RESUMEN
Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.
Asunto(s)
Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Mutación , Fosfolipasa C gamma/genética , Adolescente , Agammaglobulinemia/terapia , Autoinmunidad/genética , Biomarcadores , Caspasa 1/metabolismo , Niño , Citocinas/metabolismo , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedades Autoinflamatorias Hereditarias/terapia , Humanos , Inflamasomas/metabolismo , Masculino , Linaje , Fenotipo , Fosfolipasa C gamma/química , Fosfolipasa C gamma/metabolismo , Relación Estructura-ActividadRESUMEN
Human parechovirus-3 has been associated with severe clinical manifestations in infants, such as sepsis-like illness and meningoencephalitis. Nevertheless, the vast majority of patients have a favorable outcome. We report the occurrence of this infection in dizygotic infants with extreme hyperferritinemia and a transient impairment of natural killer cell cytotoxicity.
Asunto(s)
Trastornos del Metabolismo del Hierro , Parechovirus , Infecciones por Picornaviridae , Femenino , Humanos , Lactante , Linfohistiocitosis Hemofagocítica , Masculino , Gemelos DicigóticosAsunto(s)
Antígenos CD19/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Terapia Recuperativa , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: During the last decades remarkable scientific advances have been made toward the prevention of HIV mother-to-child transmission, in particular in developed nations. The aim of this review was to analyze the latest findings and available international recommendations on the prevention of HIV mother-to-child transmission in high-income countries. METHODS: We performed a literature search of the Cochrane Library, MEDLINE by PubMed and EMBASE from database inception through June 2014, using the following terms: HIV, mother-to-child transmission and mother-to-child-transmission prevention. All types of articles in the English language were included. US and available European guidelines were searched and included in the analysis. RESULTS: One hundred fifty articles were selected for inclusion in this review. CONCLUSIONS: Global epidemiology of HIV infection is rapidly evolving, in particular in high-resource countries. The interpretation of clinical and epidemiological studies is crucial for the development of evidence-based recommendations to guide the management of HIV mother-to-child transmission. Although significant progress has been made, heterogeneity between countries in specific interventions still exists, which may address future research.