RESUMEN
BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is considered a prototypic autoimmune disease of the CNS. It is the leading cause of chronic neurologic disability in young adults. Proinflammatory B cells and autoreactive T cells both play important roles in its pathogenesis. We aimed to study alterations of regulatory T cells (Tregs), which likely also contribute to the disease, but their involvement is less clear. METHODS: By combining multiple experimental approaches, we examined the Treg compartments in 41 patients with relapsing-remitting MS and 17 healthy donors. RESULTS: Patients with MS showed a reduced frequency of CD4+ T cells and Foxp3+ Tregs and age-dependent alterations of Treg subsets. Treg suppressive function was compromised in patients, who were treated with natalizumab, while it was unaffected in untreated and anti-CD20-treated patients. The changes in natalizumab-treated patients included increased proinflammatory cytokines and an altered transcriptome in thymus-derived (t)-Tregs, but not in peripheral (p)-Tregs. DISCUSSION: Treg dysfunction in patients with MS might be related to an altered transcriptome of t-Tregs and a proinflammatory environment. Our findings contribute to a better understanding of Tregs and their subtypes in MS.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Natalizumab , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Adulto , Femenino , Masculino , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/farmacología , Persona de Mediana Edad , Timo/inmunología , Factores Inmunológicos/farmacología , Adulto JovenAsunto(s)
Cromosomas Humanos Par 22 , Síndrome de DiGeorge , Linfopenia , Tamizaje Neonatal , Linfocitos T , Humanos , Recién Nacido , Linfopenia/genética , Linfopenia/diagnóstico , Cromosomas Humanos Par 22/genética , Linfocitos T/inmunología , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/inmunología , Síndrome de DiGeorge/complicaciones , Duplicación Cromosómica , Masculino , FemeninoRESUMEN
BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
Asunto(s)
Fosfatidilinositol 3-Quinasa , Enfermedades de Inmunodeficiencia Primaria , Humanos , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasa Clase I , Antígeno CTLA-4/genética , Mutación , Enfermedades de Inmunodeficiencia Primaria/genética , Sistema de RegistrosRESUMEN
BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Mutación , Subunidad p50 de NF-kappa B/genética , Fenotipo , Adulto , Anciano , Autoinmunidad/genética , Variación Biológica Poblacional , Biomarcadores , Manejo de la Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Asociación Genética/métodos , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.
Asunto(s)
Deficiencia de IgA/epidemiología , Adolescente , Enfermedad Celíaca/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Hipersensibilidad/epidemiología , Deficiencia de IgA/diagnóstico , Italia , Estudios Longitudinales , Masculino , Infecciones del Sistema Respiratorio/epidemiologíaAsunto(s)
Absceso/etiología , Infecciones Bacterianas/etiología , Candidiasis/etiología , Síndrome de Job/complicaciones , Neumonía/etiología , Enfermedades de la Piel/etiología , Absceso/sangre , Absceso/genética , Adolescente , Adulto , Infecciones Bacterianas/sangre , Infecciones Bacterianas/genética , Candidiasis/sangre , Candidiasis/genética , Niño , Preescolar , Humanos , Inmunoglobulina E/sangre , Lactante , Recién Nacido , Italia , Síndrome de Job/sangre , Síndrome de Job/genética , Persona de Mediana Edad , Mutación , Neumonía/sangre , Neumonía/genética , Factor de Transcripción STAT3/genética , Enfermedades de la Piel/sangre , Enfermedades de la Piel/genética , Adulto JovenRESUMEN
This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Linfopoyesis/genética , Subunidad p52 de NF-kappa B/genética , Células Precursoras de Linfocitos B/inmunología , Adulto , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Mutación del Sistema de Lectura , Humanos , MasculinoAsunto(s)
Anemia Hemolítica Autoinmune/genética , Enfermedades Autoinmunes/genética , Antígeno CTLA-4/genética , Inmunodeficiencia Variable Común/genética , Púrpura Trombocitopénica Idiopática/genética , Adalimumab/uso terapéutico , Adolescente , Anemia Hemolítica Autoinmune/terapia , Antiinflamatorios/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Azatioprina/uso terapéutico , Niño , Preescolar , Inmunodeficiencia Variable Común/terapia , Diarrea/genética , Diarrea/patología , Enfermedades Duodenales/genética , Enfermedades Duodenales/patología , Femenino , Eliminación de Gen , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/genética , Púrpura Trombocitopénica Idiopática/terapia , Análisis de Secuencia de ADN , Tomografía Computarizada por Rayos X , Adulto JovenAsunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/inmunología , Senescencia Celular/inmunología , Células Asesinas Naturales/inmunología , Adulto , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Ligando de CD40/deficiencia , Humanos , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Recuento de Linfocitos , MasculinoRESUMEN
Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.
