RESUMO
OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort. METHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3. RESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002). CONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.
Assuntos
Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Enteropatias/genética , Poliendocrinopatias Autoimunes/genética , Autoanticorpos/sangue , Variação Biológica da População , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Fatores de Transcrição Forkhead/imunologia , França , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Terapia de Imunossupressão , Lactente , Recém-Nascido , Enteropatias/imunologia , Enteropatias/terapia , Nefropatias/genética , Masculino , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/terapia , Estudos Retrospectivos , Dermatopatias Genéticas/genética , Taxa de Sobrevida , SíndromeRESUMO
TTC7A mutations cause multiple neonatal intestinal atresias with early inflammatory bowel disease and severe combined immunodeficiency. There are no treatment protocols for this rare disease. Two new cases are described for which radical early treatment measures - total enterectomy, home parenteral nutrition, immunoglobulin therapy and intravenous antibiotic prophylaxis - have allowed both patients to develop optimally.
RESUMO
OBJECTIVE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-ß superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. DESIGN, SETTING AND SUBJECTS: A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. RESULTS: Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells µL(-1) vs. 832 cells µL(-1) , P < 0.001), CD8 (295 cells µL(-1) vs. 501 cells µL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells µL(-1) vs. 221 cells µL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. CONCLUSIONS: Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Hipergamaglobulinemia/etiologia , Linfopenia/etiologia , Telangiectasia Hemorrágica Hereditária/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipergamaglobulinemia/imunologia , Imunidade Inata/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/imunologia , Adulto JovemRESUMO
OBJECTIVES: The use of mesenchymal stem cells (MSC), which display immunosuppressive activity, seems to be a promising therapeutic approach in solid organ transplantation. However, little is known about their interactions with immunosuppressive drugs. The objective of this study was to assess these interactions in allogeneic responses. METHODS: We studied the effects on alloimmune responses in mixed lymphocyte reactions of MSC plus five agents-cyclosporine, tacrolimus, rapamycin, mycophenolate acid (MPA), and dexamethasone (DEX). RESULTS: Human MSC isolated from bone marrow were characterized by their phenotype and their ability to differentiate into adipocytes or osteoblastes. MSC plus the agents inhibited allogeneic lymphocyte proliferation in a dose-dependent manner. Calcineurin inhibitors and rapamycin antagonized the inhibitory effect of MSC, whereas MPA promoted it and DXM did not modify it. CONCLUSION: MPA seems to be the best immunosuppressant to associated with MSC for transplanted patients.
Assuntos
Imunossupressores/farmacologia , Células-Tronco Mesenquimais/imunologia , Transplante Homólogo/imunologia , Adipócitos/efeitos dos fármacos , Adipócitos/imunologia , Antígenos CD/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Diferenciação Celular , Ciclosporina/farmacologia , Dexametasona/farmacologia , Citometria de Fluxo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Sirolimo/farmacologiaRESUMO
Recent evidence indicates that microglial cells may not derive from blood circulating mature monocytes as they express features of myeloid progenitors. Here, we observed that a subpopulation of microglial cells expressed CD34 and B220 antigens during brain development. We thus hypothesized that microglia, or a subset of microglial cells, originate from blood circulating CD34+/B220+ myeloid progenitors, which could target the brain under developmental or neuroinflammatory conditions. Using experimental allergic encephalomyelitis (EAE) as a model of chronic neuroinflammation, we found that a discrete population of CD34+/B220+ cells expands in both blood and brain of diseased animals. In EAE mice, intravenous transfer experiments showed that macrophage-colony stimulating factor (M-CSF) -expanded CD34+ myeloid progenitors target the inflamed central nervous system (CNS) while keeping their immature phenotype. Based on these results, we then assessed whether CD34+/B220+ cells display in vitro differentiation potential toward microglia. For this purpose, CD34+/B220+ cells were sorted from M-CSF-stimulated bone marrow (BM) cultures and exposed to a glial cell conditioned medium. Under these experimental conditions, CD34+/B220+ cells were able to differentiate into microglial-like cells showing the morphological and phenotypic features of native microglia. Overall, our data suggest that under developmental or neuroinflammatory conditions, a subpopulation of microglial cells derive from CNS-invading CD34+/B220+ myeloid progenitors.
