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1.
J Clin Immunol ; 39(4): 363-369, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31102035
2.
Immunotherapy ; 11(5): 397-406, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30626238

RESUMO

AIM: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. PATIENTS & METHODS: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n = 6], 6-11 years [n = 22] and 12-17 years [n = 22]) receiving Ig20Gly in two Phase II/III trials. RESULTS: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30 ml/h/site; 30 ml/site) versus 6-11 years (20 ml/h/site; 15 ml/site) and 2-5 years (18 ml/h/site; 14 ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. CONCLUSION: Ig20Gly infused at relatively high rates and volumes was well tolerated in children.

3.
Orv Hetil ; 159(23): 937-947, 2018 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-29860885

RESUMO

Primary immunodeficiency diseases (PIDs) are inherited, genetic disorders. The majority of PIDs are diagnosed in infancy or early childhood, but manifestation in adulthood may also occur. Frequent, recurrent and prolonged infections, which respond poorly to treatment may be heralding signs. PID patients may have increased suspectibility to infections, that mostly affect the sino-pulmonary and intestinal tracts and the skin. PIDs are also frequently associated with autoimmune and inflammatory disorders. Cutaneous manifestations affect 40% to 70% of patients with diagnosed PID. Bacterial and fungal infections of the skin, recurrent pyogen abscesses are common complications. Severe atopy, eczema and erythroderma occurring early in childhood should raise awareness of PID. Cutaneous granulomas, pigment changes and dysplasia of skin, hair, and nails can also be seen frequently in some of these conditions. Here we overview the most frequent dermatological diseases occuring in patients with PID. Orv Hetil. 2018; 159(23): 937-947.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Dermatopatias Infecciosas/imunologia , Dermatopatias/imunologia , Pele/patologia , Adulto , Autoimunidade/imunologia , Criança , Humanos , Síndromes de Imunodeficiência/complicações , Pele/imunologia , Dermatopatias/diagnóstico
6.
Artigo em Inglês | MEDLINE | ID: mdl-29649853

RESUMO

BACKGROUND: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. METHODS: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. RESULTS: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). CONCLUSION: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

9.
Blood ; 127(25): 3154-64, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27114460

RESUMO

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.


Assuntos
Candidíase Mucocutânea Crônica/genética , Estudos de Associação Genética , Mutação , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
10.
J Clin Immunol ; 35(7): 681-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26453584

RESUMO

PURPOSE: Hyper-IgE syndrome (HIES) is a severe primary immunodeficiency, characterized by increased serum IgE levels as well as recurrent infections and atopic dermatitis (AD)-like skin lesions. AD is a chronic inflammatory skin disease with immunologic alterations (Th2-Th22 polarization) and characteristic skin barrier dysfunctions. Our aim was to investigate physicochemical skin barrier alterations and allergic sensitization in STAT3-HIES patients in order to explore whether skin barrier dysfunction can play a role in the eczematoid skin lesions in these patients. METHODS: In our experiments STAT3 and FLG mutation analyses were performed in STAT3-HIES (n = 7) and AD (n = 49) patients. Laboratory parameters (LDH and Eos counts), immunologic alterations (Th17 cell counts), allergic sensitization (total and specific IgE levels, skin prick tests, and medical history records), skin barrier changes [transepidermal water loss (TEWL), skin pH], serum and stratum corneum thymic stromal lymphopoietin (TSLP) levels were also examined. RESULTS: Impaired Th17 cell numbers, but normal physicochemical barrier functions, as well as serum and stratum corneum TSLP levels, were found in STAT3-HIES, while these parameters were significantly altered in AD patients. Allergic sensitization was detected in nearly all AD patients, while no signs of sensitization occurred in STAT3-HIES. CONCLUSIONS: Our study demonstrated that the skin barrier functions of STAT3-HIES patients are not damaged and they differ significantly from the altered skin barrier functions of AD patients. A well-functioning physicochemical skin barrier may be one of the explanations on the contradiction between the extremely high total IgE levels and the lack of allergic sensitization in these patients. Our study underlines the importance of skin barrier in the development of allergic sensitization.


Assuntos
Dermatite Atópica/imunologia , Síndrome de Job/imunologia , Fator de Transcrição STAT3/genética , Pele/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Imunização , Imunoglobulina E/sangue , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Pele/patologia , Adulto Jovem
11.
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
12.
Int Rev Immunol ; 34(4): 348-63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26154078

