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1.
Clin Exp Immunol ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31799703

RESUMO

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the IL-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype, the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in 2 siblings: a 4-year-old boy with lethal Epstein Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ NK+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation, and reduced levels of T cell receptor excision circles. After confirming normal IL2RG expression (CD132) on T lymphocytes, STAT5 phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with JAK3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL2RG may allow partial phosphorylation of STAT5 through a JAK3-independent pathway. We identified a region of 3 amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable better understanding of partial defects leading to leaky phenotypes.

2.
Front Immunol ; 10: 2325, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681265

RESUMO

Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.

3.
Front Immunol ; 10: 2406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695692

RESUMO

Severe combined immunodeficiency (SCID), the most severe form of T-cell immunodeficiency, can be screened at birth by quantifying T-cell receptor excision circles (TRECs) in dried blood spot (DBS) samples. Early detection of this condition speeds up the establishment of appropriate treatment and increases the patient's life expectancy. Newborn screening for SCID started in January 2017 in Catalonia, the first Spanish and European region to universally include this testing. The results obtained in the first 2 years of experience are evaluated here. All babies born between January 2017 and December 2018 were screened. TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland). In 2018, the retest cutoff in the detection algorithm was updated based on the experience gained in the first year, and changed from 34 to 24 copies/µL. This decreased the retest rate from 3.34 to 1.4% (global retest rate, 2.4%), with a requested second sample rate of 0.23% and a positive detection rate of 0.02%. Lymphocyte phenotype (T, B, NK populations), expression of CD45RA/RO isoforms, percentage and intensity of TCR αß and TCR γδ, presence of HLA-DR+ T lymphocytes, and in vitro lymphocyte proliferation were studied in all patients by flow cytometry. Of 130,903 newborns screened, 30 tested positive, 15 of which were male. During the study period, one patient was diagnosed with SCID: incidence, 1 in 130,903 births in Catalonia. Thirteen patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 10,069 newborns (43% of positive detections). Nine patients were considered false-positive cases because of an initially normal lymphocyte count with normalization of TRECs between 3 and 6 months of life, four infants had transient lymphopenia due to an initially low lymphocyte count with recovery in the following months, and three patients are still under study. The results obtained provide further evidence of the benefits of including this disease in newborn screening programs. Longer follow-up is needed to define the exact incidence of SCID in Catalonia.

4.
Mol Genet Genomic Med ; : e1016, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663686

RESUMO

BACKGROUND: The current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T-cell receptor excision circles (TRECs), a byproduct of correct T-cell development. However, in addition to SCID, other T-cell-deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected. METHODS: We present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain). RESULTS: Thirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA. CONCLUSION: Newborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team.

5.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31272810

RESUMO

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening condition in immunocompromised children. Our aim is to analyze the epidemiologic and clinical characteristics of PJP cases in our setting, describing the prognosis and related risk factors. METHODS: Retrospective study including all pediatric patients (≤18 years) with PJP admitted to our hospital (January 1989-December 2016). Case definition: patient with acute pneumonitis and P.jirovecii detection in bronchoalveolar lavage or tracheal aspirate using methenamine silver or direct antibody fluorescence staining, or Real-Time Polymerase Chain Reaction. RESULTS: Twenty-five cases (0.9 cases/year) were identified. Median age was 2.2 years (interquartile range: 0.5-12.3), 64% were male, and 12% were receiving appropriate antimicrobial prophylaxis. Cytomegalovirus coinfection was detected in 26% cases. The most common underlying diseases were primary immunodeficiencies (36%) and 16% were human immunodeficiency virus (HIV)-infected children. Eighteen were admitted to the pediatric intensive care unit (PICU) and overall 30-day mortality was 20% (31.25% in HIV non-infected vs 0% in HIV-infected patients; OR: 0.33, 95% CI: 0.02-7.24, p=0.55). Clinical outcome was worse in girls and those patients requiring adjuvant steroid therapy. HIV non-infected patients, higher initial LDH, younger age and shorter time elapsed between diagnosis of PJP and the underlying disease were identified as risk factors to be admitted to the PICU (p=0.05, p=0.026, p=0.04 and p=0.001 respectively). CONCLUSION: Accompanying the widespread use of combined antiretroviral therapy, PJP has been diagnosed almost exclusively in HIV non-infected children at our institution. Moreover, significant higher morbidity rates associated with PJP are seen in this group of patients.

