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2.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

4.
J Infect Dis ; 218(1): 26-34, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29722823

RESUMO

Background: Vaccine-induced memory B-cell (MBC) subsets have distinct roles in the establishment of protective immunity; MBCs expressing nonswitched immunoglobulin M (IgM+ MBCs) replenish the MBC pool, whereas MBCs expressing isotype-switched immunoglobulin (sIg+ MBCs) differentiate into plasma cells upon antigen reencounter. We investigated immunogenicity and MBCs induced by combined 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPV23) in human immunodeficiency virus (HIV)-infected adults. Methods: Forty HIV-seropositive adults receiving ART with undetectable viral loads were enrolled. Seventeen had a CD4+ T-cell count of ≥400 cells/µL (group A), and 23 had a CD4+ T-cell count of 200-399 cells/µL (group B). All adults received PCV13 and, 1 year later, PPV23. Levels of IgM+ MBCs (defined as polysaccharide [PS]-specific CD19+CD10-CD27+CD21++IgM+ MBCs) and sIg+ MBCs (defined as PS-specific CD19+CD10-CD27+CD21++IgM- MBCs) and antibodies against PS14 and PS3 were measured prior and 1 month after each vaccination. Results: Immunization caused a significant increase in PS antibodies, compared with levels at baseline (P < .001). Group B achieved significantly lower titers than group A (P < .05 for both PS14 and PS3). After receipt of PCV13, levels of IgM+ MBCs were unchanged, whereas levels of sIg+ MBCs increased significantly (P < .05 for PS14 and P < .001 for PS3). In contrast, following PPV23 receipt, levels of IgM+ MBCs were significantly reduced, and levels of sIg+ MBCs remained stable. A positive correlation was observed between baseline IgM+ and sIg+ MBC counts 1 month after PCV13 receipt but not after PPV23 receipt. Conclusions: PPV23 receipt 12 months after PCV13 receipt improved PCV13 immunogenicity. The reduction in the IgM+ MBC count observed after PPV23 receipt suggests that PPV23 has a depleting effect on PCV13-associated immunological memory. Clinical Trials Registration: NCT03041051.


Assuntos
Infecções por HIV/complicações , Memória Imunológica , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Adulto , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Feminino , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
5.
J Pediatr Hematol Oncol ; 40(3): 240-242, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28859046

RESUMO

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency characterized by various clinical phenotypes. We report the case of a 3-year-old immigrant boy presenting with persistent infant-onset thrombocytopenia treated for refractory immune thrombocytopenic purpura. Sequence analysis confirmed the diagnosis of WAS. The patient responded neither to IV infusions of immunoglobulin (Ig) nor a thrombopoietin receptor agonist and is currently planned for stem cell transplantation. Raised awareness is thus vital of this potentially misdiagnosed and lethal disorder. The diagnosis of WAS should be considered in all males with infant-onset immune thrombocytopenic purpura-like features, especially, if mean platelet volume is decreased (<7 fL) and good increment to platelet transfusions are evident.


Assuntos
Púrpura Trombocitopênica Idiopática/diagnóstico , Síndrome de Wiskott-Aldrich/diagnóstico , Pré-Escolar , Erros de Diagnóstico , Humanos , Masculino
6.
J Cyst Fibros ; 15(5): 587-96, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26922860

RESUMO

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus sensitization (AFS) are quite often observed in cystic fibrosis (CF) patients. The aim of this study was to evaluate the use of basophil activation test (BAT) in these manifestations of hypersensitivity reactions. METHODS: BAT (CD63 and CD203c) was performed for 56 CF patients (17 ABPA, 24 AFS and 15 non-AFS). A receiver operating characteristic (ROC) curve analysis and a survival analysis were performed. RESULTS: Both markers significantly contributed in ABPA diagnosis (P value<0.001 for both). Twelve AFS patients fulfilled the criteria for ABPA diagnosis during the follow-up period. The median time to ABPA diagnosis was 9months for patients whose values were over the best cutoffs (P value<0.001 for both). CONCLUSIONS: BAT could be considered as an additional criterion for ABPA diagnosis in CF as well as a potential marker for the monitoring of patients with AFS.


Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergillus fumigatus , Basófilos/imunologia , Fibrose Cística , Testes Imunológicos/métodos , Tetraspanina 30/análise , Adolescente , Alérgenos/análise , Antígenos de Fungos/análise , Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/isolamento & purificação , Biomarcadores/análise , Criança , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/imunologia , Técnicas Citológicas/métodos , Feminino , Humanos , Masculino , Curva ROC , Reprodutibilidade dos Testes , Escarro/imunologia
7.
Biomed Res Int ; 2015: 806042, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26550577

RESUMO

OBJECTIVE: We assessed the lipopolysaccharide (LPS) or heat shock (HS) induction of heat shock protein-72 (HSP72) in peripheral blood mononuclear cells (PBMCs) of patients with severe sepsis (SS) or trauma-related systemic inflammatory response syndrome (SIRS), compared to healthy individuals (H); we also investigated any pre- or posttreatment modulating glutamine (Gln) effect. METHODS: SS (11), SIRS (10), and H (19) PBMCs were incubated with 1 µg/mL LPS or 43°HS. Gln 10 mM was either added 1 h before or 1 h after induction or was not added at all. We measured monocyte (m), lymphocyte (l), mRNA HSP72, HSP72 polymorphisms, interleukins (ILs), monocyte chemoattractant protein-1 (MCP-1), and cortisol levels. RESULTS: Baseline lHSP72 was higher in SS (p < 0.03), and mHSP72 in SIRS (p < 0.02), compared to H. Only HS induced l/mHSP72/mRNA HSP72; LPS induced IL-6, IL-8, IL-10, and MCP-1. Induced mRNA was related to l/mHSP72, and was related negatively to cytokines. Intracellular l/mHSP72/HSP72 mRNA was related to serum ILs, not being influenced by cortisol, illness severity, and HSP72 polymorphisms. Gln did not induce mRNA in any group but modified l/mHSP72 after LPS/HS induction unpredictably. CONCLUSIONS: HSP72 mRNA and l/mHSP72 are higher among critically ill patients, further induced by HS, not by LPS. HSP72 proteins and HSP72 mRNA are related to serum ILs and are negatively related to supernatant cytokines, not being influenced by HSP72 polymorphisms, cortisol, or illness severity. Gln may depress l/mHSP72 after LPS exposure and enhance them after HS induction, but it may not affect early induced HSP72 mRNA.


Assuntos
Glutamina/administração & dosagem , Proteínas de Choque Térmico HSP72/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Sepse/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Células Cultivadas , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP72/genética , Resposta ao Choque Térmico , Humanos , Lipopolissacarídeos/administração & dosagem , Linfócitos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , RNA Mensageiro/metabolismo , Sepse/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/patologia
8.
Cancer Epidemiol ; 39(6): 1047-59, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26329264

RESUMO

OBJECTIVE: To systematically review studies and meta-analyze the literature on the association of maternal and/or index child's coffee, tea, and cola consumption with subsequent development of childhood leukemia and its major subtypes. METHODS: Eligible studies were identified through a detailed algorithm and hand-search of eligible articles' references; thereafter, summary-effect estimates were calculated by leukemia subtype and dose-response meta-analyses were performed. RESULTS: Twelve case-control studies, comprising a total of 3649 cases and 5705 controls, were included. High maternal coffee consumption was positively associated with acute lymphoblastic leukemia (ALL; OR: 1.43, 95%CI: 1.22-1.68) and acute myeloid leukemia (AML; OR: 2.52, 95%CI: 1.59-3.57). Any or low to moderate maternal cola consumption was also positively associated with overall leukemia (AL) and ALL, A linear trend between coffee and cola consumption and childhood leukemia was observed in the dose-response analyses. On the contrary, low to moderate tea consumption was inversely associated with AL (OR: 0.85, 95%CI: 0.75-0.97), although the trend was non-significant. A null association between offspring's cola consumption and leukemia was noted. CONCLUSIONS: Our findings confirm the detrimental association between maternal coffee consumption and childhood leukemia risk and provide indications for a similar role of maternal cola intake. In contrast, an inverse association with tea was found, implying that other micronutrients contained in this beverage could potentially counterbalance the deleterious effects of caffeine. Further research should focus on the intake of specific micronutrients, different types of coffee and tea, specific immunophenotypes of the disease, and the modifying effect of genetic polymorphisms.


Assuntos
Bebidas/efeitos adversos , Café/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Cafeína/efeitos adversos , Estudos de Casos e Controles , Criança , Feminino , Humanos , Gravidez , Risco , Chá/efeitos adversos
9.
Cell Reprogram ; 16(6): 447-55, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25354259

