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1.
J Clin Immunol ; 42(6): 1171-1192, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35503492

RESUMEN

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.


Asunto(s)
Inmunodeficiencia Combinada Grave , Brasil/epidemiología , Niño , ADN/genética , Humanos , Lactante , Recién Nacido , Tamizaje Neonatal , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genética , Linfocitos T
4.
Front Pediatr ; 6: 230, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30177960

RESUMEN

We report a novel homozygous JAK3 mutation in two female Brazilian SCID infants from two unrelated kindreds. Patient 1 was referred at 2 months of age due to a family history of immunodeficiency and the appearance of a facial rash. The infant was screened for TRECs (T-cell receptor excision circles) and KRECs (kappa-deleting recombination excision circles) for the assessment of newly formed naïve T and B cells respectively, which showed undetectable TRECs and normal numbers of KRECs. Lymphocyte immunophenotyping by flow cytometry confirmed the screening results, revealing a T-B+NK- SCID. The patient underwent successful HSCT. Patient 2 was admitted to an intensive care unit at 8 months of age with severe pneumonia, BCGosis, and oral moniliasis; she also had a positive family history for SCID but newborn screening was not performed at birth. At 10 months of age she was diagnosed as a T-B+NK- SCID and underwent successful HSCT. JAK3 sequencing revealed the same homozygous missense mutation (c.2350G>A) in both patients. This mutation affects the last nucleotide of exon 17 and it is predicted to disrupt the donor splice site. cDNA sequencing revealed skipping of exon 17 missing in both patients, confirming the predicted effect on mRNA splicing. Skipping of exon 17 leads to an out of frame deletion of 151 nucleotides, frameshift and creation of a new stop codon 60 amino acids downstream of the mutation resulting in a truncated protein which is likely nonfunctional.

5.
Arq. Asma, Alerg. Imunol ; 1(4): 422-426, out.dez.2017. ilus
Artículo en Portugués | LILACS | ID: biblio-1380653

RESUMEN

A Síndrome de Wiskott-Aldrich (WAS) é uma imunodeficiência congênita ligada ao cromossomo X, caracterizada por mutações no gene WAS, responsável pela proteína WASP. As principais manifestações clínicas são trombocitopenia com plaquetas de volume reduzido, eczema, infecções recorrentes e maior incidência de doenças autoimunes e neoplasias. Relatamos o caso de um paciente do sexo masculino com sintomas clássicos desta síndrome (eczema, trombocitopenia e infecções recorrentes), porém com plaquetas de volume normal. Existem poucos relatos desta síndrome em pacientes com plaquetas de volume normal, o que atrasou o encaminhamento do paciente ao imunologista, o qual foi tratado como portador de Síndrome de Evans e dermatite atópica até os quatro anos de idade. A confirmação diagnóstica foi por teste genético. O diagnóstico precoce possibilita profilaxia com antibioticoterapia e uso de imunoglobulina endovenosa, devido ao risco de infecções graves, e encaminhamento para transplante de células-tronco hematopoiéticas, que até o momento é o único tratamento curativo. A suspeita clínica deve existir em pacientes com trombocitopenia inexplicável, mesmo se as plaquetas tiverem o tamanho normal, associada às outras manifestações da doença.


Wiskott-Aldrich syndrome (WAS) is an X-linked congenital immunodeficiency characterized by mutations in the WAS gene of the WASP protein. The main clinical manifestations are thrombocytopenia with small-sized platelets, eczema, recurrent infections and a higher incidence of autoimmune diseases and cancer. We report the case of a male patient with classical symptoms of this syndrome (eczema, thrombocytopenia and recurrent infections), however presenting platelets with normal size. There are few reports of this syndrome in patients with normal-sized platelets, which delayed our patient's referral to the immunologist. The patient received treatment for Evans syndrome and atopic dermatitis until he was four years old. Confirmation of WAS diagnosis was made by genetic testing. Early diagnosis allows prophylactic treatment with antibiotics and the use of intravenous immunoglobulin due to the risk of serious infections, in addition to referral for hematopoietic stem cell transplantation, which is the only curative treatment available so far. WAS should be suspected when patients develop unexplained thrombocytopenia even with normal-sized platelets, especially in the presence of other manifestations.


