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1.
Sci Rep ; 10(1): 19387, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168927

RESUMO

Recently, flood risk assessments have been extended to national and continental scales. Most of these assessments assume homogeneous scenarios, i.e. the regional risk estimate is obtained by summing up the local estimates, whereas each local damage value has the same probability of exceedance. This homogeneity assumption ignores the spatial variability in the flood generation processes. Here, we develop a multi-site, extreme value statistical model for 379 catchments across Europe, generate synthetic flood time series which consider the spatial correlation between flood peaks in all catchments, and compute corresponding economic damages. We find that the homogeneity assumption overestimates the 200-year flood damage, a benchmark indicator for the insurance industry, by 139%, 188% and 246% for the United Kingdom (UK), Germany and Europe, respectively. Our study demonstrates the importance of considering the spatial dependence patterns, particularly of extremes, in large-scale risk assessments.

2.
Blood ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32603431

RESUMO

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

3.
Pediatr Allergy Immunol ; 31(5): 528-536, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32060950

RESUMO

BACKGROUND: There are no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. METHOD: Between the years 1992 and 2018, from five tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. RESULTS: The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male-to-female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5-51). The median age at diagnosis of malignancy was 10 years (range: 1.5-51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n = 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n = 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n = 7/43, 16.3%) was higher than AT (n = 19/193, 9.8%), Wiskott-Aldrich syndrome (n = 2/22, 9.1%), and common variable immunodeficiency (n = 11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. CONCLUSION: This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency compared to AT.

4.
Allergy ; 75(4): 921-932, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31596517

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS: DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION: DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

5.
Pediatr Blood Cancer ; 66(10): e27923, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31321910

RESUMO

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Neutropenia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Lactente , Masculino , Mutação , Sistema de Registros , Turquia , Adulto Jovem
6.
J Allergy Clin Immunol Pract ; 7(8): 2790-2800.e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

7.
Turk J Med Sci ; 49(1): 147-152, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30764591

RESUMO

Background/aim: Ig level assessment is frequently used in the diagnosis and follow-up of immunodeficiency, as well as in studies investigating the prevalence of low serum Ig level in specific diseases. Materials and methods: Patients who underwent Ig testing in the inpatient and outpatient clinics of our hospital in the years 2010­2016 were included. The Ig levels of the patients were assessed separately according to two reference systems commonly used in Turkey and another reference system used in the USA. Results: A total of 20,138 patients (57.6% male) were included in the study. The median age of the patients was 55.7 months (interquartile range: 23.1­96.7). According to the reference intervals determined by Tezcan et al., 30.6% of the patients were deficient in one or more Ig values. This rate was 4 times higher than those based on the reference intervals determined by Aksu et al. (7.7%) and those in the Nelson Textbook of Pediatrics (6.8%). We also determined that the frequency of low Ig levels with three reference systems Conclusion: In this study, we found that the rates of low Ig level in a group of pediatric patients differed significantly when evaluated using three different reference systems for age-related serum Ig levels


Assuntos
Imunoglobulinas , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/classificação , Testes Imunológicos/métodos , Pacientes Internados/estatística & dados numéricos , Masculino , Pacientes Ambulatoriais/estatística & dados numéricos , Pediatria/métodos , Valores de Referência , Turquia
9.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.

10.
Turk J Haematol ; 35(4): 229-259, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30040071

RESUMO

Objective: To examine granulocytic and non-granulocytic cells in children with severe congenital neutropenia (SCN) and their non-neutropenic parents. Materials and Methods: Fifteen patients with SCN and 21 non-neutropenic parents were evaluated for a) CD95, CD95 ligand, annexin V, propidium iodide, cell cycle, and lymphocyte subsets by flow cytometry; b) rapid cell senescence (of leukocytes) by senescence-associated ß-galactosidase stain; c) aggregation tests by aggregometer; d) in vitro bleeding time by PFA-100 instrument; e) mepacrine-labeled dense granule number of thrombocytes by fluorescence microscope; and f) hematomorphology by light and electron microscope. HAX1, ELANE, G6PC3, CSF3R, and JAGN1 mutations associated with SCN were studied in patients and several parents. Results: Significant increase in apoptosis and secondary necrosis in monocytes, lymphocytes, and granulocytes of the patients and parents was detected, irrespective of the mutation type. CD95 and CD95 ligand results implied that apoptosis was non-CD95-mediated. Leukocytes of 25%, 12.5%, and 0% of patients, parents, and controls showed rapid cell senescence. The cell cycle analysis testable in four cases showed G1 arrest and apoptosis in lymphocytes of three. The patients had HAX1 (n=6), ELANE (n=2), G6PC3 (n=2), and unidentified (n=5) mutations. The CD3, CD4, and NK lymphocytes were below normal levels in 16.6%, 8.3%, and 36.4% of the patients and in 0%, 0%, and 15.4% of the parents (controls: 0%, 0%, 5.6%). The thrombocytes aggregated at low rates, dense granule number/thrombocyte ratio was low, and in vitro bleeding time was prolonged in 37.5%-66.6% of patients and 33.3%-63.2% of parents (vs. 0% in controls). Under electron and/or light microscope, the neutrophils, monocytes, lymphocytes, and thrombocytes in the peripheral blood of both patients and parents were dysplastic and the bone marrow of patients revealed increased phagocytic activity, dysmegakaryopoiesis, and necrotic and apoptotic cells. Ultrastructurally, thrombocyte adhesion, aggregation, and release were inadequate. Conclusion: In cases of SCN, patients' pluripotent hematopoietic stem cells and their non-neutropenic parents are both affected irrespective of the genetic defect.


