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1.
Brain ; 142(9): 2631-2643, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31334757

RESUMO

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

2.
Genet Med ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

3.
Genome Med ; 11(1): 38, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31203817

RESUMO

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

4.
Nat Commun ; 10(1): 2837, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253775

RESUMO

The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Análise de Sequência de RNA/métodos , Transcriptoma , Bases de Dados de Ácidos Nucleicos , Humanos , Modelos Genéticos , Análise de Componente Principal , Software , Interface Usuário-Computador
5.
Am J Hum Genet ; 101(1): 139-148, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686853

RESUMO

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.


Assuntos
Facies , Marcha/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Proteínas/genética , Convulsões/genética , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Deleção Cromossômica , Feminino , Crescimento e Desenvolvimento/genética , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação/genética , Proteínas/química , Estabilidade de RNA/genética , Convulsões/complicações , Síndrome
6.
Eur J Paediatr Neurol ; 21(2): 396-403, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27913086

RESUMO

INTRODUCTION: Early-onset epileptic encephalopathy caused by biallelic SLC13A5 mutations is characterized by seizure onset in the first days of life, refractory epilepsy and developmental delay. Little detailed information about the brain MRI features is available in these patients. METHODS: Observational study describing the neuro-imaging findings in eight patients (five families) with mutations in the SLC13A5 gene. Seven infants had an MRI in the neonatal period, two had a follow-up MRI at the age of 6 and 18 months and one only at 13 months. One patient had follow-up MRIs at 11 and 16 months and 3 and 6 years of age, but no neonatal MRI. RESULTS: All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy and term delivery. Six out of seven infants with a neonatal MRI had a characteristic MRI pattern, with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months, but led to gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. One infant had signal abnormalities in the white matter suspected of PWML on T2WI, but these could not be confirmed on other sequences. CONCLUSION: In infants presenting with therapy resistant seizures in the first days after birth, without a clear history of hypoxic-ischemic encephalopathy, but with PWML on their neonatal MRI, a diagnosis of SCL13A5 related epileptic encephalopathy should be considered.


Assuntos
Encéfalo/patologia , Espasmos Infantis/genética , Espasmos Infantis/patologia , Simportadores/genética , Substância Branca/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Mutação , Neuroimagem , Gravidez
7.
J Clin Invest ; 125(8): 3051-62, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26168268

RESUMO

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3ß, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.


Assuntos
Agenesia do Corpo Caloso , Corpo Caloso , Transtornos Mentais , Mutação de Sentido Incorreto , Proteína Fosfatase 2 , Adolescente , Adulto , Agenesia do Corpo Caloso/enzimologia , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Substituição de Aminoácidos , Criança , Pré-Escolar , Corpo Caloso/enzimologia , Corpo Caloso/patologia , Feminino , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Lactente , Masculino , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Fosforilação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
8.
Arthritis Rheumatol ; 66(2): 350-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24504807

RESUMO

OBJECTIVE: Autologous stem cell transplantation (ASCT) induces long-term drug-free disease remission in patients with juvenile idiopathic arthritis. This study was undertaken to further unravel the immunologic mechanisms underlying ASCT by using a mouse model of proteoglycan-induced arthritis (PGIA). METHODS: For initiation of PGIA, BALB/c mice received 2 intraperitoneal injections of human PG in a synthetic adjuvant on days 0 and 21. Five weeks after the first immunization, the mice were exposed to total body irradiation (7.5 Gy) and received (un)manipulated bone marrow (BM) grafts from mice with PGIA. Clinical scores, T cell reconstitution, (antigen-specific) T cell cytokine production, and intracellular cytokine expression were determined following autologous BM transplantation (ABMT). RESULTS: ABMT resulted in amelioration and stabilization of arthritis scores. BM grafts containing T cells and T cell-depleted grafts provided the same clinical benefit, with similar reductions in PG-induced T cell proliferation and the number of PG-specific autoantibodies. In vivo reexposure to PG did not exacerbate disease. Following ABMT, basal levels of disease-associated proinflammatory cytokines (interferon-γ [IFNγ], interleukin-17 [IL-17], and tumor necrosis factor α [TNFα]) were reduced. In addition, restimulation of T cells with PG induced a strong reduction in disease-associated proinflammatory cytokine production. Finally, although the remaining host T cells displayed a proinflammatory phenotype following ABMT, IFNγ, IL-17, and TNFα production by the newly reconstituted donor-derived T cells was significantly lower. CONCLUSION: Taken together, our data suggest that ABMT restores immune tolerance by renewal and modulation of the Teff cell compartment, leading to a strong reduction in proinflammatory (self antigen-specific) T cell cytokine production.