Asunto(s)
Humanos , Preescolar , Trombocitopenia , Síndrome de Wiskott-Aldrich , Plaquetas , Pruebas Genéticas , Trasplante de Células Madre Hematopoyéticas , Eccema , Signos y Síntomas , Terapéutica , Inmunoglobulinas Intravenosas , Proteína del Síndrome de Wiskott-Aldrich , Reinfección , Infecciones , Mutación
6.
Arthritis Res Ther ; 19(1): 235, 2017 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-29052524

RESUMEN

BACKGROUND: Studies have suggested that soluble factors in plasma from patients with active (aBD) and inactive (iBD) Behçet's disease (BD) stimulate neutrophil function. Soluble CD40 ligand (sCD40L) is an important mediator of inflammation in BD. Its expression and effect on neutrophil oxidative burst and neutrophil extracellular trap (NET) release have not been characterized. In this study, we sought to investigate the role of plasma and the CD40L pathway on NET release and the oxidative burst profile in patients with aBD and iBD. METHODS: Neutrophils and peripheral blood mononuclear cells (PBMCs) were obtained from patients with aBD (n = 30), patients with iBD (n = 31), and healthy control subjects (HCs; n = 30). sCD40L plasma concentration was determined in individual samples. A pool of plasma for each group was created. In some experiments, plasma pools were treated with recombinant CD40 (rhCD40-muIg) for sCD40L blockade. NET release and H2O2/O2- production were determined after stimulation with phorbol 12-myristate 13-acetate, sCD40L, or plasma pool. Flow cytometric analysis was performed to evaluate the expression of (1) CD40, Mac-1, and phosphorylated NF-κB p65 on neutrophils and monocytes and (2) CD40L on activated T cells and platelets. CD40L gene expression in PBMCs was determined by qRT-PCR. RESULTS: sCD40L plasma levels were significantly higher in patients with iBD (median 17,234, range 2346-19,279 pg/ml) and patients with aBD (median 18,289, range 413-19,883 pg/ml) than in HCs (median 47.5, range 33.7-26.7 pg/ml; p < 0.001). NET release was constitutively increased in BD compared with HC. NET release and H2O2/O2- were higher after stimulation with sCD40L or BD plasma and decreased after sCD40L blockade. Mac-1 expression was constitutively increased in neutrophils of patients with aBD (88.7 ± 13.2% of cells) and patients with iBD (89.2 ± 20.1% of cells) compared with HC (27.1 ± 18.8% of cells; p < 0.01). CD40 expression on phagocytes and CD40L expression on platelets were similar in the three groups. PBMCs as well as nonactivated and activated CD4+ T cells from patients with BD showed higher CD40L expression. CONCLUSIONS: Plasma from patients with aBD exerts a stimulus on NET release and oxidative burst, probably induced by sCD40L.


Asunto(s)
Síndrome de Behçet/sangre , Síndrome de Behçet/inmunología , Ligando de CD40/sangre , Activación Neutrófila/fisiología , Estallido Respiratorio/fisiología , Adulto , Trampas Extracelulares/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
7.
J Infect Dis ; 216(12): 1623-1634, 2017 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-29029192

RESUMEN

Background: Mutations in genes affecting interferon-γ (IFN-γ) immunity have contributed to understand the role of IFN-γ in protection against intracellular pathogens. However, inborn errors in STAT4, which controls interleukin-12 (IL-12) responses, have not yet been reported. Our objective was to determine the genetic defect in a family with a history of paracoccidioidomycosis. Methods: Genetic analysis was performed by whole-exome sequencing and Sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-γ release by patient lymphocytes, and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells. Results: A heterozygous missense mutation, c.1952 A>T (p.E651V) in STAT4 was identified in the index patient and her father. Patient's and father's lymphocytes showed reduced pSTAT4, nuclear translocation, and impaired IFN-γ production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient's and father's peripheral blood mononuclear cells and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-γ, but not rhIL-12. Conclusion: Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-γ immunity associated with susceptibility to paracoccidioidomycosis.


