RESUMEN
BACKGROUND: Immune defects in chronic pulmonary aspergillosis (CPA) are poorly characterized. We compared peripheral blood cytokine profiles in patients with CPA versus healthy controls and explored the relationship with disease severity. METHODS: Interferon-gamma (IFNγ), interleukin (IL)-17, tumor necrosis factor-α, IL-6, IL-12, and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohemagglutinin, ß-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production. RESULTS: Cytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with ß-glucanâ +â IL-12 (312 vs 988 pg/mL), LPSâ +â IL-12 (252 vs 1033 pg/mL), ZYMâ +â IL-12 (996 vs 2347 pg/mL), and IL-18â +â IL-12 (7193 vs 12 330 pg/mL). Ageâ >60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.00-2.91; Pâ =â .05) and chronic obstructive pulmonary disease (HR, 1.69; 95% CI, 1.03-2.78; Pâ =â .039) were associated with worse survival, whereas high IFNγ production in response to beta-glucanâ +â IL-12 stimulation (HR, 0.48; 95% CI, .25-0.92; Pâ =â .026) was associated with reduced mortality. CONCLUSIONS: Patients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA.
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Interferón gamma , Aspergilosis Pulmonar , Citocinas , Femenino , Humanos , Interleucina-12 , Interleucina-18 , Lipopolisacáridos , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa , beta-GlucanosRESUMEN
Objective: To evaluate the characteristics of patients with autoimmune disease with hypogammaglobulinemia following rituximab (RTX) and describe their long-term outcomes, including those who commenced immunoglobulin replacement therapy. Methods: Patients received RTX for autoimmune disease between 2003 and 2012 with immunoglobulin G (IgG) <7g/L were included in this retrospective series. Hypogammaglobulinemia was classified by nadir IgG subgroups of 5 to <7g/L (mild), 3 to <5g/L (moderate) and <3g/L (severe). Characteristics of patients were compared across subgroups and examined for factors associated with greater likelihood of long term hypogammaglobulinemia or immunoglobulin replacement. Results: 142 patients were included; 101 (71%) had anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV), 18 (13%) systemic lupus erythematosus (SLE) and 23 (16%) other conditions. Mean follow-up was 97.2 months from first RTX. Hypogammaglobulinemia continued to be identified during long-term follow-up. Median time to IgG <5g/L was 22.5 months. Greater likelihood of moderate hypogammaglobulinemia (IgG <5g/L) and/or use of immunoglobulin replacement therapy at 60 months was observed in patients with prior cyclophosphamide exposure (odds ratio (OR) 3.60 [95% confidence interval (CI) 1.03 - 12.53], glucocorticoid use at 12 months [OR 7.48 (95% CI 1.28 - 43.55], lower nadir IgG within 12 months of RTX commencement [OR 0.68 (95% CI 0.51 - 0.90)] and female sex [OR 8.57 (95% CI 2.07 - 35.43)]. Immunoglobulin replacement was commenced in 29/142 (20%) and associated with reduction in infection rates, but not severe infection rates. Conclusion: Hypogammaglobulinemia continues to occur in long-term follow-up post-RTX. In patients with recurrent infections, immunoglobulin replacement reduced rates of non-severe infections.
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Agammaglobulinemia/inducido químicamente , Enfermedades Autoinmunes/tratamiento farmacológico , Factores Inmunológicos/efectos adversos , Rituximab/efectos adversos , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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Enfermedades de Inmunodeficiencia Primaria/genética , Secuenciación Completa del Genoma , Complejo 2-3 Proteico Relacionado con la Actina/genética , Teorema de Bayes , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteínas de Unión al ARN/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Factores de Transcripción/genéticaAsunto(s)
Inmunodeficiencia Variable Común/diagnóstico , Hipertensión Portal/diagnóstico , Cirrosis Hepática/diagnóstico , Inmunodeficiencia Variable Común/mortalidad , Diagnóstico Precoz , Femenino , Humanos , Hipertensión Portal/mortalidad , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 µg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.
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Agammaglobulinemia/tratamiento farmacológico , Agammaglobulinemia/epidemiología , Inmunoglobulinas/uso terapéutico , Pautas de la Práctica en Medicina , Agammaglobulinemia/diagnóstico , Profilaxis Antibiótica , Femenino , Humanos , Inmunoglobulinas/administración & dosificación , Inmunoglobulinas Intravenosas , Irlanda/epidemiología , Masculino , Vacunas Neumococicas/administración & dosificación , Pautas de la Práctica en Medicina/estadística & datos numéricos , Derivación y Consulta , Reino Unido/epidemiología , VacunaciónAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/mortalidad , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/prevención & control , Hepatopatías/complicaciones , Biomarcadores , Biopsia , Diagnóstico por Imagen , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/diagnóstico , Estimación de Kaplan-Meier , Hepatopatías/diagnóstico , Tiempo de TratamientoAsunto(s)
Autoanticuerpos/inmunología , Citocinas/inmunología , Mutación/genética , Subunidad p52 de NF-kappa B/genética , Linfocitos T CD4-Positivos/inmunología , Preescolar , Femenino , Heterocigoto , Humanos , Memoria Inmunológica/inmunología , Masculino , Subunidad p52 de NF-kappa B/inmunología , LinajeRESUMEN
Common variable immunodeficiency (CVID) is the most common form of primary immunodeficiency characterized by antibody deficiency, recurrent bacterial infections, and autoimmunity. Advanced chronic liver disease occurs in a subset of patients with CVID and manifests with various histological features, such as nodular regenerative hyperplasia, inflammation, fibrosis, and cholangiopathy. We present a case series characterizing the outcomes in adult patients transplanted for primary CVID-related liver disease. We discuss the unique transplantation challenges faced in this primary immunodeficiency group including susceptibility to infections and early disease recurrence. There is a statistically significant decrease in 3-year and 5-year survival after liver transplantation in those with CVID-related liver disease (55% at 3 and 5 years) compared with all-comers (89% at 3 years, 81% at 5 years), prompting a need for discussion of suitability of transplantation in this group of patients as well as methods for reducing posttransplantation risk such as scrupulous search for infectious agents and reduction of immunosuppression. Liver Transplantation 24 171-181 2018 AASLD.
