RESUMEN
The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).
Asunto(s)
Ciclopentanos/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Guanidinas/administración & dosificación , Gripe Humana/tratamiento farmacológico , Neuraminidasa/antagonistas & inhibidores , Oseltamivir/administración & dosificación , Zanamivir/análogos & derivados , Zanamivir/administración & dosificación , Ácidos Carbocíclicos , Adolescente , Niño , Preescolar , Ciclopentanos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Guanidinas/uso terapéutico , Humanos , Lactante , Recién Nacido , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Betainfluenzavirus/efectos de los fármacos , Betainfluenzavirus/genética , Japón , Masculino , Oseltamivir/uso terapéutico , Piranos , Estaciones del Año , Ácidos Siálicos , Resultado del Tratamiento , Zanamivir/uso terapéuticoRESUMEN
OBJECTIVE: We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency. PATIENTS AND METHODS: Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed. RESULTS: Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm(3) and 1248/mm(3), approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential. CONCLUSIONS: Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.
Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Agammaglobulinemia/genética , Agammaglobulinemia/terapia , Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/inmunología , Adenosina Desaminasa/uso terapéutico , Adolescente , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/inmunología , Edad de Inicio , Diferenciación Celular , Preescolar , Activación Enzimática , Terapia de Reemplazo Enzimático , Gammaretrovirus/genética , Expresión Génica , Vectores Genéticos/genética , Hematopoyesis , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunidad , Inmunofenotipificación , Lactante , Recién Nacido , Japón , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Mutación , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/inmunología , Transducción Genética , Transgenes , Resultado del TratamientoRESUMEN
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for >7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication.
Asunto(s)
Absceso Epidural/etiología , Fusarium/aislamiento & purificación , Enfermedad Granulomatosa Crónica/complicaciones , Micosis/complicaciones , Adolescente , Absceso Epidural/diagnóstico , Absceso Epidural/microbiología , Estudios de Seguimiento , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Micosis/microbiología , Factores de TiempoRESUMEN
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is the most representative subtype of mitochondrial diseases. Administration of L-arginine (L-Arg) or a precursor of nitric oxide (NO) has been proposed as a promising medication for MELAS because one of the pathophysiological mechanisms is supposedly a decreased capacity for NO-dependent vasodilation. We experienced a girl with MELAS and frequent stroke-like episodes who was treated with L-Arg infusion. We evaluated the efficacy of L-Arg infusion therapy based on whether her headache and nausea were disappeared and neurological symptoms were improved within 24 hours of L-Arg administration. L-Arg infusions were effective in all four episodes when the treatment was started within 4 hours of the onset of stroke-like episodes. On the other hand, the infusion was effective in only one out of five episodes when the medication was delayed by more than 4 hours after the onset. Furthermore, the early administration of L-Arg resulted in better outcomes regarding new lesions determined by brain MRI. Our data suggest that L-Arg infusion may be most effective when it is started within 4 hours of the onset of neurological symptoms in the acute phase of MELAS. The study of a large number of episodes in many patients will be needed to determine the critical time point of L-Arg administration after the onset of the acute phase of MELAS.
Asunto(s)
Arginina/uso terapéutico , Síndrome MELAS/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Arginina/administración & dosificación , Niño , Humanos , Infusiones Intravenosas , Síndrome MELAS/diagnóstico , Imagen por Resonancia Magnética/métodos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.