Asunto(s)
Predisposición Genética a la Enfermedad , Interferón gamma/deficiencia , Subunidad p35 de la Interleucina-12/metabolismo , Mutación Missense , Paracoccidioidomicosis/genética , Factor de Transcripción STAT4/genética , Adulto , Anciano , Línea Celular , Salud de la Familia , Femenino , Genotipo , Heterocigoto , Humanos , Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Análisis de Secuencia de ADN
8.
J Clin Immunol ; 35(3): 264-72, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25753012

RESUMEN

UNLABELLED: The signal transducer and activator of transcription (STAT) family of proteins regulate gene transcription in response to a variety of cytokines. STAT5B, in particular, plays an important role in T cells, where it is a key mediator of interleukin-2 (IL-2) induced responses. STAT5B deficiency causes a rare autosomal recessive disorder reported in only a handful of individuals. There are currently ten published cases of STAT5B deficiency, four of which are Argentinians. AIM: This is a report of more than 10 years follow up of the clinical and immunological features of three Argentinian STAT5B deficient patients. CONCLUSION: More than a decade of follow-up demonstrates that STAT5B deficiency is associated with various clinical pathologies that cause significant morbidity. Early diagnosis is critical for the prevention and improvement of clinical outcomes for STAT5B deficient patients.


Asunto(s)
Síndromes de Inmunodeficiencia/inmunología , Factor de Transcripción STAT5/deficiencia , Adulto , Argentina , Autoanticuerpos/sangre , Linfocitos B/inmunología , Femenino , Humanos , Inmunoglobulinas/sangre , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/genética , Recuento de Linfocitos , Mutación , Factor de Transcripción STAT5/genética , Linfocitos T/inmunología , Adulto Joven
9.
J Clin Immunol ; 34(2): 146-56, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24402618

RESUMEN

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.


Asunto(s)
Síndrome de Inmunodeficiencia con Hiper-IgM/epidemiología , Ligando de CD40/deficiencia , Ligando de CD40/genética , Preescolar , Comorbilidad , Citidina Desaminasa/deficiencia , Citidina Desaminasa/genética , Femenino , Hispánicos o Latinos , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Síndrome de Inmunodeficiencia con Hiper-IgM/terapia , Lactante , Recién Nacido , Infecciones/diagnóstico , Infecciones/etiología , Pulmón/patología , Masculino , Sistema de Registros , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
10.
J Clin Immunol ; 32(2): 212-20, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22193914

RESUMEN

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.


Asunto(s)
Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/genética , Paracoccidioidomicosis/complicaciones , Adolescente , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Secuencia de Bases , Brasil/epidemiología , Ligando de CD40/deficiencia , Ligando de CD40/genética , Ligando de CD40/metabolismo , Niño , Preescolar , Estudios de Cohortes , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/diagnóstico , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Incidencia , Lactante , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Datos de Secuencia Molecular , Mutación , Paracoccidioidomicosis/epidemiología , Paracoccidioidomicosis/patología , Linaje , Alineación de Secuencia , Adulto Joven
11.
J Allergy Clin Immunol ; 129(3): 778-86, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22154528

RESUMEN

BACKGROUND: Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood. OBJECTIVE: To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens. METHODS: DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans- and P brasiliensis-pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (T(H)) 17 cells, and production of IFN-γ, TGF-ß, IL-4, IL-5, and IL-17. RESULTS: Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed T(H)2 pattern response. CONCLUSION: Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.


Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Células Dendríticas/metabolismo , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/inmunología , Paracoccidioides/inmunología , Paracoccidioidomicosis/inmunología , Adolescente , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Candida albicans/patogenicidad , Candidiasis/complicaciones , Candidiasis/genética , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular , Células Cultivadas , Niño , Preescolar , Técnicas de Cocultivo , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/patología , Células Dendríticas/virología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/genética , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Masculino , Mutación/genética , Paracoccidioides/patogenicidad , Paracoccidioidomicosis/complicaciones , Paracoccidioidomicosis/genética , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/patología
13.
J Pediatr ; 147(2): 256-9, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16126062

RESUMEN

IPEX (immune-dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is an autoimmune disorder with an often lethal outcome in spite of immunosuppressive therapy. We report the successful use of sirolimus in 3 patients with IPEX. The efficacy of sirolimus is probably due to its different mode of action compared to calcineurin-dependent agents.


Asunto(s)
Inmunosupresores/uso terapéutico , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Sirolimus/uso terapéutico , Niño , Humanos , Masculino , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/fisiopatología , Síndrome
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