous to heart proteins. However, little is known about the efector role of the T cells in the infiltrate, or about the nature of the antigen that lead to their accumulation in tissue. In this paper, we will review the published evidence on autoimmunity and immunological cross-reactivity between T. cruzi and the mammalian host, along with data generated in our laboratory. The definition of the precise role played by autoimmunity in the pathogenesis of Chagas' disease cardiopathy may have important consequences both for immunoprophylaxis and for the therapeutic approach of chronic Chagas' disease.

Prevalência de insuficiência de vitamina D em pacientes com tireoidite de Hashimoto e sua relação com autoimunidade tireoideana = Prevalence of vitamin D insufficiency in patients with Hashimoto's thyroiditis and its relationship with thyroid autoimmunity; Prevalence of vitamin D insufficiency in patients with Hashimoto's thyroiditis and its relationship with thyroid autoimmunity

Ilka Mara Borges Botelho
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/08/2014 Português
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Introdução: Vitamina D tem sido apontada como importante regulador da resposta imune. Estudos tem demonstrado haver relação entre insuficiência de vitamina D e presença de doenças autoimunes como Tireoidite de Hashimoto (TH). É possível que o processo autoimune na TH seja inibido em diferentes estágios pela vitamina D em sua forma ativa. Nossos objetivos foram estudar a prevalência de insuficiência de vitamina D e a relação de suas concentrações séricas com marcadores de função e autoimunidade tireoideana. Material e Métodos: Amostras de sangue foram coletadas de 54 pacientes com TH e 54 indivíduos saudáveis sem diagnóstico de TH com idade entre 18 e 75 anos. Foram realizadas dosagens séricas de vitamina D (25OHD), TSH, T4 livre, cálcio, fósforo, paratormônio (PTH), anticorpos anti-tireoperoxidase (AcTPO), anti-tireoglobulina (AcTG) e anti-receptor de TSH (TRAb). Volume tireoideano foi estimado por ultrassonografia. Foram coletados dados demográficos, de peso, altura, índice de massa corporal (IMC) e tempo de diagnóstico. Pacientes e indivíduos do grupo de controle foram pareados por idade e sexo. O nível de significância estatística adotado foi 5%. Resultados: Prevalência de insuficiência de vitamina D foi encontrada em 68.5% dos pacientes e em 38.9% dos indivíduos do grupo de controle (p =0...

The Gatekeeper of TCR Signaling: LAT in T cell Homeostasis and Autoimmunity

O'Brien, Sarah A
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2015 Português
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Linker for Activation of T cells, LAT, is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals that modulate T cell development, activation, and proliferation. Upon engagement of the T cell receptor, LAT is phosphorylated and associates with Grb2, Gads, and PLCγ1 through its four distal tyrosine residues. Mutation of tyrosine 136 abolishes LAT binding to PLCγ1. This results in impaired TCR-mediated calcium mobilization and Erk activation. LATY136F knock-in mice have a severe but incomplete block in T cell development. Yet, CD4+ αβ T cells undergo uncontrolled expansion in the periphery, resulting in a severe autoimmune syndrome characterized by Th2 skewing and resultant B cell autoreactivity. Here, we further studied the role of LAT-PLCγ1 signaling in T cell lineage commitment, cytokine production, and autoimmunity.

First, we investigated the importance of the LAT-PLCγ1 interaction in γδ T cells by crossing LATY136F mice with TCRβ-deficient mice. Our data showed that the LATY136F mutation had no major effect on the homeostasis of epithelial γδ T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4+ γδ T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL4...

Analysis of TCR Signaling and Erk Activation in T Cell Development and Autoimmunity

Fuller, Deirdre Marie
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2012 Português
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LAT is a transmembrane adaptor protein that is critical for the emanation of signals downstream of the TCR. Following TCR engagement, LAT is phosphorylated on multiple tyrosine residues, allowing it to serve as a scaffold for a multi-protein signaling complex. Mutation of tyrosine 136 on LAT abrogates binding of PLC-γ1. The disruption of this interaction has severe consequences on TCR-mediated calcium signaling and MAPK activation. Mice harboring a mutation at this tyrosine, LATY136F (LATm/m) mice, have drastically impaired thymocyte development; however, CD4+ T cells in the periphery rapidly expand and instigate a fatal lymphoproliferative syndrome. In order to bypass the severe developmental defects exhibited in LATm/m mice, our laboratory previously developed a conditional knock-in mouse line in which the mutated LAT allele is expressed in mature T cells following deletion of a floxed wildtype LAT allele (ERCre+LATf/m mice). LATf/m mice develop a similar lymphoproliferative syndrome as LATm/m mice. We used both of these mouse models to analyze the contribution of two other proteins that are essential for TCR-mediated signaling...

Genetic lesions in thymic T cell clonal deletion and thresholds for autoimmunity

Liston, Adrian; Goodnow, Christopher
Fonte: John Wiley & Sons Inc Publicador: John Wiley & Sons Inc
Tipo: Parte de Livro
Português
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The cause of common polygenic autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. We have investigated the mechanisms of two genetic causes of organ-specific autoimmunity by tracking the fate of high