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1.
Nat Immunol ; 11(9): 836-45, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20676093

RESUMEN

BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.


Asunto(s)
Linfocitos B/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Animales , Células Cultivadas , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal
2.
J Clin Immunol ; 41(6): 1339-1351, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34052995

RESUMEN

BACKGROUND: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. METHODS: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. RESULTS: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). CONCLUSIONS: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.


Asunto(s)
Enfermedades Genéticas Congénitas/epidemiología , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Adolescente , Adulto , África del Norte/epidemiología , Anciano , Niño , Consenso , Años de Vida Ajustados por Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medio Oriente/epidemiología , Sistema de Registros , Adulto Joven
3.
Clin Exp Immunol ; 205(3): 354-362, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34050927

RESUMEN

Signal transducer and activator of transcription 3 (STAT-3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT-3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. In addition, the patient had lymphoproliferation, short stature and interstitial lung disease. Chest computerized tomography examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. Using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT-3 variant affecting the coiled coil domain of STAT-3. Functional studies confirmed that p.D170H was a GOF variant, as shown by increased phosphorylated STAT-3 (pSTAT-3) and STAT-3 transcriptional activity. Our observation suggests that STAT-3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections. We suggest that patients with lymphoproliferation, hypogammaglobulinemia and severe recurrent infections should be screened for STAT-3 variants, even if autoimmune manifestations are missing.


Asunto(s)
Agammaglobulinemia/genética , Mutación con Ganancia de Función/genética , Trastornos Linfoproliferativos/genética , Infecciones del Sistema Respiratorio/genética , Factor de Transcripción STAT3/genética , Agammaglobulinemia/inmunología , Desarrollo Óseo/genética , Bronquiectasia/genética , Humanos , Masculino , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/mortalidad , Factor de Transcripción STAT3/metabolismo , Adulto Joven
6.
Blood ; 127(25): 3154-64, 2016 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-27114460

RESUMEN

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.


Asunto(s)
Candidiasis Mucocutánea Crónica/genética , Estudios de Asociación Genética , Mutación , Factor de Transcripción STAT1/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenotipo , Adulto Joven
7.
Orv Hetil ; 159(23): 937-947, 2018 Jun.
Artículo en Húngaro | MEDLINE | ID: mdl-29860885

RESUMEN

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.


Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Enfermedades Cutáneas Infecciosas/inmunología , Enfermedades de la Piel/inmunología , Piel/patología , Adulto , Autoinmunidad/inmunología , Niño , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Piel/inmunología , Enfermedades de la Piel/diagnóstico
8.
J Clin Immunol ; 42(6): 1151-1155, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35532839

Asunto(s)
Rosa , Humanos
11.
J Clin Immunol ; 41(1): 262-265, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33078350
14.
J Clin Immunol ; 35(7): 681-8, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26453584

RESUMEN

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.


Asunto(s)
Dermatitis Atópica/inmunología , Infecciones/inmunología , Síndrome de Job/inmunología , Factor de Transcripción STAT3/genética , Piel/metabolismo , Adolescente , Adulto , Niño , Preescolar , Citocinas/metabolismo , Femenino , Proteínas Filagrina , Humanos , Inmunización , Inmunoglobulina E/sangre , Interleucinas/metabolismo , Masculino , Persona de Mediana Edad , Mutación/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Piel/patología , Adulto Joven , Linfopoyetina del Estroma Tímico , Interleucina-22
15.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26271390

RESUMEN

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.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndrome de Nijmegen/diagnóstico , Factores de Tiempo , Adolescente , Adulto , Niño , Preescolar , Inestabilidad Cromosómica , Femenino , Humanos , Síndromes de Inmunodeficiencia , Lactante , Linfoma no Hodgkin , Masculino , Microcefalia , Síndrome de Nijmegen/genética , Síndrome de Nijmegen/terapia , Pronóstico , Estudios Retrospectivos , Adulto Joven
16.
J Clin Immunol ; 35(2): 189-98, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25627830

RESUMEN

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.


Asunto(s)
Estudios de Asociación Genética , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Incidencia , Lactante , Infecciones/diagnóstico , Infecciones/epidemiología , Infecciones/etiología , Síndrome de Job/complicaciones , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/inmunología , Síndrome de Job/mortalidad , Síndrome de Job/terapia , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/epidemiología , Neoplasias/etiología , Fenotipo , Adulto Joven
17.
Eur J Haematol ; 95(1): 93-8, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25082437

RESUMEN

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.


Asunto(s)
Exones , Mutación INDEL , Proteína del Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/genética , Secuencia de Bases , Humanos , Lactante , Intrones , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/patología , Proteína del Síndrome de Wiskott-Aldrich/deficiencia
18.
J Allergy Clin Immunol ; 133(1): 172-80.e1-10, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24012209

RESUMEN

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.


Asunto(s)
Linfocitos B/inmunología , Síndromes de Inmunodeficiencia/diagnóstico , Activación de Linfocitos/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Diferenciación Celular , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Niño , Femenino , Perfilación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Citometría de Imagen , Cambio de Clase de Inmunoglobulina , Síndromes de Inmunodeficiencia/inmunología , Recién Nacido , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , ARN Mensajero/análisis , Transcriptoma/inmunología , Adulto Joven
19.
J Clin Immunol ; 39(4): 363-369, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31102035
20.
J Clin Immunol ; 34(2): 181-93, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24493573

RESUMEN

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.


Asunto(s)
Autoanticuerpos/inmunología , Candidiasis Mucocutánea Crónica/patología , Interleucina-17/inmunología , Poliendocrinopatías Autoinmunes/diagnóstico , Poliendocrinopatías Autoinmunes/inmunología , Adolescente , Adulto , Niño , Preescolar , Citocinas/biosíntesis , Citocinas/inmunología , Análisis Mutacional de ADN , Femenino , Heterocigoto , Homocigoto , Humanos , Interferón Tipo I/inmunología , Interleucinas/inmunología , Masculino , Mutación , Linaje , Poliendocrinopatías Autoinmunes/terapia , Polimorfismo Genético , Índice de Severidad de la Enfermedad , Factores de Transcripción/genética , Adulto Joven , Proteína AIRE , Interleucina-22
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