Assuntos
Encéfalo , Diferenciação Celular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Inflamação/patologia , Microglia/citologia , Animais , Animais Recém-Nascidos , Antígenos CD34 , Células da Medula Óssea , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Linhagem da Célula , Movimento Celular , Encefalomielite Autoimune Experimental/patologia , Feminino , Antígenos Comuns de Leucócito , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Autoimmune manifestations (AIM) are associated to common variable immunodeficiency (CVI) in about 20 to 25% of the cases. This study presents the clinical, biological characteristics and the evolution of nine patients developing CVI and AIM. A peripheral B-cell compartment analysis has been performed in seven cases. METHOD: This multicenter retrospective study analyses nine patients, six men and three women, within a population of 32 CVI. RESULTS: The mean age was 27 years at the time of diagnosis of AIM and 30 years at the time of diagnosis of CVI. The diagnosis of AIM preceded the diagnosis of CVI in five cases. Thirteen AIM of different types were observed: autoimmune hemolytic anemia (AHA, 3), immune thrombocytopenic purpura (ITP, 2), Evan's syndrome (2), primary biliary cirrhosis (1), rheumatoid arthritis (1), alopecia totalis (1), myasthenia gravis (1). The peripheral B-cell compartment was investigated in seven patients: five patients with autoimmune cytopenia presented with a diminution of memory B cells (CD27+IgD-) and immature B cells (CD21-) levels; the patient with primary biliary cirrhosis and myasthenia gravis had only a diminution of memory B cells level; the last patient with ITP presented with a normal level of memory B cells. Five among the seven patients with autoimmune cytopenia required a specific treatment using corticosteroids, high dosages of intravenous immunoglobulin, then splenectomy after failure of the medical management, with severe infectious complications in one case. CONCLUSION: The association of AIM and CVI is not fortuitous. The most common AIM is autoimmune cytopenia. The peripheral B-cell compartment analyses show that a majority of patients have a defect in memory B-cells. Treatment regimens are not standardized and splenectomy increases the risk of infectious complications.
Assuntos
Doenças Autoimunes/complicações , Imunodeficiência de Variável Comum/complicações , Adolescente , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Alopecia/complicações , Alopecia/imunologia , Anemia Hemolítica/complicações , Anemia Hemolítica/imunologia , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/imunologia , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Humanos , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/imunologia , Imunoglobulina M , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Imunofenotipagem , Lactente , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/imunologia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/imunologia , Estudos Retrospectivos , Esplenectomia , Síndrome , Trombocitopenia/complicações , Trombocitopenia/imunologiaRESUMO
Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha, as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.
Assuntos
Astrócitos/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Ácido Glutâmico/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Glicoproteínas de Membrana/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sistema X-AG de Transporte de Aminoácidos , Animais , Animais Recém-Nascidos , Transporte Biológico , Linhagem Celular , Células Cultivadas , Contactina 2 , Feto , Humanos , RNA Mensageiro/metabolismo , Ratos , Linfócitos T/virologiaAssuntos
Adenocarcinoma/terapia , Adenoviridae , Neoplasias do Sistema Digestório/terapia , Terapia Genética , Interleucina-2/uso terapêutico , Adenocarcinoma/sangue , Adenoviridae/genética , Adenoviridae/imunologia , Adenoviridae/isolamento & purificação , Adulto , Anticorpos Antivirais/sangue , Antígenos CD/sangue , Neoplasias do Colo/sangue , Neoplasias do Colo/terapia , Neoplasias do Sistema Digestório/sangue , Feminino , Vetores Genéticos/uso terapêutico , Humanos , Injeções Intralesionais , Interleucina-2/sangue , Interleucina-2/genética , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/terapia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Ad CFTR, a replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator (CFTR), was administered by aerosolization in a single escalating dose to three pairs (cohorts) of cystic fibrosis (CF) patients. Buffer only was administered to the nose and lungs 9-14 days before nasal instillation of virus followed the day after by aerosolization of Ad CFTR to the lung. Nasal doses (defined in terms of viral plaque forming units, pfu) were 10(5), 10(7), and 4 x 10(8), whereas aerosolized doses were 10(7), 10(8), 5.4 x 10(8) for each cohort, respectively. No acute toxic effects were observed in the first 4 weeks after virus treatment. Shedding of infectious Ad CFTR was never detected, whereas detection of vector DNA sequences and CFTR expression demonstrated DNA transfer to the nose and airways of patients. No significant deviations in immunological and inflammatory parameters were observed in serum and in bronchoalveolar lavage (BAL). Importantly, for all patients, the serum anti-adenovirus antibody levels did not change significantly from baseline and no antibodies against adenovirus were found in BAL.
