Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation - 22/07/20

Doi : 10.1016/j.jaci.2019.12.004

Janet Chou, MD ^a,^{∗
These authors contributed equally to this work.}^⁎ , Anas M. Alazami, PhD ^b,^{∗
These authors contributed equally to this work.}, Faris Jaber, MD ^a,^{∗
These authors contributed equally to this work.}, Rodrigo Hoyos-Bachiloglu, MD ^a, Jennifer Jones, BA ^a, Sabrina Weeks, BA ^a, Mohammed F. Alosaimi, MD ^a,^c, Wayne Bainter, MMSc ^a, Brittney Cangemi, BA ^a, Yousef R. Badran, MD ^a, Reem Mohammed, MD ^d, Fayhan Alroqi, MD ^e, Abduarahman Almutairi, MD ^a, Noufa Al-Onazi, MD ^f, Sulaiman AlAjaji, MD ^e, Bander Al-Saud, MD ^d, Rand Arnaout, MD ^d, Megan Elkins, MSc ^a, Sridevi Devana, BS, MT(ASCP) ^g, Juliet Imperial, BSMT, AMT ^g, Betty Li, MS, MD ^g, Linnea Drexhage, MSc ^a, Anas M. Abdel Rahman, PhD ^b,^h,ⁱ, Minnie Jacob, MS ^b,^j, Hadi Haddad, MD ^k, Rima Hanna-Wakim, MD ^l, Ghassan Dbaibo, MD ^l, Michel J. Massaad, PhD ^a,^{^{‡
Current address: Faculty of Medicine, American University of Beirut, Beirut, Lebanon.}}, Majed Dasouki, MD ^b, Raymond Mikhael, MD ^m,^{§
These authors contributed equally to this work.}, Zeina Baz, MD ^n,^{§
These authors contributed equally to this work.}, Raif S. Geha, MD ^a,^{§
These authors contributed equally to this work.}, Hamoud Al-Mousa, MD ^b,^d,^h,^{§
These authors contributed equally to this work.}
^a Division of Immunology, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass
^b Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
^c Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
^d Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
^e King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
^f Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
^g Department of Laboratory Medicine, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass
^h College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
ⁱ Department of Chemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada
^j Department of Molecular & Cell Biology, Division of Tropical Health, James Cook University, Townsville, Australia
^k Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon
^l Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon
^m Pediatrics Department, Hotel Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon
ⁿ Saint George Hospital, University Medical Center, Beirut, Lebanon

^∗Corresponding author: Janet Chou, MD, Boston Children's Hospital, 1 Blackfan Circle, Karp 10127, Boston, MA 02115.Boston Children's Hospital1 Blackfan Circle, Karp 10127BostonMA02115

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. AK2^G100S and AK2^A182D 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.

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Key words : AK2, adenylate kinase 2, hypogammaglobulinemia, mitochondria, oxidative phosphorylation, primary immunodeficiencies, B cells, common variable immunodeficiency

Abbreviations used : ADP, AK, AK2, CMV, HSCT, MFI, NMP, OCR, Olig, ROS

Plan

Methods

Case studies

Immunologic and genetic analysis

Statistical analysis

Results

Clinical characteristics

Abnormalities in laboratory results

Identification of 2 distinct homozygous variants in AK2

AK2^G100S and AK2^A182D variants impair B-cell function and mitochondrial respiration

Defects in T cells in patients with AK2^G100S and AK2^A182D variants

Discussion

	Supported by grant 5K08AI116979-04 (to J.C.), grant 1R01AI139633-01 (to R.S.G.), the Perkin Fund (to R.S.G.), the National Science, Technology and Innovation Plan program of Saudi Arabia (grant KACST 13-BIO-755-2 to M.J.D. and H.A.A.), and the Saudi Human Genome Program.
	The authors declare that they have no relevant conflicts of interest.

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Vol 146 - N° 1

P. 192-202 - juillet 2020 Retour au numéro

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Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation - 22/07/20

Abstract

Background

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Results

Conclusions

Plan

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