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Inmunodeficiencia Variable Común/inmunología , Hepatopatías/cirugía , Trasplante de Hígado/efectos adversos , Adulto , Enfermedad Crónica , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Resultado Fatal , Femenino , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Hepatopatías/diagnóstico , Hepatopatías/inmunología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Recurrencia , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Anti-cytokine autoantibodies (ACAAs) are pathogenic in a handful of rare immunodeficiencies. However, the prevalence and significance of other ACAAs across immunodeficiencies have not yet been described. OBJECTIVE: We profiled ACAAs in a diverse cohort of serum samples from patients with immunodeficiency and assessed the sensitivity and specificity of protein microarrays for ACAA identification and discovery. METHODS: Highly multiplexed protein microarrays were designed and fabricated. Blinded serum samples from a cohort of 58 immunodeficiency patients and healthy control subjects were used to probe microarrays. Unsupervised hierarchical clustering was used to identify clusters of reactivity, and after unblinding, significance analysis of microarrays was used to identify disease-specific autoantibodies. A bead-based assay was used to validate protein microarray results. Blocking activity of serum containing ACAAs was measured in vitro. RESULTS: Protein microarrays were highly sensitive and specific for the detection of ACAAs in patients with autoimmune polyendocrine syndrome type I and pulmonary alveolar proteinosis, detecting ACAA levels consistent with those reported in the published literature. Protein microarray results were validated by using an independent bead-based assay. To confirm the functional significance of these ACAAs, we tested and confirmed the blocking activity of select ACAAs in vitro. CONCLUSION: Protein microarrays are a powerful tool for ACAA detection and discovery, and they hold promise as a diagnostic for the evaluation and monitoring of clinical immunodeficiency.
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Autoanticuerpos/sangre , Citocinas/inmunología , Síndromes de Inmunodeficiencia/inmunología , Humanos , Síndromes de Inmunodeficiencia/sangre , Análisis por Matrices de ProteínasAsunto(s)
Sitios de Unión , Inmunodeficiencia Variable Común/genética , Subunidad gamma Común de Receptores de Interleucina/genética , Células Asesinas Naturales/metabolismo , Linfopenia/genética , Mutación , Regiones Promotoras Genéticas , Adulto , Preescolar , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/metabolismo , Humanos , Linfopenia/diagnóstico , Linfopenia/metabolismo , Masculino , Unión Proteica , Proteínas Proto-Oncogénicas c-ets/metabolismoRESUMEN
OBJECTIVE: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab. METHODS: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls. RESULTS: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment. CONCLUSION: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab. CLASSIFICATION OF EVIDENCE: This pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunocompetencia/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Adulto , Alemtuzumab , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Proyectos Piloto , Resultado del Tratamiento , Adulto JovenRESUMEN
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
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Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/genética , Infecciones por Mycobacterium no Tuberculosas/genética , Infecciones por Salmonella/genética , Adolescente , Adulto , Edad de Inicio , Asia Occidental/epidemiología , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Penetrancia , Análisis de Supervivencia , Túnez/epidemiología , Adulto JovenRESUMEN
Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis.
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Células Dendríticas/citología , Susceptibilidad a Enfermedades/etiología , Antígenos HLA-DR/sangre , Leucopenia/genética , Monocitos/citología , Adulto , Antígenos CD/metabolismo , Células de la Médula Ósea/citología , Niño , Células Dendríticas/patología , Susceptibilidad a Enfermedades/microbiología , Susceptibilidad a Enfermedades/virología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Interferón gamma/sangre , Leucopenia/sangre , Leucopenia/complicaciones , Microscopía Fluorescente , Monocitos/patología , Infecciones por Mycobacterium/inmunología , SíndromeRESUMEN
Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.
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Quinasas Asociadas a Receptores de Interleucina-1/deficiencia , Factor 88 de Diferenciación Mieloide/deficiencia , Adolescente , Antibacterianos/uso terapéutico , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/prevención & control , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunidad , Lactante , Quinasas Asociadas a Receptores de Interleucina-1/genética , Masculino , Mutación , Factor 88 de Diferenciación Mieloide/genética , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
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Sudunidad beta 1 del Receptor de Interleucina-12/deficiencia , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Citocinas/sangre , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Sudunidad beta 1 del Receptor de Interleucina-12/genética , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/genética , Mycobacterium bovis/aislamiento & purificación , Mycobacterium tuberculosis/aislamiento & purificación , Micobacterias no Tuberculosas/aislamiento & purificación , Análisis de SupervivenciaRESUMEN
BACKGROUND: IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood. OBJECTIVE: We sought to evaluate T-cell function in IRAK-4 deficient patients. METHODS: We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28. RESULTS: Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients. CONCLUSIONS: IRAK-4-deficient patients have defects in T-cell activation.