Assuntos
Adenoviridae/metabolismo , Aerossóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Terapia Genética , Adolescente , Adulto , Southern Blotting , Lavagem Broncoalveolar , Regulador de Condutância Transmembrana em Fibrose Cística/análise , Regulador de Condutância Transmembrana em Fibrose Cística/genética , DNA/análise , Feminino , Expressão Gênica/genética , Vetores Genéticos/genética , Humanos , Imuno-Histoquímica , Masculino , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/análiseRESUMO
We have previously shown that, in experimentally inoculated mice, canine distemper virus (CDV), a neurotropic virus, selectively infects certain brain structures (hypothalamus, hippocampus, monoaminergic nuclei, etc). Here we demonstrate that tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 transcripts are selectively expressed in these CDV-targeted structures, except in the dentate gyrus, where cytokines are induced without prior CDV replication. The time-course of TNF-alpha expression vs. viral replication in the hypothalamus was different from that in hippocampus. In addition, we show that a substantial number of neurons express TNF-alpha and IL-6. These findings provide new insights into the possible participation of cytokines in the neurological disorders triggered by CDV infection.
Assuntos
Citocinas/genética , Vírus da Cinomose Canina/imunologia , Hipocampo/imunologia , Hipotálamo/imunologia , Infecções por Morbillivirus/imunologia , Animais , Sequência de Bases , Citocinas/imunologia , Vírus da Cinomose Canina/genética , Feminino , Regulação da Expressão Gênica , Regulação Viral da Expressão Gênica/imunologia , Hipocampo/citologia , Hipocampo/virologia , Hipotálamo/citologia , Hipotálamo/virologia , Hibridização In Situ , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Dados de Sequência Molecular , Neurônios/imunologia , Neurônios/virologia , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
At present it is conceivable to think that gene therapy represents a way to treat or even prevent the respiratory manifestations of cystic fibrosis. Consistent to such a concept, there is sufficient evidence that Ad-CFTR, a recombinant replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator cDNA, can vectorize the expression of a functional CFTR (cystic fibrosis transmembrane conductance regulator) to the nasal and airway epithelia. The clinical protocol was designed to assess the safety of single escalating doses of a replication defective adenovirus expressing the cystic fibrosis transmembrane conductance regulator gene (Ad-CFTR) when administered to the tracheobronchial portion of the airways and whether biological efficacy of CFTR delivery could be demonstrated. Six cystic fibrosis patients received nasal instillation and subsequent aerosol (Optineb, Air Liquide, Paris, France) administration of Ad-CFTR the following day. Doses (pfu) applied to the nose were 10(5) (patients SG and PB), 10(7) (patients FP and EP) and 4 x 10(8) (patients DS and FG), while aerosolised doses were 10(7) (patients SG and PB), 10(8) (patients FP and EP) and 5.4 x 10(8) (patients DS and FG), respectively. No acute toxic effects, no increase in the titer of anti-adenovirus antibodies and no spreading or shedding of Ad-CFTR were detected. In one patient Ad-CFTR DNA was found in the urine and blood two days after aerosolisation. Ad-CFTR DNA was detected in nasal and bronchial brush samples, in BAL, in saliva and tonsils 21, 8, 14 and 4 days post virus administration, respectively. Ad-CFTR mRNA (RT-PCR on bronchial cells) and CFTR protein (immunochemistry on nasal and bronchial cells) were detected up to 14 days following Ad-CFTR administration. These results show that the nebulisation of Ad-CFTR is a possible approach for treating the respiratory manifestation of cystic fibrosis.