RESUMO

Synthetic modified mRNA molecules encoding pluripotency transcription factors have been used successfully in reprogramming human fibroblasts to induced pluripotent stem cells (iPSCs). We have applied this method on bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from a patient with ß-thalassemia (ß-thal) with the aim to generate trangene-free ß-thal-iPSCs. Transfection of 10(4) BM-MSCs by lipofection with mRNA encoding the reprogramming factors Oct4, Klf4, Sox2, cMyc, and Lin28 resulted in formation of five iPSC colonies, from which three were picked up and expanded in ß-thal-iPSC lines. After 10 serial passages in vitro, ß-thal-iPSCs maintain genetic stability as shown by array comparative genomic hybridization (aCGH) and are capable of forming embryoid bodies in vitro and teratomas in vivo. Their gene expression profile compared to human embryonic stem cells (ESCs) and BM-MSCs seems to be similar to that of ESCs, whereas it differs from the profile of the parental BM-MSCs. Differentiation cultures toward a hematopoietic lineage showed the generation of CD34(+) progenitors up to 10%, but with a decreased hematopoietic colony-forming capability. In conclusion, we report herein the generation of transgene-free ß-thal-iPSCs that could be widely used for disease modeling and gene therapy applications. Moreover, it was demonstrated that the mRNA-based reprogramming method, used mainly in fibroblasts, is also suitable for reprogramming of human BM-MSCs.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , RNA Mensageiro/genética , Fatores de Transcrição/genética , Talassemia beta , Diferenciação Celular , Linhagem Celular , Hibridização Genômica Comparativa , Fibroblastos/citologia , Humanos
10.
Pediatr Blood Cancer ; 61(12): 2305-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25154619

RESUMO

The authors describe two young brothers and a 12-year-old male with long-standing thrombocytopenia with normal sized platelets, in whom novel mutations of the WAS gene were identified. Their clinical picture and the in vitro assessment of the T-cell function were consistent with X-linked thrombocytopenia (XLT). A high index of suspicion for XLT is required, even in the setting of normal sized platelets for males with affected maternally-related male family members, and males with moderately severe chronic thrombocytopenia that have failed to respond to treatments that are usually effective for immune thrombocytopenia.


Assuntos
Plaquetas/fisiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Trombocitopenia/genética , Proteína da Síndrome de Wiskott-Aldrich/genética , Criança , Pré-Escolar , Humanos , Masculino , Prognóstico
11.
J Clin Immunol ; 34(7): 836-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24981038

RESUMO

Primary Immunodeficiencies (PID) represent a group of heterogeneous immune diseases with important biological significance. We reviewed the records of children diagnosed with PID in the Referral Center for PID in our country in order to describe the epidemiological, clinical and laboratory characteristics of immunodeficient patients. During a 30-year period, 147 patients (101 males, 68.7 %), with a mean age of 6.5 years at the time of diagnosis, were diagnosed with PID. The most prevalent diagnoses of PID were: "Combined Immunodeficiency" in 46 (31.3 %) patients, "Well-defined immunodeficiency syndrome" in 35 (23.1 %) patients, "Predominantly antibody deficiency" in 30 (20.4 %) patients and "Congenital defect of phagocyte function or both" in 28 (19 %) patients. There was a higher prevalence of males with "Combined immunodeficiency" (p < 0.033) and "Predominantly antibody deficiency" (p < 0.02) compared to females. The median age of children at the onset of symptoms and at the time of diagnosis was 0.5y (IQR: 0.1-2.5) and 2y (IQR: 0.6-7.2), respectively. The median diagnostic delay was 0.9y (IQR: 0.2-4.8). This period was shorter for patients with "Combined immunodeficiency" [median 0.3y (IQR: 0.1-1)], and longer for those with "Predominantly antibody deficiency" [median 3.2y (IQR: 0.2-5.9) or "Disease of immune dysregulation" [median 3.2y (IQR: 0.1-6.6)]. Comparing the rates in our population with those of the European Registry (ESID), the rates of "Combined immunodeficiencies", "Well-defined syndromes" and "Congenital birth defects and/or function of phagocytes" were significantly higher in this study (p <0,001). PID registry analysis improves knowledge in the field of Immunology and enhances awareness, early detection, diagnosis, and management of this rare but significant group of diseases.


Assuntos
Síndromes de Imunodeficiência/epidemiologia , Grupos Populacionais , Sistema de Registros , Fatores Sexuais , Criança , Pré-Escolar , Diagnóstico Precoce , Europa (Continente) , Grécia , Troca de Informação em Saúde , Humanos , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Prevalência , Encaminhamento e Consulta
12.
J Clin Immunol ; 33(8): 1302-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24081483