Assuntos
Granulócitos/patologia , Linfócitos/patologia , Neutropenia/congênito , Neutrófilos/patologia , Adolescente , Adulto , Morte Celular , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Granulócitos/metabolismo , Humanos , Lactente , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/metabolismo , Adulto Jovem
11.
Hum Mol Genet ; 27(22): 3919-3935, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31222290

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-γ receptor 2 (IFN-γR2) deficiency. Patients with partial IFN-γR2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-γR2 resulting in an impaired, but not abolished, response to IFN-γ. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-γ, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-γ. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-γR2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-γR2 deficiency. Residual levels of IFN-γ signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-γR2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-γ signaling were higher.


Assuntos
Alelos , Códon de Iniciação , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Homozigoto , Infecções por Mycobacterium/genética , Receptores de Interferon/genética , Criança , Pré-Escolar , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Turquia , Sequenciamento Completo do Exoma
13.
Turk J Med Sci ; 47(2): 592-598, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28425252

RESUMO

BACKGROUND/AIM: IgA deficiency is the most common human primary immunodeficiency. The prevalence of allergic disorders and autoimmunity is thought to be increased in selective IgA deficiency (sIgAD). However, it is currently unclear if these disorders coincide within these families. We aimed to evaluate the frequency of allergic and autoimmune disorders in children with sIgAD and their first-degree relatives (FDRs). MATERIALS AND METHODS: The study included 81 children diagnosed with sIgAD and 274 of their FDRs. The presence of allergic and autoimmune disorders was evaluated and serum antithyroglobulin and antithyroid peroxidase levels were measured in both patients and their first-degree relatives. RESULTS: The mean age of the patients was 9.9 ± 3.9 years. Among the patients with sIgAD, 45.7% of them had at least one allergic disorder and 17.3% of them had at least one autoimmune disorder. The frequencies of asthma, allergic rhinitis, and eczema in the FDRs of sIgAD patients were 10.9%, 9.1%, and 7.7%, respectively. Among their FDRs, 14.6% had autoimmunity, compared to an estimate of 5% in the general population. CONCLUSION: Increased frequency of allergic and autoimmune disorders in patients with sIgAD and their FDRs suggests a possible common predisposing genetic component for sIgAD and autoimmunity in these families.


Assuntos
Doenças Autoimunes/epidemiologia , Hipersensibilidade/epidemiologia , Deficiência de IgA/epidemiologia , Adolescente , Adulto , Autoanticorpos/sangue , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Criança , Estudos de Coortes , Família , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Deficiência de IgA/complicações , Deficiência de IgA/genética , Deficiência de IgA/imunologia , Masculino , Adulto Jovem
14.
J Pediatr Endocrinol Metab ; 30(2): 181-187, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27997351

RESUMO

BACKGROUND: Dyslipidemia increases the frequency and severity of micro and macrovascular complications of type 1 diabetes (T1D). The present study aims to determine the prevalence of dyslipidemia and its association with clinical and laboratory findings in diabetic children and adolescents. METHODS: The study included 202 children and adolescents with T1D. Demographic data and laboratory findings were obtained from patients files. RESULTS: Dyslipidemia prevalence was found to be 26.2%. Hypercholesterolemia (15.8%) and hyperglyceridemia (12.9%) were most common findings. Age, body mass index (BMI), hemoglobin A1c (A1C) and poor metabolic control were significantly higher in cases with dyslipidemia. Smoking rate was 14.1% in the pubertal group. Poor metabolic control and dyslipidemia was found higher among smokers (p<0.05). CONCLUSIONS: Blood lipid levels should be monitored regularly and nutrition education should be repeated periodically to prevent and control dyslipidemia in patients with T1D. Smoking-related risks should be a part of patient education in the pubertal period.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 1/complicações , Dislipidemias/epidemiologia , Lipídeos/sangue , Adolescente , Criança , Dislipidemias/sangue , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Masculino , Prevalência , Prognóstico , Fatores de Risco , Turquia/epidemiologia
15.
Turk J Pediatr ; 58(4): 356-361, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28276206