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/terapia , Tolerância Imunológica/fisiologia , Transplante de Células-Tronco , Subpopulações de Linfócitos T/patologia , Linfócitos T/patologia , Animais , Artrite Experimental/induzido quimicamente , Autoenxertos , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteoglicanas/efeitos adversos , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Ann Rheum Dis ; 71(10): 1706-15, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22562976

RESUMO

OBJECTIVES: Peptide-based immune tolerance induction is considered an attractive treatment option for autoimmune diseases. The authors have developed a novel method that can enhance the induction of protective peptide-specific T-cell responses, using a rat arthritis model. The authors focused on the Toll-like receptor 9 ligand CpG, which was shown to stimulate regulatory T-cell proliferation when added to plasmacytoid dendritic cells (pDC) using in-vitro cultures. METHODS: The peptide used is a heat shock protein 60 epitope (p1) that elicits tolerogenic peptide-specific immune responses in human arthritis patients and was recently shown to have protective capacity as a bystander antigen in the rat adjuvant arthritis model. Rats were treated with three nasal doses of p1, CpG or a combination of p1 and CpG. Antigen-presenting cells were studied in nose-draining lymph nodes (mandibular lymph nodes; MLN) after nasal treatment, and T-cell responses were analysed in joint-draining lymph nodes after arthritis induction. RESULTS: Nasal co-administration of p1/CpG significantly augmented the arthritis-protective effect of p1, while CpG treatment alone did not. Co-treatment of p1/CpG increased both the number and activation status of pDC in draining MLN, which was accompanied by amplified p1-specific T-cell proliferation and interleukin (IL)-10 production. During early arthritis, p1-specific IL-10 production was identified at the site of inflammation. P1 and p1/CpG-treated rats showed a greater amount of CD4+FoxP3+ regulatory T cells in the joint-draining lymph nodes, which correlated with lower arthritis scores. CONCLUSIONS: These clinical and immunological data suggest the use of CpG as a potent adjuvant for mucosal peptide-specific immune therapy in arthritis.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Artrite Reumatoide/imunologia , Chaperonina 60/imunologia , Oligodesoxirribonucleotídeos/imunologia , Vacinas de Subunidades/imunologia , Administração Intranasal , Animais , Artrite Experimental/imunologia , Chaperonina 60/administração & dosagem , Células Dendríticas/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Ativação Linfocitária/imunologia , Masculino , Oligodesoxirribonucleotídeos/administração & dosagem , Ratos , Ratos Endogâmicos Lew , Linfócitos T Reguladores/imunologia , Receptor Toll-Like 9/agonistas , Vacinas de Subunidades/administração & dosagem
10.
Ann Rheum Dis ; 70(12): 2199-206, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21914624