RESUMO

Chronic Granulomatous Disease (CGD) is an uncommon primary immunodeficiency caused by the absence or dysfunction of one of NADPH oxidase subunits, with heterogeneous genetic aetiologies. The aim of this study was the CGD patient registry in Greece, the identification of the responsible genotype and the potential correlation with the patient's clinical phenotype. Medical charts of 24 CGD patients, investigated by NBT test or DHR for NADPH oxidase activity, Western blot analysis for NADPH oxidase component expression and DNA sequencing (pyro- and cycle sequencing) for mutation analysis, were reviewed. All patients, but one, were classified into the different types of CGD. Sixteen patients from 14 unrelated families had X-linked CGD (66.7 %), four had mutations in the NCF1 gene (19 %), and three, from two unrelated families, had mutations in NCF2 (9.5 %) [Corrected]. Fifteen mutations were detected in the CYBB gene, including nonsense (53.8 %), splice site (30.8 %) and missense mutations (7.7 %), and deletions (7.7 %). Two novel mutations were identified; one in CYBB and one in NCF1. Carrier detection for X-CGD revealed that the de novo mutation rate was about 7 %. Prenatal diagnosis identified one affected male in three male fetuses tested. In both the X-linked and the autosomal recessive (AR-CGD) group, the gastrointestinal and respiratory manifestations were more common, followed by lympadenopathy in X-CGD and skin infections in the AR-CGD group. The patients with a mutation in CYBB had a wider variability of clinical manifestations and earlier diagnosis (4.6 years) compared to the AR-CGD group (12.9 years). The incidence of CGD in Greece is estimated at 0.90 (95 % CI 0.89-0.91) per 100,000 live births for the last decade.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Sistema de Registros , Doença Granulomatosa Crônica/genética , Grécia , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Glicoproteínas de Membrana/genética , Mutação , NADPH Oxidase 2 , NADPH Oxidases/genética , Encaminhamento e Consulta
13.
PLoS One ; 8(8): e72326, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23977280

RESUMO

The most frequent targets of genetic alterations in human leukemias are transcription factor genes with essential functions in normal blood cell development. The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas. Very few studies have reported an association of IRF4 with childhood malignancy, whereas high transcript levels have been observed in the more mature immunophenotype of ALL. Our aim was to investigate the expression levels of IRF4 in the diagnostic samples of pediatric leukemias and compare them to those of healthy controls, in order to determine aberrant gene expression and whether it extends to leukemic subtypes other than the relatively mature ALL subpopulation. Quantitative real-time RT-PCR methodology was used to investigate IRF4 expression in 58 children with acute leukemias, 4 leukemic cell lines and 20 healthy children. We show that aberrant IRF4 gene expression is implicated in a variety of leukemic subtypes; higher transcript levels appear in the more immature B-common ALL subtype and in T-cell than in B-cell leukemias, with the highest expression levels appearing in the AML group. Interestingly, we show that childhood leukemia, irrespective of subtype or cell maturation stage, is characterised by a minimum of approximately twice the amount of IRF4 gene expression encountered in healthy children. A statistically significant correlation also appeared to exist between high IRF4 expression and relapse. Our results show that ectopic expression of IRF4 follows the reverse expression pattern of what is encountered in normal B-cell development and that there might be a dose-dependency of childhood leukemia for aberrantly expressed IRF4, a characteristic that could be explored therapeutically. It is also suggested that high IRF4 expression might be used as an additional prognostic marker of relapse at diagnosis.


Assuntos
Regulação Leucêmica da Expressão Gênica , Fatores Reguladores de Interferon/genética , Leucemia de Células B/genética , Leucemia de Células T/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Estudos de Casos e Controles , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia de Células B/mortalidade , Leucemia de Células B/patologia , Leucemia de Células T/mortalidade , Leucemia de Células T/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Análise de Sobrevida
14.
BMC Immunol ; 14: 33, 2013 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-23915345

RESUMO

BACKGROUND: Data regarding the quantitative expression of TCR Vß subpopulations in children with autoimmune diseases provided interesting and sometimes conflicting results. The aim of the present study was to assess by comparative flow cytometric analysis the peripheral blood CD4+ TCR Vß repertoire of children with an organ-specific autoimmune disorder, such as type 1 diabetes mellitus (T1DM), in comparison to children with a systemic autoimmune disease, such as Systemic Lupus Erythematosus (SLE) in comparison to healthy age-matched controls of the same ethnic origin. The CD4+ TCR Vß repertoire was analysed by flow cytometry in three groups of participants: a) fifteen newly diagnosed children with T1DM (mean age: 9.2 ± 4.78 years old), b) nine newly diagnosed children with SLE, positive for ANA and anti-dsDNA, prior to treatment (mean age: 12.8 ±1.76 years old) and c) 31 healthy age-matched controls (mean age: 6.58 ± 3.65 years old), all of Hellenic origin. RESULTS: CD4 + TCR Vß abnormalities (± 3SD of controls) were observed mainly in SLE patients. Statistical analysis revealed that the CD4 + Vß4 chain was significantly increased in patients with T1DM (p < 0.001), whereas CD4 + Vß16 one was significantly increased in SLE patients (p < 0.001) compared to controls. CONCLUSIONS: CD4 + Vß4 and CD4 + Vß16 chains could be possibly involved in the cascade of events precipitating the pathogenesis of T1DM and SLE in children, respectively.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Adolescente , Antígenos de Superfície/metabolismo , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
15.
J Clin Immunol ; 31(5): 778-83, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21732012