RESUMO

The discovery of interleukin (IL)-17-mediated immunity has provided a robust framework upon which our current understanding of the mechanism involved in host defense against mucocutaneous candidiasis (CMC) has been built. Studies have shed light on how pattern recognition receptors expressed by innate immune cells recognize various components of Candida cell wall. Inborn errors of immunity affecting IL-17+ T cell differentiation have recently been defined, such as deficiencies of signal transducer and activator of transcription (STAT)3, STAT1, IL-12Rß1 and IL-12p40, and caspase recruitment domain 9. Impaired receptor-ligand coupling was identified in patients with IL-17F and IL-17 receptor A (IL17RA) deficiency and autoimmune polyendocrine syndrome (APS) type 1. Mutation in the nuclear factor kappa B activator (ACT) 1 was described as a cause of impaired IL-17R-mediated signaling. CMC may be part of a complex clinical phenotype like in patients with deficiencies of STAT3, IL-12Rß1/IL-12p40 and APS-1 or may be the only or dominant phenotypic manifestation of disease which is referred to as CMC disease. CMCD may result from deficiencies of STAT1, IL-17F, IL-17RA and ACT1. In this review we discuss how recent research on IL-17-mediated immunity shed light on host defense against mucocutaneous infection by Candida and how the discovery of various germ-line mutations and the characterization of associated clinical phenotypes have provided insights into the role of CD4+IL-17+ lymphocytes in the regulation of anticandidal defense of body surfaces.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Interleucina-17/metabolismo , Células Th17/imunologia , Animais , Humanos , Imunidade Inata , Interleucina-17/genética
13.
Cell Host Microbe ; 17(4): 507-14, 2015 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-25771792

RESUMO

Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1ß induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.


Assuntos
Aspergillus fumigatus/imunologia , Candida albicans/imunologia , Interações Hospedeiro-Patógeno , Tolerância Imunológica , Neutrófilos/imunologia , Animais , Aspergilose/imunologia , Aspergilose/microbiologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candidíase/imunologia , Candidíase/microbiologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Lectinas Tipo C/metabolismo , Camundongos , Transdução de Sinais
14.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25627830

RESUMO

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.


Assuntos
Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Incidência , Lactente , /epidemiologia , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Síndrome de Job/terapia , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Neoplasias/etiologia , Fenótipo , Adulto Jovem
15.
Eur J Haematol ; 95(1): 93-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25082437

RESUMO

Deletion mutations of WAS are relatively rare and the precise localization of large deletions in the genome has rarely been described in previous studies. We report here a 5-month-old boy with a large deletion mutation in WAS that completely abolished protein expression. To localize the deletion, a 2816-bp-length sequence that spans between exons 9 and 12 was amplified. PCR amplification of the patient's sample revealed a single band of about 1 kb in contrast to the 2816-bp-amplicon in the control. Genomic DNA sequencing of the patient revealed a 1595-bp-deletion and an adenine insertion (g.5247_6841del1595insA). This large deletion of WAS resulted in partial loss of exon 10 and intron 11, and a complete loss of intron 10 and exon 11.


Assuntos
Éxons , Mutação INDEL , Proteína da Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/genética , Sequência de Bases , Humanos , Lactente , Íntrons , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/deficiência
16.
Sci Transl Med ; 6(227): 227ra33, 2014 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-24622513

RESUMO

Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.


Assuntos
Terapia Genética/efeitos adversos , Mutagênicos/efeitos adversos , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/uso terapêutico , Síndrome de Wiskott-Aldrich/terapia , Adolescente , Animais , Plaquetas/metabolismo , Criança , Pré-Escolar , Células Clonais , Colite/etiologia , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Trombocitopenia/terapia , Transplante Autólogo , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
17.
J Clin Immunol ; 34(2): 181-93, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24493573

RESUMO

The relative roles of various autoantibodies against IL-17-type cytokines in susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) remain poorly defined. The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies. We studied six APECED patients from four families with various disease manifestations. Clinical data were collected during regular follow-up. Anti-endocrine organ antibody levels and clinical chemistry and immunology parameters were determined in routine laboratory assays on freshly isolated serum. Levels of autoantibodies against IL-17A, IL-17F, IL-22, IFN-α, IFN-ω and TNF-α, and cytokine release by Candida-exposed blood cells were determined by ELISA. Mutations were analyzed by sequencing genomic DNA. Four patients carried the germline c.769C > T homozygous nonsense mutation, which results in R257X truncation of the AIRE protein, and two patients from the same family were compound heterozygous for the c.769C > T/c.1344delC mutation. We found persistently high levels of antibodies against IL-17A in the serum samples of one patient presenting CMC since infancy and low or undetectable anti-IL-17A antibody levels in the sera of five patients with no candidiasis or without severe candidiasis. By contrast, levels of autoantibodies against IL-17F and IL-22 were higher in all patients than in healthy controls. Release of IL-17-type cytokines by Candida-exposed blood mononuclear cells was low or negligible in all patients tested. We suggest that anti-IL-17A antibodies may play an important role in the predisposition to candidiasis of APECED patients. However, the lack of severe CMC in APECED patients with high levels of IL-17F and anti-IL-22 autoantibodies clearly calls into question the role of these antibodies as the principal cause of cutaneous and mucosal candidiasis in at least some APECED patients. These data also suggest that the impaired release of IL-17-type cytokines by blood cells may be an element of the immunopathology of CMC in APECED patients.