Asunto(s)
Infecciones Bacterianas/prevención & control , Vacunas Bacterianas/administración & dosificación , Huésped Inmunocomprometido , Guías de Práctica Clínica como Asunto , Vacunas Virales/administración & dosificación , Virosis/prevención & control , Adulto , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/virología , Niño , Política de Salud , Humanos , Esquemas de Inmunización , Síndromes de Inmunodeficiencia/microbiología , Síndromes de Inmunodeficiencia/virología , Italia , Evaluación de Procesos, Atención de Salud , Vacunación/métodos , Vacunas de Productos Inactivados , Virosis/inmunología , Virosis/virologíaAsunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Mutación , Nucleotidiltransferasas/genética , Anomalías Múltiples/inmunología , Agammaglobulinemia/diagnóstico , Anemia Sideroblástica/diagnóstico , Linfocitos B/inmunología , Linfocitos B/patología , Cardiomiopatía Hipertrófica/diagnóstico , Discapacidades del Desarrollo/diagnóstico , Homocigoto , Humanos , Lactante , Infecciones/diagnóstico , Masculino , Linaje , Recurrencia , Linfocitos T/inmunología , Linfocitos T/patología , Secuenciación del Exoma/métodosRESUMEN
PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD.
Asunto(s)
Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/diagnóstico por imagen , Enfermedades Pulmonares Fúngicas/diagnóstico por imagen , Enfermedades Pulmonares Fúngicas/etiología , Tomografía Computarizada por Rayos X/métodos , Biomarcadores , Preescolar , Diagnóstico Precoz , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades Pulmonares Fúngicas/terapia , Masculino , Estudios Retrospectivos , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/patologíaRESUMEN
STAT proteins are a family of transcription factors that mediate cellular response to cytokines and growth factors. Study of patients with familial susceptibility to pathogens and/or autoimmune diseases has led to the identification of 7 inherited disorders that are caused by mutations of 4 STAT family genes. Homozygous or compound heterozygous mutations of STAT1 lead to complete or partial forms of STAT1 deficiency that are associated with susceptibility to intracellular pathogens and herpetic infections. Patients with heterozygous STAT1 gain-of-function (GOF) mutations usually present with chronic mucocutaneous candidiasis (CMC) but may also experience bacterial and viral infections, autoimmune manifestations, lymphopenia, cerebral aneurysms, and increased risk to develop tumors. STAT2 deficiency has been described in 5 family members and is characterized by selective susceptibility to viral infections, whereas STAT3 loss-of-function (LOF) mutations are causative of the autosomal-dominant hyper-IgE syndrome (HIES), a condition that is characterized by cutaneous and respiratory infections in association with mucocutaneous candidiasis, eczema, skeletal and connective tissue abnormalities, eosinophilia, and high levels IgE. STAT5B LOF and STAT3 GOF mutations are both associated with disorders characterized by autoimmune or allergic manifestations, together with increased risk of infections. Particularly, STAT5b deficiency results in growth hormone (GH) insensitivity, immunodeficiency, diarrhea, and generalized eczema, whereas STAT3 GOF mutations result in autoimmune cytopenia, lymphadenopathy, short stature, infections, enteropathy, and multiorgan autoimmunity, including early-onset type I diabetes, thyroiditis, hepatitis, arthritis, and interstitial lung disease.
Asunto(s)
Enfermedades Autoinmunes/genética , Síndromes de Inmunodeficiencia/genética , Mutación/genética , Factores de Transcripción STAT/genética , Susceptibilidad a Enfermedades , Humanos , Modelos BiológicosRESUMEN
BACKGROUND: Partial DiGeorge syndrome (pDGS) is caused by deletion of the 22q11.2 region. Within this region lies CrK-like (CRKL), a gene encoding an adapter protein belonging to the Crk family that is involved in the signaling cascade of IL-2, stromal cell-derived factor 1α, and type I interferon. Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood. OBJECTIVE: We aimed to investigate the role of CRKL in T-cell functional responses in patients affected with pDGS. METHODS: Protein expression levels and phosphorylation of CRKL were evaluated in patients with pDGS. T-cell functional assays in vitro and gene-silencing experiments were also performed. RESULTS: CRKL protein expression, as well as its phosphorylation, were reduced in all patients with pDGS, especially on IL-2 stimulation. Moreover, T cells presented impaired proliferation and reduced IL-2 production on anti-CD3/CD28 stimulation and decreased c-Fos expression. Finally, CRKL silencing in Jurkat T cells resulted in impaired T-cell proliferation and reduced c-Fos expression. CONCLUSIONS: The impaired T-cell proliferation and reduction of CRKL, phosphorylated CRKL, and c-Fos levels suggest a possible role of CRKL in functional deficiencies of T cells in patients with pDGS.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de DiGeorge/etiología , Síndrome de DiGeorge/metabolismo , Regulación de la Expresión Génica , Proteínas Nucleares/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Biomarcadores , Estudios de Casos y Controles , Línea Celular , Niño , Preescolar , Citocinas/biosíntesis , Síndrome de DiGeorge/diagnóstico , Silenciador del Gen , Humanos , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Lactante , Activación de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Fenotipo , Fosforilación , Interferencia de ARN , Factor de Transcripción STAT5/metabolismo , Adulto JovenRESUMEN
B cell developmental defects in CVID were recently described in a limited number of cases. To date, a detailed correlation between this maturational defect and the clinical presentation of affected patients has not been reported. In this study, we correlated bone marrow B cell evaluation, peripheral B and T lymphocyte subsets and clinical findings in 15 CVID patients. Early B cell developmental defects were observed in one third of patients. Combined bone marrow and peripheral lymphocytes evaluation allowed to further subdivide CVID patients in three groups with shared clinical features at diagnosis and during follow-up. These data broaden the number of CVID patients with early B cell developmental defects and, together with the peripheral lymphocytes evaluation, offer insight into the related clinical features in affected patients.