Assuntos
Ligante Coestimulador de Linfócitos T Induzíveis/deficiência , Imunodeficiência Combinada Severa/genética , Adulto , Substituição de Aminoácidos , Apresentação de Antígeno , Quimiotaxia de Leucócito , Complexo de Golgi/química , Humanos , Imunogenicidade da Vacina , Ligante Coestimulador de Linfócitos T Induzíveis/química , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Infecções/etiologia , Ativação Linfocitária , Masculino , Mutação de Sentido Incorreto , Fenótipo , Transporte Proteico , Recidiva , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologiaRESUMO
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.