6.
Euro Surveill ; 24(26)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31266591

RESUMO

BackgroundChagas disease is endemic in Latin America and affects 8 million people worldwide. In 2010, Catalonia introduced systematic public health surveillance to detect and treat congenital Chagas disease.AimThe objective was to evaluate the health outcomes of the congenital Chagas disease screening programme during the first 6 years (2010-2015) after its introduction in Catalonia.MethodsIn a surveillance system, we screened pregnant women and newborns and other children of positive mothers, and treated Chagas-positive newborns and children. Diagnosis was confirmed for pregnant women and children with two positive serological tests and for newborns with microhaematocrit and/or PCR at birth or serology at age 9 months.ResultsFrom 2010 to 2015, the estimated screening coverage rate increased from 68.4% to 88.6%. In this period, 33,469 pregnant women were tested for Trypanosoma cruzi and 937 positive cases were diagnosed. The overall prevalence was 2.8 cases per 100 pregnancies per year (15.8 in Bolivian women). We followed 82.8% of newborns until serological testing at age 9-12 months and 28 were diagnosed with Chagas disease (congenital transmission rate: 4.17%). Of 518 siblings, 178 (34.3%) were tested and 14 (7.8%) were positive for T. cruzi. Having other children with Chagas disease and the heart clinical form of Chagas disease were maternal risk factors associated with congenital T. cruzi infection (p < 0.05).ConclusionThe increased screening coverage rate indicates consolidation of the programme in Catalonia. The rate of Chagas disease congenital transmission in Catalonia is in accordance with the range in non-endemic countries.

7.
Medicine (Baltimore) ; 98(20): e15532, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096455

RESUMO

INTRODUCTION: Zika virus (ZIKV) has caused one of the most challenging global infectious epidemics in recent years because of its causal association with severe microcephaly and other congenital malformations. The diagnosis of viral infections usually relies on the detection of virus proteins or genetic material in clinical samples as well as on the infected host immune responses. Serial serologic testing is required for the diagnosis of congenital infection when diagnostic molecular biology is not possible. PATIENT CONCERNS: A 2-year-old girl, born to a mother with confirmed ZIKV infection during pregnancy, with a confirmed ZIKV infection in utero, showed at birth a severe microcephaly and clinical characteristics of fetal brain disruption sequence compatible with a congenital ZIKV syndrome (CZS). DIAGNOSIS: ZIKV-RNA and ZIKV-IgM serological response performed at birth and during the follow-up time tested always negative. Serial serologic ZIKV-IgG tests were performed to assess the laboratory ZIKV diagnosis, ZIKV-IgG seroreversion was observed at 21 months of age. ZIKV diagnosis of this baby had to be relied on her clinical and radiological characteristics that were compatible with a CZS. INTERVENTIONS: The patient was followed-up as per protocol at approximately 1, 4, 9, 12, 18-21, and 24 months of age. Neurological, radiological, audiological, and ophthalmological assessment were performed during this period of time. Prompt rehabilitation was initiated to prevent potential adverse long-term neurological outcomes. OUTCOMES: The growth of this girl showed a great restriction at 24 months of age with a weight of 8.5 kg (-2.5 z-score) and a head circumference of 40.5 cm (-4.8 z-score). She also had a great neurodevelopmental delay at the time of this report. CONCLUSION: We presume that as a consequence of prenatal ZIKV infection, the fetal brain and other organs are damaged before birth through direct injury. Following this, active infection ends during intrauterine life, and as a consequence the immune system of the infant is unable to build up a consistent immune response thereafter. Further understanding of the mechanisms taking part in the pathogenesis of ZIKV congenital infection is needed. This finding might change our paradigm regarding serological response in the ZIKV congenital infection.


Assuntos
Complicações Infecciosas na Gravidez/diagnóstico , Infecção por Zika virus/diagnóstico , Encéfalo/anormalidades , Pré-Escolar , Feminino , Humanos , Microcefalia/etiologia , Gravidez , Testes Sorológicos , Espanha , Infecção por Zika virus/complicações
8.
Orphanet J Rare Dis ; 14(1): 82, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995915

RESUMO

BACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.