Asunto(s)
ADN/metabolismo , Genes Dominantes/genética , Inmunoglobulina E/biosíntesis , Mutación/genética , Factor de Transcripción STAT3/química , Factor de Transcripción STAT3/metabolismo , Alelos , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , Células Cultivadas , Citocinas/farmacología , Heterocigoto , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina M/metabolismo , Interferón-alfa/farmacología , Interleucina-10/farmacología , Interleucina-6/farmacología , Estructura Terciaria de Proteína , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Síndrome , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Severe infantile form of nemaline myopathy is clinically characterized by marked muscle hypotonia and weakness with respiratory and feeding difficulties since infancy. Recently, mutations in the skeletal muscle alpha-actine gene (ACTA1) have been identified in many patients with the nemaline myopathy. We experienced two cases of severe infantile form of nemaline myopathy with ACTA1 mutation (missence heterozygous mutation;c.553C>T, p.R185C) in siblings presenting with different clinical symptoms and courses. The elder brother was a typical "floppy infant" at birth. Because he could not suck and swallow at all, he was fed completely through a nasogastric tube. At 2 months of age, he developed respiratory insufficiency and was placed on a respirator all day. He was diagnosed with having nemaline myopathy from his muscle biopsy, which revealed marked variation in muscle fiber size with large numbers of nemaline bodies on Gomori-trichrome stain. In contrast, the younger brother presented with mild muscular hypotonia and feeding difficulty during the neonatal stage;therefore, he was partly fed through a nasogastric tube. At 2 months of age, he was admitted to our hospital because of respiratory distress, and he required nasal continuous positive airway pressure with oxygen followed by noninvasive positive pressure ventilation intermittently, mainly at night. He was followed at his home by parents with no serious problems;however he unexpectedly died at the age of 15 months. Although most cases of severe infantile form of nemaline myopathy caused by ACTA1 mutations are sporadic and have no family history, we emphasize that clinical symptoms are variable in siblings with the same mutation.
Asunto(s)
Músculo Esquelético/patología , Enfermedades Musculares/genética , Mutación/genética , Miopatías Nemalínicas/genética , Actinas/genética , Humanos , Recién Nacido , Masculino , Enfermedades Musculares/patología , Miopatías Nemalínicas/patología , HermanosRESUMEN
We report a 19-year-old patient with systemic-onset juvenile idiopathic arthritis (JIA) who developed a mediastinal germinoma during treatment with infliximab. Although the cancer risk of infliximab is controversial, this agent may have accelerated the growth of the germinoma. We conclude that the indications for tumor necrosis factor (TNF) inhibitors should be strictly decided and that a nationwide cohort study is necessary to assess the risk of cancer in patients with JIA exposed to biologics.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/patología , Germinoma/patología , Neoplasias del Mediastino/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Artritis Juvenil/complicaciones , Terapia Combinada , Sustitución de Medicamentos , Germinoma/complicaciones , Germinoma/terapia , Glucocorticoides/uso terapéutico , Humanos , Infliximab , Masculino , Neoplasias del Mediastino/complicaciones , Neoplasias del Mediastino/terapia , Prednisolona/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The presence of the anti-melanoma differentiation-associated gene 5 antibody was evaluated in 13 patients with juvenile dermatomyositis (JDM). The antibody was positive in 5 of the 6 patients with JDM-associated interstitial lung disease (ILD), but not in the 7 patients without ILD. This antibody is a useful marker for early diagnosis of JDM-associated ILD.
Asunto(s)
ARN Helicasas DEAD-box/inmunología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Niño , Preescolar , Dermatomiositis/complicaciones , Dermatomiositis/inmunología , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1 , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Estudios RetrospectivosRESUMEN
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton's tyrosine kinase (Btk). Most XLA patients have severely reduced or absent peripheral blood B cells and serum immunoglobulins, since the expression or function of Btk, critical for the maturation of B cell lineages at pro-B and pre-B cell stages, is deficient. Early and accurate diagnosis of XLA is important, since the affected patients suffer from severe and recurrent infections unless they receive intravenous immunoglobulin (IVIG) replacement therapy. However, the diagnosis of XLA is not always easy because some patients have detectable ( approximately 2%) B cells in the peripheral blood and have significant levels of serum immunoglobulins. In this study, we report on a patient who was diagnosed with XLA at the age of 10years. The diagnosis was delayed due to near-normal levels of serum immunoglobulins, although he presented with severe and recurrent bacterial infections since the age of 1year. He was demonstrated to have a novel non-invariant splice-site mutation in intron 10 (IVS10 -11C-->A) of the Btk gene, which was not detected by the standard PCR-based mutation analysis. This mutation resulted in no detectable Btk expression. This case suggests that patients suffering from severe or recurrent bacterial infection should be suspected to have XLA even though they may have significant levels of serum immunoglobulins. Furthermore, significant levels of serum immunoglobulins in XLA patients do not necessarily mean less severe phenotype.
