RESUMO
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.
Assuntos
Linfócitos B/metabolismo , Imunodeficiência de Variável Comum/genética , Genoma/genética , RNA Mensageiro/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Receptor do Fator Ativador de Células B/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Análise de Sequência de DNA , Análise de Sequência de RNA , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adulto JovemRESUMO
XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.
Assuntos
Proteínas de Transporte de Cátions/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/etiologia , Mutação , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Encéfalo/patologia , Análise Mutacional de DNA , Fluordesoxiglucose F18 , Humanos , Imunofenotipagem , Linfonodos/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Tomografia por Emissão de Pósitrons , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/diagnósticoRESUMO
This review of the currently available literature from more than two decades of clinical experience with self-infusions of immunoglobulin at home provides evidence to support the feasibility, safety, and efficacy in all age groups. Self-infusions at home not only increase patient confidence and their understanding of the immune deficiency but also contribute to the improvement of health-related quality of life. Such home therapy programs should be encouraged, and wherever possible, experienced centers should extend their services to include patients who require immunoglobulin therapy for immunomodulation. Home therapy programs play an important role in long-term health outcome.
Assuntos
Terapia por Infusões no Domicílio/métodos , Imunização Passiva/métodos , Síndromes de Imunodeficiência/terapia , Terapia por Infusões no Domicílio/economia , Terapia por Infusões no Domicílio/psicologia , Terapia por Infusões no Domicílio/tendências , Humanos , Imunização Passiva/economia , Imunização Passiva/psicologia , Imunização Passiva/tendências , Síndromes de Imunodeficiência/economia , Educação de Pacientes como Assunto , Guias de Prática Clínica como Assunto , Desenvolvimento de Programas/economia , Desenvolvimento de Programas/métodos , Qualidade de VidaRESUMO
In a double-blind study, we randomly assigned 84 patients with chronic lymphocytic leukemia who were judged to be at increased risk of bacterial infection to receive intravenous immunoglobulin G (400 mg per kilogram of body weight) or a placebo every three weeks for one year. Eligible patients had hypogammaglobulinemia, a history of infection, or both. The patients receiving immunoglobulin had significantly fewer bacterial infections during the study period than those receiving placebo (23 vs. 42; P = 0.01). This reduction was most striking in the patients who completed a full year of treatment (14 vs. 36; P = 0.001). The period from study entry to the first serious bacterial infection was significantly longer in the patients receiving immunoglobulin (P = 0.026). There was no significant difference between the two groups in the incidence of nonbacterial infection. Immunoglobulin therapy was tolerated well; there were no serious adverse reactions, and the incidence of minor reactions was low. We conclude that selected patients with chronic lymphocytic leukemia who are at risk of bacterial infection can be substantially protected from this complication by the regular intravenous administration of immunoglobulin.