Assuntos
Adenoviridae/genética , Regulador de Condutância Transmembrana em Fibrose Cística/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/terapia , DNA Recombinante/administração & dosagem , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Adolescente , Adulto , Aerossóis , Animais , Vírus Defeituosos/genética , Tolerância a Medicamentos , Terapia Genética/métodos , Humanos , Recombinação Genética , Eficiência Biológica Relativa , Sistema Respiratório/virologiaRESUMO
Primitive neuroectodermal tumors are thought to result from disturbed differentiation of neuroepithelial stem cells. These tumor cells retain the capacity to differentiate toward the neuron or glia phenotype under extrinsic stimuli. Previously, we have developed a model for the differentiation of a medulloblastoma cell line (Dev cells) induced by infection with the human retrovirus HTLV-I. This virus delivers signals which trigger the Dev cells to differentiate toward an astrocytic lineage. The aim of this study was to characterize the time course of viral infection, to identify the soluble factors released and to analyze their effects on Dev cells. The early phase of viral replication is followed by latent infection. Viral infection induces glial differentiation in a subpopulation of cells and results in the death of others. The inflammatory cytokines TNF alpha, IL1 alpha and IL6 were detected in medium conditioned by infected Dev cells. TNF alpha was cytotoxic and cytostatic for subpopulations of Dev cells. Furthermore, TNF alpha treatment reproduced the modulation of expression of the major histocompatibility complex antigens (MHC class I) observed in infected Dev cells. These observations support the view that HTLV-I infection, which triggers glial differentiation of medulloblastoma Dev cells, also causes the release of soluble factors capable of downregulating proliferation of dividing tumor cells and of modifying their recognition by cellular immune effectors.
Assuntos
Infecções por HTLV-I/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Meduloblastoma/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Diferenciação Celular , Criança , Citocinas/fisiologia , Citometria de Fluxo , Imunofluorescência , Genoma Viral , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Masculino , Meduloblastoma/patologia , Meduloblastoma/virologia , Fenótipo , Testes de Precipitina , Fatores de Tempo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The monitoring of plasma soluble interleukin-2 receptor (S IL-2R) concentrations has been proposed in organ transplantation, especially to detect early manifestations of rejection. In organ transplantation, immune activation occurs in various circumstances such as rejections and infections. We performed S IL-2R determination 3 times a week in the sera of 106 patients undergoing kidney and/or pancreas transplantation. In kidney transplantation, S IL-2R was increased before the transplant. It also increased under prophylactic and especially under curative anti-rejection OKT3 or ATG therapy. In 90% cases, S IL-2R increased 2 to 4 days before creatininemia rise. In the other 10% cases, no correlation could be found with any clinical status modification. S IL-2R concentrations never increased in isolated acute tubular necrosis or in cyclosporine A (CsA) nephrotoxicity. In pancreas transplantation, the correlation between S IL-2R concentrations and possible pancreas rejection, was very poor. During cytomegalovirus (CMV) infection, only 50% patients with clinical CMV manifestations had high concentrations of S IL-2R. During Dihydroxy Propoxy Methyl Guanine (DPHG = Ganciclovir) treatment, S IL-2R still increased at the beginning, then it decreased progressively when therapy was efficient on CMV infection. The monitoring of S IL-2R concentrations may be useful in the weeks following organ transplantation provided that results are interpreted in the context of clinical and other laboratory findings, particularly with the renal function status and creatininemia.