The Journal of allergy and clinical immunology · 2019
Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.
Клиническое исследованиеСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Chou Janet, Alazami Anas M, Jaber Faris, Hoyos-Bachiloglu Rodrigo, Jones Jennifer, Weeks Sabrina, Alosaimi Mohammed F, Bainter Wayne, Cangemi Brittney, Badran Yousef R, Mohammed Reem, Alroqi Fayhan, Almutairi Abduarahman, Al-Onazi Noufa, AlAjaji Sulaiman, Al-Saud Bander, Arnaout Rand, Elkins Megan, Devana Sridevi, Imperial Juliet, Li Betty, Drexhage Linnea, Abdel Rahman Anas M, Jacob Minnie, Haddad Hadi, Hanna-Wakim Rima, Dbaibo Ghassan, Massaad Michel J, Dasouki Majed, Mikhael Raymond, Baz Zeina, Geha Raif S, Al-Mousa Hamoud
Аннотация
BACKGROUND: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival.
OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection.
METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function.
RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function.
CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.
OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection.
METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function.
RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function.
CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.