Asunto(s)
Agammaglobulinemia/genética , Genes Ligados a X , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas Tirosina Quinasas/genética , Sitios de Empalme de ARN/genética , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/enzimología , Infecciones Bacterianas/etiología , Niño , Diagnóstico Tardío , Predisposición Genética a la Enfermedad , Humanos , Inmunoglobulinas/análisis , Intrones/genética , Leucocitos Mononucleares/enzimología , Masculino , Fenotipo , Proteínas Tirosina Quinasas/sangre , Proteínas Tirosina Quinasas/deficiencia , Recurrencia , Análisis de Secuencia de ADNRESUMEN
Prader-Willi syndrome (PWS) is often related to severe obesity and diabetes mellitus (DM). Clinical findings suggesting the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists for glycemic control of DM in PWS have been recently increasing. However, there are only a few reports describing the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors for PWS. We present a diabetic female with PWS, whose glycemic control was deteriorated at the age of 19 but improved to a certain extent by introducing the GLP-1 analog liraglutide. At the age of 20, the SGLT2 inhibitor empagliflozin was administered. Subsequently, her HbA1c level and body weight markedly decreased. Improvement in both insulin resistance and secretion was observed during the subsequent six months. In addition to GLP-1 receptor agonists, SGLT2 inhibitors may be a potential approach for the management of DM in PWS, especially in young patients whose pancreatic insulin secretion capabilities are still preserved.
RESUMEN
Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology. It is quite difficult to diagnose CD without typical localized signs or symptoms. We present a 5-year-old boy with unicentric plasma cell CD in the mesentery, which was too small to be detected by any conventional imaging. (18)F-fluorodeoxyglucose positron emission tomography image and a serum cytokine profile prompted us to perform a curative surgical excision, confirming his diagnosis. Our case also supported an important role of interleukin-6 in the pathophysiology of plasma cell CD.
Asunto(s)
Enfermedad de Castleman/diagnóstico , Interleucina-6/sangre , Mesenterio/diagnóstico por imagen , Tomografía de Emisión de Positrones , Enfermedad de Castleman/sangre , Enfermedad de Castleman/diagnóstico por imagen , Enfermedad de Castleman/fisiopatología , Enfermedad de Castleman/cirugía , Preescolar , Fiebre/etiología , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Humanos , Interleucina-6/genética , Interleucina-6/fisiología , Escisión del Ganglio Linfático , Masculino , Células Plasmáticas/patología , RadiofármacosAsunto(s)
Anticuerpos Monoclonales Humanizados , Enfermedad de Castleman , Epidermólisis Ampollosa Distrófica , Receptores de Interleucina-6 , Humanos , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/complicaciones , Enfermedad de Castleman/inmunología , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/inmunología , Epidermólisis Ampollosa Distrófica/complicaciones , Epidermólisis Ampollosa Distrófica/inmunología , Epidermólisis Ampollosa Distrófica/tratamiento farmacológico , Epidermólisis Ampollosa Distrófica/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Masculino , Piel/patología , FemeninoAsunto(s)
Imagen por Resonancia Magnética/métodos , Metaloproteinasa 3 de la Matriz/sangre , Síndrome Mucocutáneo Linfonodular/complicaciones , Osteoartritis de la Rodilla/etiología , Biomarcadores/sangre , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/enzimología , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/enzimologíaAsunto(s)
Artritis Juvenil/diagnóstico por imagen , Radioisótopos de Galio , Artritis Juvenil/sangre , Artritis Juvenil/clasificación , Artritis Juvenil/tratamiento farmacológico , Niño , Femenino , Humanos , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Metaloproteinasa 3 de la Matriz/sangre , Metotrexato/uso terapéutico , CintigrafíaRESUMEN
X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency disease of phagocytes caused by mutations in the cytochrome b(558)ß (CYBB) gene. We, for the first time, detected somatic mosaicism in two unrelated male patients with X-CGD caused by de novo nonsense mutations (p.Gly223X and p.Glu462X) in the CYBB gene. In each patient, a small subset of granulocytes was normal in terms of respiratory burst (ROB) activity, gp91(phox) expression, and CYBB sequences. Cells with wild-type CYBB sequence were also detected in buccal swab specimens and in peripheral blood mononuclear cells. The normal cells were shown to be of the patient origin by fluorescent in situ hybridization analysis of X/Y chromosomes, and by HLA DNA typing. Two possible mechanisms for this somatic mosaicism were considered. The first is that the de novo disease-causing mutations in CYBB occurred at an early multicellular stage of embryogenesis with subsequent expansion of the mutated cells, leaving some unmutated cells surviving. The second possibility is that the de novo mutations occurred in oocytes which was followed by reversion of the mutations in a small subset of cells in early embryogenesis.
