Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.,Journal of Allergy and Clinical Immunology

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Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2019-12-17 , DOI: 10.1016/j.jaci.2019.12.004
Janet Chou ₁ , Anas M Alazami ₂ , Faris Jaber ₁ , Rodrigo Hoyos-Bachiloglu ₁ , Jennifer Jones ₁ , Sabrina Weeks ₁ , Mohammed F Alosaimi ₃ , Wayne Bainter ₁ , Brittney Cangemi ₁ , Yousef R Badran ₁ , Reem Mohammed ₄ , Fayhan Alroqi ₅ , Abduarahman Almutairi ₁ , Noufa Al-Onazi ₆ , Sulaiman AlAjaji ₅ , Bander Al-Saud ₄ , Rand Arnaout ₄ , Megan Elkins ₁ , Sridevi Devana ₇ , Juliet Imperial ₇ , Betty Li ₇ , Linnea Drexhage ₁ , Anas M Abdel Rahman ₈ , Minnie Jacob ₉ , Hadi Haddad ₁₀ , Rima Hanna-Wakim ₁₁ , Ghassan Dbaibo ₁₁ , Michel J Massaad ₁ , Majed Dasouki ₂ , Raymond Mikhael ₁₂ , Zeina Baz ₁₃ , Raif S Geha ₁ , Hamoud Al-Mousa ₁₄

Affiliation

Division of Immunology, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass.
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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.
Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Department of Laboratory Medicine, Boston Children's Hospital, and Department of Pediatrics Harvard Medical School, Boston, Mass.
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.
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.
Lebanese American University Medical Center-Rizk Hospital, Beirut, Lebanon.
Division of Pediatric Infectious Diseases, American University of Beirut, Beirut, Lebanon.
Pediatrics Department, Hotel Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.
Saint George Hospital, University Medical Center, Beirut, Lebanon.
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.

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.

中文翻译：

AK2的亚同型变异揭示了线粒体功能对B细胞活化的贡献。

背景

基因AK2编码磷酸转移酶腺苷酸激酶2（AK2）。AK2的人类变异会导致网状细胞发育不全，严重的免疫缺陷和粒细胞缺乏症，淋巴细胞减少和感觉神经性耳聋，需要造血干细胞移植才能生存。

客观的

我们调查了3到34岁，9个亲属的15例复发性肺肺感染和低血球蛋白血症的潜在机制。仅2例均轻度损害T细胞增殖的患者，每例均具有一次临床上明显的机会性感染。

方法

用下一代DNA测序，串联质谱法以及淋巴细胞和线粒体功能测定研究了患者细胞。

结果

我们在AK2中鉴定了2个不同的纯合变异体。AK2 ^G100S和AK2 ^A182D允许残留蛋白表达，酶活性以及中性粒细胞和淋巴细胞的正常数量。除1名患者外，所有患者均完整无损。患者的B细胞增殖和体外严重受损免疫球蛋白分泌。通过激活，患者的B细胞表现出线粒体呼吸缺陷，并破坏了线粒体膜电位和质量的调节。尽管机会性感染患者的活化T细胞表现出线粒体功能受损，但T细胞中的线粒体质量得以保留。与活化的T细胞利用线粒体代谢的能力一致，这些发现揭示了T细胞功能对AK2活性的细胞依赖性较不严格。在控制性T细胞和B细胞中，ATP合成的化学抑制作用同样表明B细胞对线粒体功能的依赖性更大。