TY - JOUR
T1 - Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation
AU - Chou, Janet
AU - Alazami, Anas M.
AU - Jaber, Faris
AU - Hoyos-Bachiloglu, Rodrigo
AU - Jones, Jennifer
AU - Weeks, Sabrina
AU - Alosaimi, Mohammed F.
AU - Bainter, Wayne
AU - Cangemi, Brittney
AU - Badran, Yousef R.
AU - Mohammed, Reem
AU - Alroqi, Fayhan
AU - Almutairi, Abduarahman
AU - Al-Onazi, Noufa
AU - AlAjaji, Sulaiman
AU - Al-Saud, Bander
AU - Arnaout, Rand
AU - Elkins, Megan
AU - Devana, Sridevi
AU - Imperial, Juliet
AU - Li, Betty
AU - Drexhage, Linnea
AU - Abdel Rahman, Anas M.
AU - Jacob, Minnie
AU - Haddad, Hadi
AU - Hanna-Wakim, Rima
AU - Dbaibo, Ghassan
AU - Massaad, Michel J.
AU - Dasouki, Majed
AU - Mikhael, Raymond
AU - Baz, Zeina
AU - Geha, Raif S.
AU - Al-Mousa, Hamoud
N1 - Publisher Copyright:
© 2019
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - AK2
KW - B cells
KW - adenylate kinase 2
KW - common variable immunodeficiency
KW - hypogammaglobulinemia
KW - mitochondria
KW - oxidative phosphorylation
KW - primary immunodeficiencies
UR - https://www.scopus.com/pages/publications/85078099954
U2 - 10.1016/j.jaci.2019.12.004
DO - 10.1016/j.jaci.2019.12.004
M3 - Article
C2 - 31862378
AN - SCOPUS:85078099954
SN - 0091-6749
VL - 146
SP - 192
EP - 202
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -