原发性免疫缺陷
错义突变
生物
免疫学
T细胞受体
分子生物学
T细胞
突变
免疫系统
基因
遗传学
作者
Rana Mansour,Rana El-Hassan,Youmna El-Orfali,A.Y. Saidu,Habib Alkalamouni,Qian Chen,Mehdi Benamar,Ghassan Dbaibo,Rima Hanna-Wakim,Talal A. Chatila,Michel J. Massaad
标识
DOI:10.1016/j.jaci.2023.08.005
摘要
Background Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. Objective We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death. Methods Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry. Results The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient’s heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced. Conclusions The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity. Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death. Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry. The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient’s heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced. The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
科研通智能强力驱动
Strongly Powered by AbleSci AI