Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation.
J Allergy Clin Immunol
; 146(1): 192-202, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-31862378
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Ativação Linfocitária
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Adenilato Quinase
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Imunodeficiência Combinada Severa
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Mutação de Sentido Incorreto
/
Homozigoto
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2020
Tipo de documento:
Article