Assuntos
Autoanticorpos/imunologia , Candidíase Mucocutânea Crônica/patologia , Interleucina-17/imunologia , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Citocinas/biossíntese , Citocinas/imunologia , Análise Mutacional de DNA , Feminino , Heterozigoto , Homozigoto , Humanos , Interferon Tipo I/imunologia , Interleucinas/imunologia , Masculino , Mutação , Linhagem , Poliendocrinopatias Autoimunes/terapia , Polimorfismo Genético , Índice de Gravidade de Doença , Fatores de Transcrição/genética , Adulto Jovem
18.
J Allergy Clin Immunol ; 133(1): 172-80.e1-10, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24012209

RESUMO

BACKGROUND: Primary antibody deficiencies represent the most prevalent, although very heterogeneous, group of inborn immunodeficiencies, with a puzzling complexity of cellular and molecular processes involved in disease pathogenesis. OBJECTIVE: We aimed to study in detail the kinetics of CD40 ligand/IL-21-induced B-cell differentiation to define new biomarker sets for further research into primary antibody deficiencies. METHODS: We applied high-content screening methods to monitor B-cell activation on the cellular (chip cytometry) and transcriptomic (RNA microarray) levels. RESULTS: The complete activation process, including stepwise changes in protein and RNA expression patterns, entry into the cell cycle, proliferation and expression of activation-induced cytidine deaminase (AID), DNA repair enzymes, and post-class-switch expression of IgA and IgG, was successfully monitored during in vitro differentiation. We identified a number of unknown pathways engaged during B-cell activation, such as CXCL9/CXCL10 secretion by B cells. Finally, we evaluated a deduced set of biomarkers on a group of 18 patients with putative or proved intrinsic B-cell defects recruited from the European Society for Immunodeficiencies database and successfully predicted 2 AID defects and 1 DNA repair defect. Complete absence of class-switched B cells was a sensitive predictor of AID deficiency and should be further evaluated as a diagnostic biomarker. CONCLUSION: The biomarkers found in this study could be used to further study the complex process of B-cell activation and to understand conditions that lead to the development of primary antibody deficiencies.


Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/diagnóstico , Ativação Linfocitária/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Diferenciação Celular , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Criança , Feminino , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Citometria por Imagem , Switching de Imunoglobulina , Síndromes de Imunodeficiência/imunologia , Recém-Nascido , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , RNA Mensageiro/análise , Transcriptoma/imunologia , Adulto Jovem
19.
Eur J Haematol ; 91(4): 369-75, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23859592

RESUMO

Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria and fungi, very high serum IgE concentrations, and a progressive deterioration of T- and B-cell-mediated immunity. We studied the genetic and immunological features of two sisters (aged 11 and 6 yr). Mutational analysis of genomic DNA and cDNA from the patients and their parents, by a combination of PCR and bidirectional targeted sequencing, failed to localize the mutation site. However, a multiplex ligation-dependent probe amplification (MLPA) assay revealed two novel large deletions, del1-14 exons and del8-18 exons, of DOCK8 in both patients. Immunoblot analysis demonstrated that DOCK8 protein was absent from the peripheral blood lymphocytes of both patients. These data suggest that compound heterozygous del1-14 exons and del8-18 exons mutations result in a loss of function of DOCK8 protein and a typical DOCK8 deficiency phenotype.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/genética , Imunidade Adaptativa , Sequência de Bases , Criança , Éxons , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Multiplex/métodos , Linhagem , Deleção de Sequência , Irmãos
20.
Ann Lab Med ; 33(4): 274-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23826564

RESUMO

Recently, lyso-globotriaosylsphingosine (lyso-Gb3) was found to be elevated in plasma of treatment naive male patients and some female patients with Fabry Disease (FD). This study tested whether lyso-Gb3 could be analyzed in dried blood spots (DBS) from filter cards and whether concentrations are elevated in newborn infants with FD. Lyso-Gb3 concentrations were analyzed in DBS following extraction using a novel HPLC-mass spectrometry (MS)/MS method. Lyso-Gb3 levels in DBS were above the lower limit of quantitation (0.28 ng/mL) in 5/17 newborn FD infants (16 males; range: 1.02-8.81 ng/mL), but in none of the newborn controls, in all 13 patients (4 males) with classic FD (range: 2.06-54.1 ng/mL), in 125/159 Taiwanese individuals with symptomatic or asymptomatic FD who carry the late onset α-galactosidase A (GLA) mutation c.936+919G>A (IVS4+919G>A) (3.75±0.69 ng/mL; range: 0.418-3.97 ng/mL) and in 20/29 healthy controls (0.77±0.24 ng/mL; range: 0.507-1.4 ng/mL). The HPLC-MS/MS method for analysis of lyso-Gb3 is robust and yields reproducible results in DBS in patients with FD. However, concentrations of lyso-Gb3 were below the limit of quantitation in most newborn infants with FD rendering this approach not suitable for newborn screening. In addition, most females with the late onset mutation have undetectable lyso-Gb3 concentrations.


Assuntos
Análise Química do Sangue/métodos , Teste em Amostras de Sangue Seco , Glicolipídeos/sangue , Esfingolipídeos/sangue , Adolescente , Adulto , Criança , Cromatografia Líquida de Alta Pressão , Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Feminino , Humanos , Recém-Nascido , Masculino , Espectrometria de Massas em Tandem , Adulto Jovem
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