Assuntos
Anemia Aplástica/genética , Reparo do DNA/genética , Disceratose Congênita/genética , Fibrose Pulmonar/genética , Encurtamento do Telômero/genética , Telômero/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Humanos , Lactente , Masculino , Linhagem , RNA/genética , Telomerase/genética , Adulto Jovem
9.
Front Immunol ; 9: 2397, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386343

RESUMO

LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30334372

RESUMO

BACKGROUND: For the accurate diagnosis of immunodeficiencies is crucial to compare patients' immunology laboratory values with age-sex matched controls, yet there is a paucity of normal values for most populations. OBJECTIVES: To define appropriate reference values of extended lymphocyte subpopulations and T-cell receptor excision circle (TRECs) levels in healthy pediatric donors between 1 month and 18 years of age. METHODS: Extended immunophenotyping values were obtained by analysis of multiparameter flow cytometry panels for the following subpopulations: CD4+ and CD8+ Naive, Effector, Effector Memory and Central Memory, T helper subpopulations and their degrees of activation, T Regulatory cells, Recent Thymic Emigrants (RTE), B Lymphocyte subpopulations (Transitional, Naive, Preswitch-Memory, Switch-Memory, Plasmablasts, CD21low, and Exhausted), and subpopulations for Monocytes, NK cells and Dendritic Cells. RESULTS: Median values and the 10th and 90th percentiles were obtained for 32 lymphocyte and monocyte subpopulations, and for TRECs levels in each age group of children. Naive CD4+ and CD8+ T-cell populations tended to decrease with age, with significant difference between the groups, in parallel with the reduction in thymic function assessed by TRECs counts and the recent thymic emigrant population. Relative numbers of Th cell populations tended to increase with age. The percentage of class-switched B cell populations showed a significant increase between the youngest group and the others. CONCLUSION: This study provides essential data for interpreting extended immunophenotyping profiles in the pediatric and young adult populations, which could be of value for the diagnosis of PIDs and immune-mediated diseases, particularly those associated with subtle immunological abnormalities. © 2018 International Clinical Cytometry Society.

11.
Clin Immunol ; 195: 49-58, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30063981

RESUMO

Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1ß, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

12.
Front Immunol ; 9: 636, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867916

RESUMO

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.

13.
J Clin Lab Anal ; : e22420, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29603375

RESUMO

BACKGROUND: Measurement of immunoglobulins and complement proteins are frontline tests used in the assessment of immune system integrity, and reference values can vary with age. Their measurement provides an insight into the function of the innate and adaptive immune systems. METHODS: We generated pediatric reference ranges for IgG, IgA, IgM, IgD, the IgG and IgA subclasses, and C3 and C4 using the Optilite™ turbidimetric analyzer. RESULTS: The concentrations of IgG, IgA, and IgD showed an increase with age, as expected, while IgM remained stable between the age groups. For the IgG subclasses, no significant differences were observed in IgG1 or IgG3, while IgG2 and IgG4 concentrations increased steadily with age. The concentration of IgG2 plateaued at 15-18 years, while IgG4 plateaued at 10-14 years. The trend of concentrations across all groups was IgG1 > IgG2 > IgG3 > IgG4. For both IgA1 and IgA2, concentrations increased significantly with age, plateauing at 15-18 years. The median IgA1 concentration was greater than IgA2 across all groups. There was a good correlation between the total IgG or IgA concentration and summation of their subclasses (R2  = 0.89, P < .0001, slope y = 0.98x + 14.51 mg/dL and R2  = 0.91, P < .0001, slope y = 1.35x-3.28 mg/dL, respectively). The concentration of C3 and C4 remained stable across the groups, with no significant differences observed. CONCLUSION: We have generated age-specific reference ranges in healthy children for C3, C4, IgG, IgA, IgM, IgD and the IgG and IgA subclasses using the Optilite™ turbidimetric analyzer. These ranges will help identify individuals with abnormal concentrations, thus will aid in the diagnosis of both primary and secondary immunological disorders.

14.
Crit Rev Clin Lab Sci ; 55(3): 184-204, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29502462

RESUMO

The integrity of the interferon (IFN)-γ circuit is necessary to mount an effective immune response to intra-macrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit that disrupt the production of, or response to, IFN-γ underlie a primary immunodeficiency known as Mendelian susceptibility to mycobacterial disease (MSMD). Otherwise healthy patients display a selective susceptibility to clinical disease caused by poorly virulent mycobacteria such as BCG (bacille Calmette-Guérin) vaccines and environmental mycobacteria, and more rarely by other intra-macrophagic pathogens, particularly Salmonella and M. tuberculosis. There is high genetic and allelic heterogeneity, with 19 genetic etiologies due to mutations in 10 genes that account for only about half of the patients reported. An efficient laboratory diagnostic approach to suspected MSMD patients is important, because it enables the establishment of specific therapeutic measures that will improve the patient's prognosis and quality of life. Moreover, it is essential to offer genetic counseling to affected families. Herein, we review the various genetic and immunological diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with MSMD.

