Asunto(s)
Ligando Coestimulador de Linfocitos T Inducibles/deficiencia , Inmunodeficiencia Combinada Grave/genética , Adulto , Sustitución de Aminoácidos , Presentación de Antígeno , Quimiotaxis de Leucocito , Aparato de Golgi/química , Humanos , Inmunogenicidad Vacunal , Ligando Coestimulador de Linfocitos T Inducibles/química , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ligando Coestimulador de Linfocitos T Inducibles/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Infecciones/etiología , Activación de Linfocitos , Masculino , Mutación Missense , Fenotipo , Transporte de Proteínas , Recurrencia , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T/inmunologíaRESUMEN
Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.