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1.
Cells ; 9(2)2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32102320

RESUMO

Over a decade ago, the formation of neutrophil extracellular traps (NETs) was described as a novel mechanism employed by neutrophils to tackle infections. Currently applied methods for NETs release quantification are often limited by the use of unspecific dyes and technical difficulties. Therefore, we aimed to develop a fully automatic image processing method for the detection and quantification of NETs based on live imaging with the use of DNA-staining dyes. For this purpose, we adopted a recently proposed Convolutional Neural Network (CNN) model called Mask R-CNN. The adopted model detected objects with quality comparable to manual counting-Over 90% of detected cells were classified in the same manner as in manual labelling. Furthermore, the inhibitory effect of GW 311616A (neutrophil elastase inhibitor) on NETs release, observed microscopically, was confirmed with the use of the CNN model but not by extracellular DNA release measurement. We have demonstrated that a modern CNN model outperforms a widely used quantification method based on the measurement of DNA release and can be a valuable tool to quantitate the formation process of NETs.

2.
J Clin Immunol ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31749033

RESUMO

OBJECTIVES: The aim of the study was to estimate the rate of adverse reactions to live BCG Moreau vaccine, manufactured by Biomed in Poland, in severe combined immunodeficiency (SCID) patients. MATERIAL: The profiles of 52 SCID patients vaccinated at birth with BCG, hospitalized in Children's Memorial Health Institute, Warsaw (CMHI), in the years 1980-2015 were compared with those of 349 BCG-vaccinated SCID patients from other countries analyzed by Beatriz E. Marciano et al. in a retrospective study (Marciano et al. J Allergy Clin Immunol. 2014;133(4):1134-1141). RESULTS: Significantly less disseminated BCG infections (10 out of 52 SCID, 19%) occurred in comparison with Marciano study-119 out of 349, 34% (p = 0.0028), with no death in patients treated with SCID anti-TB drug, except one in lethal condition. In our study, disseminated BCG infection was observed only in SCID with T-B+NK- phenotype and significantly lower NK cell counts (p = 0.0161). NK cells do not influence on the frequency of local BCG reaction. A significantly higher number of hematopoietic stem cells transplantations (HSCT) were performed in CMHI study (p = 0.0001). Anti-TB treatment with at least two medicines was provided. CONCLUSION: The BCG Moreau vaccine produced in Poland, with well-documented genetic characteristics, seems to be safer than other BCG substrains used in other regions of the world. Importantly, NK cells seem to play a role in protecting SCID patients against disseminated BCG complications, which NK- SCID patients are more prone to. HSCT and TB therapy could be relevant due to the patients' survival and the fact that they protect against BCG infection.

3.
Front Immunol ; 10: 2322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611883

RESUMO

Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

4.
Cell Mol Life Sci ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650185

RESUMO

Despite great interest, the mechanism of neutrophil extracellular traps (NETs) release is not fully understood and some aspects of this process, e.g. the role of reactive nitrogen species (RNS), still remain unclear. Therefore, our aim was to investigate the mechanisms underlying RNS-induced formation of NETs and contribution of RNS to NETs release triggered by various physiological and synthetic stimuli. The involvement of RNS in NETs formation was studied in primary human neutrophils and differentiated human promyelocytic leukemia cells (HL-60 cells). RNS (peroxynitrite and nitric oxide) efficiently induced NETs release and potentiated NETs-inducing properties of platelet activating factor and lipopolysaccharide. RNS-induced NETs formation was independent of autophagy and histone citrullination, but dependent on the activity of phosphoinositide 3-kinases (PI3K) and myeloperoxidase, as well as selective degradation of histones H2A and H2B by neutrophil elastase. Additionally, NADPH oxidase activity was required to release NETs upon stimulation with NO, as shown in NADPH-deficient neutrophils isolated from patients with chronic granulomatous disease. The role of RNS was further supported by increased RNS synthesis upon stimulation of NETs release with phorbol 12-myristate 13-acetate and calcium ionophore A23187. Scavenging or inhibition of RNS formation diminished NETs release triggered by these stimuli while scavenging of peroxynitrite inhibited NO-induced NETs formation. Our data suggest that RNS may act as mediators and inducers of NETs release. These processes are PI3K-dependent and ROS-dependent. Since inflammatory reactions are often accompanied by nitrosative stress and NETs formation, our studies shed a new light on possible mechanisms engaged in various immune-mediated conditions.