15.
Clin Immunol ; 191: 44-51, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29572183

RESUMO

There is scarce literature about autoinflammation in syndromic patients. We describe a patient who, in addition to psychomotor and growth delay, presented with fevers, neutrophilic dermatosis, and recurrent orogenital ulcers. Comparative Genomic Hybridization (CGH) array permitted to identify a 13.13Mb deletion on chromosome 6, encompassing 53 genes, and including TNFAIP3 gene (A20). A20 is a potent inhibitor of the NF-kB signalling pathway and restricts inflammation via its deubiquitinase activity. Western blotting and immunoprecipitation assays showed decreased A20 expression and increased phosphorylation of p65 and IkBa. Patient's cells displayed increased levels of total K63-linked ubiquitin and increased levels of ubiquitinated RIP and NEMO after stimulation with TNF. We describe the molecular characterization of an autoinflammatory disease due to a large chromosomal deletion and review the phenotypes of patients with A20 haploinsufficiency. CGH arrays should be the first diagnostic method for comprehensive analysis of patients with syndromic features and immune dysregulation.

16.
J Clin Immunol ; 37(8): 781-789, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28942469

RESUMO

The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete FI deficiency is a rare autosomal recessive disorder typically resulting in severe, recurrent infection by encapsulated bacteria. In the present study, we describe two patients from unrelated families with complete FI deficiency diagnosed at very different ages: Patient 1 is a 60-year-old man who had experienced several severe infections (pneumonia, meningitis, sepsis) since childhood, one of which caused significant and permanent neurologic sequelae. In contrast, patient 2 was diagnosed at the age of 4 years after a single infectious episode (otitis media) and through detection of a flat beta2 peak on serum protein electrophoresis. This early diagnosis of FI deficiency enabled prompt implementation of a therapeutic intervention consisting of vaccination with encapsulated bacteria and prophylactic antibiotics. The two patients had novel homozygous mutations in the CFI gene (p.Gly162Asp and p.His380Arg) that disrupted protein function. Interestingly, p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, and Ser525). This study illustrates the importance of early versus late diagnosis of FI deficiency and, in general, highlights the clinical relevance of prompt detection of complement system deficiencies.


Assuntos
Vacinas Bacterianas/imunologia , Complemento C3/deficiência , Fator I do Complemento/genética , Doenças Genéticas Inatas/diagnóstico , Infecção/diagnóstico , Meningites Bacterianas/diagnóstico , Mutação/genética , Antibioticoprofilaxia , Pré-Escolar , Complemento C3/genética , Diagnóstico Tardio , Diagnóstico Precoce , Família , Doenças Genéticas Inatas/genética , Homozigoto , Humanos , Imunidade Inata , Infecção/genética , Masculino , Meningites Bacterianas/genética , Meningites Bacterianas/prevenção & controle , Pessoa de Meia-Idade , Linhagem , Vacinação
17.
Pediatr Infect Dis J ; 36(2): e31-e37, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27832021

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is more common in HIV-infected adults and children than in the general population. Adipocytokines and inflammatory markers may contribute to the pathophysiology of this condition and could be useful indices for monitoring MetS. The objective of this study was to provide information on the prevalence of MetS and investigate the role of adipocytokines and other biomarkers in this syndrome in HIV-infected pediatric patients. METHODS: A cross-sectional study was conducted between October 2013 and March 2014 in the outpatient clinics of 2 tertiary pediatric referral hospitals. Fifty-four HIV-infected children and adolescents were included. MetS was defined according to the International Diabetes Federation and modified National Cholesterol Education Program Adult Treatment Panel III criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin, adiponectin, leptin, interleukin-6, vitamin D and C-reactive protein and clinical lipodystrophy assessment. RESULTS: Among the total, 3.7% of patients met the International Diabetes Federation criteria for MetS and 7.4% met the National Cholesterol Education Program Adult Treatment Panel III criteria. C-reactive protein and leptin levels were significantly higher and adiponectin level significantly lower in patients with MetS, regardless of the criteria used. Insulin resistance was observed in 40.7% of patients; abnormal quantitative insulin sensitivity check index values were found in 88.9%. Eighteen patients (33.3%) had vitamin D deficiency. CONCLUSIONS: The prevalence of MetS was similar to that observed in larger cohorts of HIV-infected patients in our setting. Adipocytokine dysregulation seems to be related to MetS in HIV-infected children. A high percentage of patients showed insulin resistance, which should be strictly monitored.