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by infections with weakly virulent mycobacteria (BCG and environmental mycobacteria), M. tuberculosis, Salmonella, candida and some other intracellular microorganisms. Nine different genetic defects have been defined to cause MSMD and IL-12Rß1 deficiency is the most common form. We present here the clinical and genetic features of 18 patients with IL12Rß1 deficiency diagnosed by surface expression of IL-12Rß1 and Sanger's sequencing. Seventeen patients showed classical presentation (infections with BCG, salmonella and candida) while one patient experienced recurrent leishmaniasis. In all patients the percentage of activated lymphocytes with surface expression of IL12Rß1 was < 1% indicating that it is an effective method for the screening of these patients. Three recurrent mutations were responsible for 85% of our families. Prognosis was good in patients, in whom specific antimicrobial therapy was given before dissemination occurs, as well as prophylactic antimicrobial treatment when needed and IFN-γ therapy for severe infectious episodes.


Assuntos
Mycobacterium tuberculosis/imunologia , Receptores de Interleucina-12/genética , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Receptores de Interleucina-12/deficiência , Adulto Jovem
17.
J Allergy Clin Immunol ; 136(2): 402-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25724123

RESUMO

BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. RESULTS: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.


Assuntos
Infecções Bacterianas/complicações , Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndrome de Job/complicações , Fenótipo , Dermatopatias/complicações , Viroses/complicações , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Antígenos Virais/sangue , Antígenos Virais/imunologia , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/genética , Imunoglobulina M/sangue , Imunoglobulina M/genética , Lactente , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/mortalidade , Máquina de Vetores de Suporte , Análise de Sobrevida , Viroses/genética , Viroses/imunologia , Viroses/mortalidade
18.
Immunol Rev ; 264(1): 103-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25703555

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.


Assuntos
Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/etiologia , Mycobacterium tuberculosis/imunologia , Tuberculose/etiologia , Fatores Etários , Criança , Genes Dominantes , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
19.
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 , Infecções/diagnóstico , Infecções/epidemiologia , Infecções/etiologia , 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
20.
Allergol Immunopathol (Madr) ; 43(1): 57-61, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24485938

RESUMO

BACKGROUND: Antibody deficiency comprises a heterogeneous group of disorders characterised by the body's inability to mount an effective antibody response to pathogens. Although it has been reported that asthma and allergic disease are frequent in antibody deficiencies, there are no data that evaluate and compare bronchial hyperreactivity (BHR) in all groups of antibody deficiencies. In this study, we aimed to evaluate and compare the frequency of BHR in patients with different antibody deficiencies. METHODS: The study was carried out on 113 patients between ages 5 and 18 diagnosed with antibody deficiencies. The patients and their families were questioned on their history of asthma and allergic diseases. Allergic skin prick tests and non-specific bronchial provocation test with methacholine was done for all patients. Complete blood count and serum total IgE levels were measured. RESULTS: The mean age of the patients was 10.8 ± 3.8 years and 66.4% were male. Within the study group 41.6% of the patients had selective IgA deficiency, 24.8% had IgG subclass deficiency, 14.2% had partial IgA deficiency, 10.6% had common variable immunodeficiency, 6.2% had transient hypogammaglobulinaemia and 2.7% X-linked agammaglobulinaemia. In total group, 42.5% had bronchial hyperreactivity with methacholine challenge test. BHR was more significant in both patients with selective IgA deficiency and partial IgA deficiency compared to those with IgG subclass deficiency (P=0.041 and P=0.038, respectively). CONCLUSION: BHR was high in antibody deficiencies, especially selective IgA deficiency compared to IgG subclass deficiency.


Assuntos
Anticorpos/genética , Hiper-Reatividade Brônquica/epidemiologia , Hipersensibilidade/epidemiologia , Deficiência de IgA/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , Adolescente , Alérgenos/imunologia , Contagem de Células Sanguíneas , Testes de Provocação Brônquica , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina E/sangue , Incidência , Masculino , Testes Cutâneos
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