RESUMO

OBJECTIVES: Mucosal immune therapy with disease-inducing antigens is an effective way to prevent experimental arthritis, but in humans these antigens are unknown. In juvenile idiopathic arthritis, however, T cell recognition of a so-called bystander antigen, heat shock protein 60 (HSP60), is associated with a good prognosis. Recently epitopes derived from HSP60, a microbial peptide (p1) and its self-homologue (p2) were reported to induce tolerogenic T cell responses in vitro in patients with arthritis. A study was undertaken to determine whether mucosal administration of these bystander epitopes can be similarly effective in suppressing arthritis. METHODS: Rats were treated nasally with p1, p2 or phosphate-buffered saline before arthritis induction. Arthritis scores were assessed and peptide-specific proliferative responses, phenotypic analysis, cytokine production and in vitro suppressive capacity of cells were measured in lymph nodes and spleens. CD4 spleen T cells from p1- or p2-treated rats were adoptively transferred into naïve rats that were subsequently injected with complete Freund's adjuvant for arthritis induction. RESULTS: Nasal administration of p1 prevented experimental arthritis whereas treatment with the self-homologue p2 did not. Adoptive transfer of CD4 T cells protected against experimental arthritis. Treatment with p1 increased peptide-specific and self-crossreactive interferon γ (IFNγ) production. Tumour necrosis factor α (TNFα) levels were reduced at the site of inflammation. Forkhead box P3 (FoxP3) expression remained stable but the suppressive capacity of T regulatory cells in p1-treated rats was enhanced. CONCLUSION: p1 immune therapy induces a population of CD4 T cells with reduced TNFα and increased peptide-specific IFNγ production at the site of inflammation. This population expresses FoxP3 and has potent suppressive capacity which, upon transfer, protects against arthritis. The bystander epitope p1 may therefore be a suitable candidate for antigen-specific immunotherapy in arthritis.


Assuntos
Artrite Experimental/prevenção & controle , Efeito Espectador/imunologia , Chaperonina 60/uso terapêutico , Administração Intranasal , Animais , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/transplante , Chaperonina 60/administração & dosagem , Chaperonina 60/imunologia , Citocinas/biossíntese , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/uso terapêutico , Adjuvante de Freund , Imunidade nas Mucosas , Imunoterapia Adotiva/métodos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Baço/imunologia , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
11.
Ann Rheum Dis ; 70(11): 2037-43, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21859687

RESUMO

OBJECTIVE: To investigate how meningococcal C vaccination in patients with remitting (oligoarticular) or progressive (polyarticular) juvenile idiopathic arthritis (JIA) influences the specific T-cell response to both the vaccine and heat shock protein 60, a regulatory auto-antigen in JIA. METHODS: Twenty six oligoarticular, 28 polyarticular JIA patients and 20 healthy adults were studied before and after MenC vaccination in a prospective follow-up study. T-cell proliferation assay, flow cytometry, carboxyfluorescein diacetate succinimidyl ester staining and multiplex immunoassay were performed to quantify and qualify the antigen-specific immune responses. RESULTS: Peripheral blood mononuclear cells (PBMC) from polyarticular JIA exemplified higher antigen-specific CD4 T-cell proliferation, interleukin 2 (IL-2) and tumour necrosis factor alpha (TNFα) production when compared with oligoarticular JIA or healthy individuals after vaccination. Furthermore, in polyarticular JIA antigen-induced CD4+CD25(bright) or CD4+FOXP3+ T cells did not increase upon vaccination. CONCLUSION: Polyarticular JIA CD4+FOXP3+ T cells did not respond to vaccination and demonstrated a higher percentage of cells irrespective of vaccination when compared with oligoarticular JIA. These cells are either activated T cells and/or regulatory cells unable to regulate the antigen-specific immune response after vaccination. When compared with oligoarticular JIA, the increased IL-2 and TNFα production underline the immune hyperresponsiveness of polyarticular JIA PBMC to an antigenic trigger. As this may hold a risk for derailment, these findings could provide a cellular basis for the presumed relationship between environmental triggers and disease in human autoimmune diseases.


Assuntos
Artrite Juvenil/imunologia , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/sangue , Vacinas Meningocócicas/imunologia , Adolescente , Proliferação de Células , Células Cultivadas , Chaperonina 60/imunologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Interleucina-2/biossíntese , Ativação Linfocitária/imunologia , Masculino , Subpopulações de Linfócitos T/imunologia , Toxoide Tetânico/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Vacinação , Vacinas Conjugadas/imunologia
12.
Ann Rheum Dis ; 66(10): 1384-7, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17284544