5.
Pediatrics ; 142(4)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30209074

RESUMO

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, severe immunodeficiency, and predisposition to lymphoid malignancy. In this report, we describe a case of a 9-year-old boy, previously diagnosed with NBS and symptoms of dyspnea, dry cough, and fever. Despite initial recognition of pneumonia, there was no response to broad spectrum antimicrobial treatment, negative results from microbiological tests, and unclear changes in lung imaging were observed. Therefore, further diagnostics were focused on suspected lymphoid malignancy and involved lung biopsy. Unexpectedly, histopathological examination revealed noncaseating granulomas. The introduction of systemic steroids resulted in significant improvement of the patient's clinical condition. This is the first description of primary pulmonary noncaseating granulomas without nodular involvement in a child with NBS.


Assuntos
Granuloma/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Síndrome de Quebra de Nijmegen/diagnóstico por imagem , Criança , Granuloma/complicações , Granuloma/terapia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/terapia , Masculino , Síndrome de Quebra de Nijmegen/complicações , Síndrome de Quebra de Nijmegen/terapia
6.
Adv Med Sci ; 63(1): 173-178, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29128760

RESUMO

PURPOSE: The objective of this study was to evaluate thevitamin D concentration in patients with recurrent respiratory infections with or without immunoglobulin G, A or M (IgG, IgA, IgM) deficiency, and to find a correlation between the vitamin D concentration and the response to hepatitis B vaccination. MATERIALS AND METHOD: The study involved 730 patients with recurrent respiratory infections. The concentration of 25-hydroxyvitamin D (25(OH)D), immunoglobulins G, A and M, anti-HBs was determined. RESULTS: The tests showed that 11% of patients presented IgG levels below the age related reference values. Children with reduced IgG concentration were also found to have significantly lower vitamin D concentrations in comparison to children with normal IgG. Vitamin D deficiency was observed in schoolchildren between 7 and 18 years of age. No correlation was found between 25(OH)D concentration and Hbs antibody levels. CONCLUSIONS: An investigation of a large group of patients who have recurrent infection found patients with IgG deficiency to whom special proceeding have to be performed: 1. Significantly lower vitamin D concentration observed in the group of children with IgG deficiency implicated in long-lasting monitoring of vitamin D level require adding to the practice guidelines for Central Europe 2013. 2. Intervention treatment with suitable doses of vitamin D to clarified metabolism of vitamin D has to be plan for children with IgG deficiency and significant lower vitamin D concentration.


Assuntos
Imunoglobulinas/deficiência , Infecções Respiratórias/complicações , Deficiência de Vitamina D/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Recidiva , Infecções Respiratórias/sangue , Estações do Ano , Vitamina D/sangue , Deficiência de Vitamina D/sangue
7.
Front Immunol ; 8: 1683, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29255463

RESUMO

Germline mutations in the RING finger protein gene RNF168 have been identified in a combined immunodeficiency disorder called RIDDLE syndrome. Since only two patients have been described with somewhat different phenotypes, there is need to identify further patients. Here, we report on two Polish siblings with RNF168 deficiency due to homozygosity for a novel frameshift mutation, c.295delG, that was identified through exome sequencing. Both patients presented with immunoglobulin deficiency, telangiectasia, cellular radiosensitivity, and increased alpha-fetoprotein (AFP) levels. The younger sibling had a more pronounced neurological and morphological phenotype, and she also carried an ATM gene mutation in the heterozygous state. Immunoblot analyses showed absence of RNF168 protein, whereas ATM levels and function were proficient in lymphoblastoid cells from both patients. Consistent with the absence of RNF168 protein, 53BP1 recruitment to DNA double-strand breaks (DSBs) after irradiation was undetectable in lymphoblasts or primary fibroblasts from either of the two patients. γH2AX foci accumulated normally but they disappeared with significant delay, indicating a severe defect in DSB repair. A comparison with the two previously identified patients indicates immunoglobulin deficiency, cellular radiosensitivity, and increased AFP levels as hallmarks of RNF168 deficiency. The variability in its clinical expression despite similar cellular phenotypes suggests that some manifestations of RNF168 deficiency may be modified by additional genetic or epidemiological factors.

8.
Redox Biol ; 11: 375-383, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28063379

RESUMO

Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.


