Janet Chou1, Anas M Alazami2, Faris Jaber3, Rodrigo Hoyos-Bachiloglu3, Jennifer Jones3, Sabrina Weeks3, Mohammed F Alosaimi4, Wayne Bainter3, Brittney Cangemi3, Yousef R Badran3, Reem Mohammed5, Fayhan Alroqi6, Abduarahman Almutairi3, Noufa Al-Onazi7, Sulaiman AlAjaji6, Bander Al-Saud5, Rand Arnaout5, Megan Elkins3, Sridevi Devana8, Juliet Imperial8, Betty Li8, Linnea Drexhage3, Anas M Abdel Rahman9, Minnie Jacob10, Hadi Haddad11, Rima Hanna-Wakim12, Ghassan Dbaibo12, Michel J Massaad3, Majed Dasouki2, Raymond Mikhael13, Zeina Baz14, Raif S Geha3, Hamoud Al-Mousa15. 1. Division of Immunology, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass. Electronic address: Janet.Chou@childrens.harvard.edu. 2. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 3. Division of Immunology, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass. 4. Division of Immunology, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass; Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia. 5. Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 6. King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 7. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 8. Department of Laboratory Medicine, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass. 9. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Chemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada. 10. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Department of Molecular & Cell Biology, Division of Tropical Health, James Cook University, Townsville, Australia. 11. Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon. 12. Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon. 13. Pediatrics Department, Hotel Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon. 14. Saint George Hospital, University Medical Center, Beirut, Lebanon. 15. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Abstract
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.
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.
Authors: M Dasouki; A Jabr; G AlDakheel; F Elbadaoui; A M Alazami; B Al-Saud; R Arnaout; H Aldhekri; I Alotaibi; H Al-Mousa; A Hawwari Journal: Clin Exp Immunol Date: 2020-07-21 Impact factor: 4.330