RESUMO

Severe combined immunodeficiencies (SCID) are a heterogeneous group of genetic disorders characterized by a blockade or impairment of both cellular and humoral immunity. Several epidemiological studies in different geographic areas have shown that the most common type of SCID affecting almost half of these patients is the X-linked common γ-chain (γ(c)) deficiency. The objective of the study was to document the incidence and types of SCID in our area. We conducted a retrospective analysis of patients who were diagnosed with SCID in the major immunology center in Greece for a 20-year period. During the study period, 30 children from 27 unrelated families with final diagnosis of SCID were identified. The incidence of SCID in Greece is estimated at 1.7 cases per 100,000 live births. Out of 30 children, 19 were boys (63.3%) and 26 (86.7%) had Greek maternal origin. Lymphocyte immunophenotypes that were identified were T(-)B(-)NK(+) in 12 (40%) children, T(-)B(+)NK(-) in six (20%), T(-)B(+)NK(+) in three (10%), T(-)B(-)NK(-) in two (6.7%) and T(+)B(+/-)NK(+) in seven (23.4%) (among them, four [13.4%] females with Omenn's syndrome). Molecular diagnosis was available for 12 children: γ(c) (2) with non Greek maternal origin, Jak3 (2), Rag1 (2), Artemis (3), ADA deficiency (2), PNP deficiency (1). Out of the 26 children of Greek maternal origin diagnosed with SCID representing 23 distinct families, only two (8.7%) had lymphocyte immunophenotype compatible with γ(c)-chain gene mutation (no molecular testing or enough DNA was available for them at the time of diagnosis). Findings of the present study suggest that, for unknown reasons, mutations of the γ(c) chain of several cytokine receptors have a rare occurrence in our area.


Assuntos
Subunidade gama Comum de Receptores de Interleucina/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/epidemiologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Demografia , Família , Feminino , Genética Populacional , Grécia , Humanos , Imunofenotipagem , Incidência , Lactente , Recém-Nascido , Subunidade gama Comum de Receptores de Interleucina/genética , Masculino , Mutação/genética , Estudos Retrospectivos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/diagnóstico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia
16.
Biol Blood Marrow Transplant ; 16(3): 344-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19835970

RESUMO

We report 2 children with X-linked chronic granulomatous disease (X-CGD) who underwent hematopoietic stem cell transplantation (HSCT) using grafts from their siblings selected before implantation to be both unaffected and HLA-matched donors. Preimplantation genetic diagnosis (PGD) along with HLA-typing were performed on preimplantation embryos by single-cell multiplex polymerase chain reaction using informative short tandem repeat markers in the HLA locus together with the gene region containing the mutations. Two singleton pregnancies resulted from the intrauterine transfer of selected embryos; these developed to term, producing 1 healthy female and 1 X-CGD carrier female, which are HLA-identical siblings to the 2 affected children. Combined grafts of umbilical cord blood (UCB) and bone marrow (BM) stem cells were administered to the recipients after myeloablative (MA) conditioning at the ages of 4.5 years and 4 years, respectively. Both patients are well, with complete donor hematopoietic and immunologic reconstitution, at 18 and 13 months posttransplantation, respectively. This report demonstrates that HSCT with HLA-matched sibling donors created by PGD/HLA typing of in vitro fertilized embryos is a realistic therapeutic option and should be presented as such to families with children who require a non-urgent HSCT but lack an HLA-genoidentical donor.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Diagnóstico Pré-Implantação , Irmãos , Plaquetas/citologia , Células da Medula Óssea/citologia , Contagem de Células , Pré-Escolar , Embrião de Mamíferos/imunologia , Feminino , Fertilização In Vitro , Sangue Fetal/citologia , Sobrevivência de Enxerto , Doença Granulomatosa Crônica/genética , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutação de Sentido Incorreto/genética , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Explosão Respiratória/efeitos dos fármacos , Superóxidos/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Quimeras de Transplante/genética , Quimeras de Transplante/metabolismo , Resultado do Tratamento
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