Assuntos
Ataxia Telangiectasia/genética , Síndrome de Bloom/genética , Reparo do DNA , Mitocôndrias/metabolismo , Síndrome de Quebra de Nijmegen/genética , Estresse Oxidativo/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Síndrome de Bloom/metabolismo , Síndrome de Bloom/patologia , Dano ao DNA , Regulação da Expressão Gênica , Humanos , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Mitocôndrias/patologia , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Síndrome de Quebra de Nijmegen/metabolismo , Síndrome de Quebra de Nijmegen/patologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Oxid Med Cell Longev ; 2017: 6745840, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29456787

RESUMO

This study compared the antioxidant status and major lipophilic antioxidants in patients with ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and concentrations of coenzyme Q10 (CoQ10) and vitamins A and E were estimated in the plasma of 22 patients with AT, 12 children with NBS, and the healthy controls. In AT patients, TAS (median 261.7 µmol/L) was statistically lower but TOS (496.8 µmol/L) was significantly elevated in comparison with the healthy group (312.7 µmol/L and 311.2 µmol/L, resp.). Tocopherol (0.8 µg/mL) and CoQ10 (0.1 µg/mL) were reduced in AT patients versus control (1.4 µg/mL and 0.3 µg/mL, resp.). NBS patients also displayed statistically lower TAS levels (290.3 µmol/L), while TOS (404.8 µmol/L) was comparable to the controls. We found that in NBS patients retinol concentration (0.1 µg/mL) was highly elevated and CoQ10 (0.1 µg/mL) was significantly lower in comparison with those in the healthy group. Our study confirms disturbances in redox homeostasis in AT and NBS patients and indicates a need for diagnosing oxidative stress in those cases as a potential disease biomarker. Decreased CoQ10 concentration found in NBS and AT indicates a need for possible supplementation.


Assuntos
Ataxia Telangiectasia/metabolismo , Síndrome de Quebra de Nijmegen/metabolismo , Oxirredução , Adolescente , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Criança , Feminino , Homeostase , Humanos , Masculino , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Estresse Oxidativo , Ubiquinona/análogos & derivados , Ubiquinona/sangue , Vitamina A/sangue , Vitamina E/sangue
10.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271390

RESUMO

PURPOSE: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. METHODS: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. RESULTS: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies. CONCLUSIONS: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/diagnóstico , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Instabilidade Cromossômica , Feminino , Humanos , Síndromes de Imunodeficiência , Lactente , Linfoma não Hodgkin , Masculino , Microcefalia , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
11.
J Clin Immunol ; 33(4): 731-41, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23389235

RESUMO

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naïve B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Adolescente , Idade de Início , Circulação Sanguínea , Diferenciação Celular , Separação Celular , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Testes Diagnósticos de Rotina , Progressão da Doença , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Masculino , Prognóstico , Risco , Fatores Sexuais
12.
J Exp Med ; 209(9): 1567-82, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22851595

RESUMO

Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-α/ß or IFN-λ is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-α2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients' peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS.


Assuntos
Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/imunologia , Mutação , Proteínas Serina-Treonina Quinases/genética , Receptor 3 Toll-Like/imunologia , Animais , Morte Celular/imunologia , Células Cultivadas , Criança , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/virologia , Genes Dominantes , Herpesvirus Humano 1/patogenicidade , Humanos , Interferon beta/imunologia , Masculino , Camundongos , Poli I-C/farmacologia , Proteínas Serina-Treonina Quinases/imunologia , Vesiculovirus/patogenicidade
13.
Orphanet J Rare Dis ; 6: 76, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22085750

RESUMO

The hyper-IgE syndromes are rare, complex primary immunodeficiencies characterized by clinical manifestation diversity, by particular susceptibility to staphylococcal and mycotic infections as well as by a heterogeneous genetic origin. Two distinct entities--the classical hyper-IgE syndrome which is inherited in an autosomal dominant pattern and the autosomal recessive hyper-IgE syndrome--have been recognized. The autosomal dominant hyper-IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. In the majority of affected patients with autosomal dominant hyper-IgE syndrome a mutation in the signal transducer and the activator of the transcription 3 gene has been identified, leading to an impaired Th17 cells differentiation and to a downregulation of an antimicrobial response. A mutation in the dedicator of the cytokinesis 8 gene has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome and, in one patient, a mutation in tyrosine kinase 2 gene has been demonstrated. In this paper, the authors provide a review of the clinical manifestations in the hyper-IgE syndromes with particular emphasis on the diversity of their phenotypic expression and present current diagnostic guidelines for these diseases.


Assuntos
Síndromes de Imunodeficiência/complicações , Síndrome de Job/patologia , Infecções Oportunistas/microbiologia , Criança , Pré-Escolar , Predisposição Genética para Doença , Humanos , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/imunologia , Fenótipo
14.
J Allergy Clin Immunol ; 125(2): 424-432.e8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20159255

RESUMO

BACKGROUND: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells. OBJECTIVE: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. METHODS: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. RESULTS: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. CONCLUSION: We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.


Assuntos
Síndrome de Job/diagnóstico , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Separação Celular , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina E/sangue , Lactente , Interleucina-17/imunologia , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Guias de Prática Clínica como Assunto , Linfócitos T Auxiliares-Indutores/imunologia , Adulto Jovem
15.
J Pediatr Hematol Oncol ; 32(1): e28-30, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20051774

RESUMO

SUMMARY: Ataxia-telangiectasia is an autosomal recessive disorder caused by mutation in the ATM gene. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasiae, cancer susceptibility, and variable humoral and cellular immunodeficiency. We report a patient who, because of the pattern of her immunodeficiency, was primarily diagnosed as an autosomal recessive hyper-IgM syndrome. Only a mild cerebellar ataxia was present at the age of 7 years then she developed a Wilms tumor (nephroblastoma). Conventional radiotherapy for the malignancy led to fatal consequences. Postmortem studies confirmed diagnosis of ataxia-telangiectasia.


Assuntos
Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM/etiologia , Radioterapia/mortalidade , Tumor de Wilms/radioterapia , Ataxia Cerebelar , Pré-Escolar , Evolução Fatal , Feminino , Humanos , Tumor de Wilms/etiologia
16.
Int J Hematol ; 90(5): 571-575, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19866337

RESUMO

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect of phagocyte NADPH-oxidase and characterized by severe, recurrent bacterial and fungal infections. Invasive aspergillosis (IA) is the leading cause of mortality in patients with CGD. We report the case of a 3-year-old boy with CGD, who developed IA despite antifungal prophylaxis. His treatment consisted of a 10-month-long multi-drug antifungal therapy, together with surgery, but these did not cause any substantial clinical improvement. BMT in high-risk patients with CGD remains a challenge due to both, higher risk of graft rejection and inflammatory flare in the course of immune recovery. Our patient rejected the first matched unrelated donor (MUD) allograft after RIC regimen recommended by the EBMT Inborn Errors Working Party for high-risk patients. After treosulfan-based conditioning and second MUD peripheral blood stem cell transplantation both, full reconstitution of the granulocytic series and complete recovery from IA, were achieved.


Assuntos
Aspergilose/terapia , Bussulfano/análogos & derivados , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Reoperação/métodos , Condicionamento Pré-Transplante/métodos , Antineoplásicos Alquilantes/uso terapêutico , Bussulfano/uso terapêutico , Pré-Escolar , Sobrevivência de Enxerto , Doença Granulomatosa Crônica/complicações , Humanos , Masculino
17.
Med Wieku Rozwoj ; 13(1): 19-25, 2009.
Artigo em Polonês | MEDLINE | ID: mdl-19648655

RESUMO

Hyper-IgE syndrome (HIES) is a primary immunodeficiency (PID) characterized by recurrent skin abscesses (S. aureus), recurrent pneumonia with pneumatocele formation, atopic dermatitis and elevated levels of serum IgE (>2000 IU/ml). HIES is a sporadic disease, however, two distinct entities - classic HIES inherited in an autosomal dominant pattern (AD HIES), and an autosomal recessive HIES (AR HIES) have been described. Some cases of AD HIES with predominant pulmonary manifestation are caused by mutation in STAT3 gene. It is important to differentiate cases of atopic dermatitis and AD HIES where it is necessary to implement antibacterial and antifungal prophylaxis. Opportunity of performing genetic analysis in suspicion of AD HIES leads to definitive diagnosis of the disease and earlier institution of appropriate treatment. We present the case of a 22-year-old patient with typical course of autosomal dominant hyper-IgE syndrome, confirmed in the Royal Free Hospital, University College London, UK, by finding mutation in STAT3 gene.