Assuntos
Adiponectina/sangue , Biomarcadores/sangue , Síndrome de Lipodistrofia Associada ao HIV/complicações , Leptina/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Adolescente , Criança , Estudos Transversais , Feminino , Síndrome de Lipodistrofia Associada ao HIV/epidemiologia , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Fatores de Risco , Espanha/epidemiologia , Deficiência de Vitamina D
18.
Pediatrics ; 138(2)2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27436506

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency that leads to severe recurrent infection and inflammatory complications that are usually difficult to diagnose and treat. Several hyperinflammation mechanisms, such as decreased neutrophil apoptosis, toll-like receptor activation imbalance, Th17 cell induction, Nrf2 activity deficiency, and inflammasome activation, have been described in CGD patients However, there have been no reports of chronic recurrent multifocal osteomyelitis as an inflammatory complication in CGD, and the differential diagnosis of this condition with infectious osteomyelitis is challenging. Thalidomide has been used to treat several inflammatory manifestations in CGD patients with good clinical results. Here, we report the case of a previously asymptomatic 11-year-old boy who consulted for difficulty walking and pain at the back of the right thigh, with increased inflammatory markers. Multifocal bone involvement was seen on bone scintigraphy, and acute-phase reactants were elevated. On the basis of a suspected diagnosis of infectious osteomyelitis, broad-spectrum antibiotic therapy was started, with no clinical response. Bone biopsy and microbiological tests yielded negative results; at that point, chronic recurrent multifocal osteomyelitis was suspected. The patient was unresponsive to nonsteroidal antiinflammatory drugs and corticosteroids. Thalidomide was started, and within 6 months, clinical and radiologic resolution of the condition was achieved with no adverse effects. More than 1 year after stopping thalidomide, the patient remained free of symptoms and inflammatory parameters are within normal levels. Thalidomide has a favorable safety profile compared with other alternatives and could be considered a feasible therapeutic option for this type of condition in selected patients.


Assuntos
Doença Granulomatosa Crônica/complicações , Imunossupressores/uso terapêutico , Osteomielite/diagnóstico por imagem , Talidomida/uso terapêutico , Criança , Doença Granulomatosa Crônica/tratamento farmacológico , Humanos , Masculino , Osteomielite/tratamento farmacológico , Osteomielite/etiologia , Cintilografia
19.
J Clin Immunol ; 36(4): 388-96, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27026170

RESUMO

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.


Assuntos
Complemento C5/deficiência , Complemento C5/genética , Síndromes de Imunodeficiência/genética , África , Criança , Pré-Escolar , Complemento C5/metabolismo , Feminino , Humanos , Síndromes de Imunodeficiência/metabolismo , Lactente , Masculino , Mutação , Linhagem
20.
Clin Immunol ; 163: 60-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26748374

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease characterized by early-onset life-threatening multisystemic autoimmunity. This rare hereditary disorder is caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor, which plays a key role in the differentiation and function of CD4(+)CD25(+) natural regulatory T cells (Tregs), essential for the establishment and maintenance of natural tolerance. We identified a novel mutation in the FOXP3 gene affecting the Phe367 residue of the protein (F367V) in a family with three male siblings affected by IPEX. Two other mutations affecting the FOXP3 Phe367 residue (F367L and F367C) have been described previously. This unique situation of three mutations affecting the same residue in FOXP3 led us to study the molecular impact of these mutations on the structure of FOXP3 protein. Structure analysis showed that Phe367 is involved in a rich interaction network related to both monomer and dimer structure stabilization, and is crucial for FOXP3 regulatory activity. The relevance of this location is confirmed by the results of SIFT and PolyPhen-2 pathogenicity predictions for F367V mutation. In summary, as assessment of the pathogenicity of a novel mutation is crucial to achieve a proper molecular diagnosis, we analysed the impact of mutations affecting the Phe367 residue using a combined approach that provides a mechanistic view of their pathogenic effect.


Assuntos
Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças do Sistema Imunitário/congênito , Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diarreia/imunologia , Dimerização , Eczema/genética , Eczema/imunologia , Eosinofilia/genética , Eosinofilia/imunologia , Evolução Fatal , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , Hemorragia/genética , Hemorragia/imunologia , Hepatomegalia/genética , Hepatomegalia/imunologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Imunoglobulina E/imunologia , Lactente , Infecções por Klebsiella/genética , Infecções por Klebsiella/imunologia , Leucocitose/genética , Leucocitose/imunologia , Pneumopatias/genética , Pneumopatias/imunologia , Masculino , Meningoencefalite/genética , Meningoencefalite/imunologia , Modelos Moleculares , Mutação , Fenilalanina/genética , Sepse/genética , Sepse/imunologia , Esplenomegalia/genética , Esplenomegalia/imunologia , Trombocitopenia/genética , Trombocitopenia/imunologia , Timo/anormalidades
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