RESUMO

OBJECTIVE: To assess the effect of measles, mumps and rubella (MMR) vaccination on disease activity in children with juvenile idiopathic arthritis (JIA). METHODS: A retrospective observational multicentre cohort study was performed in 314 patients with JIA, born between 1989 and 1996. Disease activity and medication use were compared during the period of 6 months before vaccination versus 6 months after vaccination. Disease activity was measured by joint counts, the Physician's global assessment scale and erythrocyte sedimentation rate. Next, we compared disease activity in patients vaccinated between 8 and 9 years of age with the activity in patients who had not been vaccinated at this time (who received MMR between the ages of 9 and 10 years). RESULTS: No increase in disease activity or medication use was seen in the 6 months after MMR vaccination (n = 207), including in patients using methotrexate (n = 49). No overt measles infections were noted. When disease activity in vaccinated patients (n = 108) was compared with activity in those not yet vaccinated (n = 86), there were no significant differences. CONCLUSIONS: The MMR booster vaccination does not seem to aggravate disease activity in JIA. This indicates that the most patients with JIA can be vaccinated safely with the MMR vaccine. A prospective study is recommended.


Assuntos
Artrite Juvenil/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Administração Oral , Adolescente , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Humanos , Metotrexato/administração & dosagem , Estudos Retrospectivos , Vacinação/efeitos adversos
13.
Arthritis Rheum ; 56(2): 639-46, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17265499

RESUMO

OBJECTIVE: To determine whether vaccinations aggravate the course of autoimmune diseases such as juvenile idiopathic arthritis (JIA) and whether the immune response to vaccinations may be hampered by immunosuppressive therapy for the underlying disease. METHODS: In this multicenter cohort study, 234 patients with JIA (ages 1-19 years) were vaccinated with meningococcal serogroup C (MenC) conjugate to protect against serogroup C disease (caused by Neisseria meningitidis). Patients were followed up for disease activity for 1 year, from 6 months before until 6 months after vaccination. IgG antibody titers against MenC polysaccharide and the tetanus carrier protein were determined by enzyme-linked immunosorbent assay and toxin binding inhibition assay, respectively. A serum bactericidal assay was performed to determine the function of the anti-MenC antibodies. RESULTS: No change in values for any of the 6 components of the core set criteria for juvenile arthritis disease activity was seen after MenC vaccination. Moreover, no increase in the frequency of disease relapse was detected. Mean anti-MenC IgG concentrations in JIA patients rose significantly within 6-12 weeks after vaccination. Of 157 patients tested, 153 were able to mount anti-MenC IgG serum levels >2 micro g/ml, including patients receiving highly immunosuppressive medication. The 4 patients with a lower anti-MenC antibody response displayed sufficient bactericidal activity despite receiving highly immunosuppressive medication. CONCLUSION: The MenC conjugate vaccine does not aggravate JIA disease activity or increase relapse frequency and results in adequate antibody levels, even in patients receiving highly immunosuppressive medication. Therefore, patients with JIA can be vaccinated safely and effectively with the MenC conjugate.


Assuntos
Artrite Juvenil/imunologia , Artrite Juvenil/fisiopatologia , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/efeitos adversos , Vacinas Meningocócicas/uso terapêutico , Adolescente , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/prevenção & controle , Atividade Bactericida do Sangue , Criança , Pré-Escolar , Feminino , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Lactente , Masculino , Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/imunologia , Países Baixos , Recidiva
14.
PLoS One ; 1: e87, 2006 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-17183718

RESUMO

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFalpha was as therapeutically effective as full dose anti-TNFalpha treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/terapia , Citocinas/antagonistas & inibidores , Epitopos de Linfócito T/imunologia , Imunoterapia/métodos , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Artrite Experimental/patologia , Autoimunidade , Sequência de Bases , Chaperonina 60/genética , Chaperonina 60/imunologia , Citocinas/genética , Citocinas/metabolismo , Primers do DNA/genética , Epitopos de Linfócito T/genética , Etanercepte , Membro Posterior/patologia , Humanos , Imunidade nas Mucosas , Imunoglobulina G/administração & dosagem , Imunoterapia Adotiva , Masculino , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Ratos , Ratos Endogâmicos Lew , Receptores do Fator de Necrose Tumoral/administração & dosagem , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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