Assuntos
Síndrome de Job/diagnóstico , Síndrome de Job/genética , Mutação , Fator de Transcrição STAT3/genética , Adulto , Humanos , Masculino
18.
Przegl Epidemiol ; 63(1): 55-60, 2009.
Artigo em Polonês | MEDLINE | ID: mdl-19522227

RESUMO

Antibody deficiency may have genetic basis or be secondary to other diseases or iatrogenic factors. Recurrent respiratory, gastrointestinal and skin infections consist on the most frequent clinical picture. Severe course of these infections, recurrences and difficulties in treatment may suggest immunodeficiency. Antibody deficiency may be associated with numerous complications. Intravenous or subcutaneous immunoglobulin substitution is the way of treating these patients. Prevention of infection in primary and secondary antibody deficiency also includes vaccinations, prophylaxis with antibiotics and education of patients, parents and caregivers.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , /imunologia , Doenças Autoimunes/imunologia , Diagnóstico Diferencial , Suscetibilidade a Doenças , Educação em Saúde/métodos , Humanos , Deficiência de IgA/imunologia , Deficiência de IgG/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/prevenção & controle , /terapia
19.
Parasitol Res ; 103(1): 37-42, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18301922

RESUMO

Cryptosporidium spp. infection is usually self-limited in immunocompetent hosts but can be severe and life threatening in children and in immunocompromised individuals including those with primary or acquired immunodeficiencies. One hundred and three faecal samples were collected from 35 hospitalised patients with different symptoms and tested for the presence of the parasite. Cryptosporidium oocysts were found in four of 35 patients (11.4%) using Ziehl-Neelsen staining of faecal smears and immunofluorescence assay, whereas 12 (34.3%) samples tested positive by nested polymerase chain reaction assay. Cryptosporidium DNA was detected in one bile sample but not in a liver tissue biopsy sample collected from a patient who suffered from sclerosing cholangitis. Sequence analysis of oocyst wall protein and beta-tubulin gene fragments revealed three different parasite species (Cryptosporidium hominis, Cryptosporidium meleagridis and Cryptosporidium parvum) in children with primary immunodeficiencies, whereas only C. parvum was found in immunocompetent individuals and in those with secondary immunodeficiencies. This study has revealed a high prevalence of Cryptosporidium infection in hospitalised patients in Poland and confirmed that molecular techniques enable a more sensitive detection of the parasite.


Assuntos
Criptosporidiose/epidemiologia , Criptosporidiose/parasitologia , Cryptosporidium/genética , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Animais , Criança , Criptosporidiose/complicações , Gastroenterite/epidemiologia , Gastroenterite/parasitologia , Genótipo , Humanos , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Lansoprazol , Polônia/epidemiologia
20.
J Pediatr Gastroenterol Nutr ; 45(4): 458-64, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18030213

RESUMO

BACKGROUND: Cryptosporidium species infection is usually self-limited in immunocompetent populations, but can be severe and life-threatening among immunocompromised individuals, particularly in patients with AIDS and in these patients with primary immunodeficiencies (PIDs). PATIENTS AND METHODS: A group of 5 patients with genetically confirmed hyper-IgM syndrome type 1 (XHIM) and one patient with primary CD4 lymphopenia were enrolled in the study. At least 2 stool samples and a bile sample in one patient were examined for Cryptosporidium oocysts by a modified Ziehl-Neelsen technique, by immunofluorescence assay using a commercial kit, as well as by molecular analysis followed by genotyping. Immunological status at the time of PID diagnosis and the complex picture of disease are presented. RESULTS: Chronic cryptosporidiosis was confirmed in 3 patients with XHIM and in one patient with primary CD4 lymphopenia. Molecular diagnosis showed the presence of C parvum, C hominis, and C meleagridis in analyzed specimens. CONCLUSIONS: Cryptosporidium infection with serious clinical symptoms observed in patients with hyper-IgM syndrome calls for regular, repeated screening in this group of patients.


Assuntos
Criptosporidiose/diagnóstico , Cryptosporidium/isolamento & purificação , Síndromes de Imunodeficiência/complicações , Animais , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Criança , Pré-Escolar , Criptosporidiose/complicações , Criptosporidiose/tratamento farmacológico , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Hospedeiro Imunocomprometido , Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Paromomicina/administração & dosagem , Polônia , Estudos Retrospectivos , T-Linfocitopenia Idiopática CD4-Positiva/complicações , T-Linfocitopenia Idiopática CD4-Positiva/imunologia , T-Linfocitopenia Idiopática CD4-Positiva/terapia
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