Asunto(s)
Enfermedad Granulomatosa Crónica/genética , Mosaicismo , Adolescente , Preescolar , Genes Ligados a X , Humanos , Masculino , Glicoproteínas de Membrana/genética , Mutación , NADPH Oxidasa 2 , NADPH Oxidasas/genéticaRESUMEN
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17-producing CD4(+) T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T(reg) cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T(reg) cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10-treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4(+) T cells to FOXP3(+) induced T(reg) cells (iT(reg) cells). These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iT(reg) cells may contribute to inflammatory changes in HIES.
Asunto(s)
Células Dendríticas/patología , Tolerancia Inmunológica/inmunología , Interleucina-10/metabolismo , Síndrome de Job/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/citología , Anticuerpos Monoclonales/inmunología , Antígenos CD/metabolismo , Antígeno B7-H1 , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Interleucina-10/farmacología , Síndrome de Job/genética , Síndrome de Job/metabolismo , Glicoproteínas de Membrana/metabolismo , Mutación/genética , Receptores Inmunológicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , TYK2 Quinasa/genéticaRESUMEN
X-linked chronic granulomatous disease is a primary immunodeficiency caused by mutations in CYBB. Although large deletions involving CYBB are known to cause contiguous gene syndrome (CGS), only a few patients have been studied precisely at the molecular levels. Our study determined the deletion breakpoints in two patients with CGS involving CYBB by array comparative genomic hybridization and the following PCR and DNA walking studies. The deletion size was 3.5 Mb in Patient 1 and 0.8 Mb in Patient 2. There were no homologous architectural features between the telomeric and centromeric breakpoint junctions in the deletions of either patient. However, the telomeric breakpoint of Patient 2 was embedded in a stretch of low-copy repeats and the centromeric breakpoint was also embedded in a stretch of short segments with significant sequence homology. These findings suggest the potential involvement of genome architecture in stimulating genomic rearrangements in Patient 2.
Asunto(s)
Deleción Cromosómica , Eliminación de Gen , Enfermedad Granulomatosa Crónica/genética , Glicoproteínas de Membrana/genética , NADPH Oxidasas/genética , Niño , Hibridación Genómica Comparativa , Enfermedad Granulomatosa Crónica/diagnóstico , Humanos , Masculino , Glicoproteínas de Membrana/deficiencia , NADPH Oxidasa 2 , NADPH Oxidasas/deficiencia , Duplicaciones Segmentarias en el Genoma/genética , Adulto JovenRESUMEN
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1beta. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell-derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.
Asunto(s)
Síndrome de Job , Infecciones Estafilocócicas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos Fúngicos/inmunología , Quimiocinas/genética , Quimiocinas/inmunología , Citocinas/genética , Citocinas/inmunología , Células Epiteliales/citología , Células Epiteliales/inmunología , Humanos , Interleucina-8/genética , Interleucina-8/inmunología , Síndrome de Job/inmunología , Síndrome de Job/microbiología , Queratinocitos/citología , Queratinocitos/inmunología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/microbiología , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Mucosa Respiratoria/citología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/microbiología , beta-Defensinas/genética , beta-Defensinas/inmunologíaRESUMEN
BACKGROUND: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. METHODS: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months-4 years). Five patients had Wiskott-Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. RESULTS: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. CONCLUSION: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.