Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation

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.

TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity

“…While STAT3 and BTK mutations are heterozygous and hemizygous (X‐linked), respectively, all remaining mutations reported here are homozygous. Clinically and biochemically, all patients with novel mutations had typical presentation except for cases 5, 6 and 7, who had atypical AK2 deficiency which was recently reported to cause hypogammaglobulinemia and limited T cell dysfunction [29], and cases 11 and 12 with zeta‐chain‐associated protein kinase 70 (ZAP70) deficiency who presented with CID phenotype without CD8 deficiency.…”

AK2 deficiency: An awkward tale for B cells

“…In addition, the patients also displayed impaired B-cell proliferation and IgG production after stimulation. 4 The parents, who displayed a heterozygotic genotype for the newly described deficient hypomorphic variants had no immunologic abnormalities or recurrent infections. 4 The fact that hypomorphic mutations result in a variety of clinical phenotypes compared with amorphic mutations in severe combined immunodeficiencies is well described.…”

“…Moreover, granulocyte colony-stimulating factor administration is not sufficient to treat the disease, and the only available treatment for reticular dysgenesis is hematopoietic stem cell transplantation. 3 In this issue of the Journal of Allergy and Clinical Immunology, Chou et al 4 provide elegant evidence indicating that cellular metabolism is crucial for adaptive immunity in humans by showing that intact AK2 function is necessary for B-cell activation and survival. The authors collected and examined data from a rare group of 15 patients (aged 3-34 years) who survived reticular dysgenesis without hematopoietic stem cell transplantation.…”

“…During the study the researchers identified 2 AK2 hypomorphic variants that result in residual protein expression and enzymatic activity, which allowed normal numbers of myeloid and lymphoid cells. 4 Previous studies in other cell types pointed out that AK2 deficiency impairs the differentiation of hematopoietic progenitor to granulocyte or lymphoid lineages. 2 Also, deletion of AK2 with short hairpin RNA led to impaired proliferation or differentiation of progenitor cells into granulocytes or lymphocytes.…”

“…2 Chou et al analyzed patients with reticular dysgenesis that lacked the classical signals associated with AK2 deficiency, which are persistent neutropenia and sensorineural deafness. 4 The absence of these classical signals suggested that patients with hypomorphic variants still possess residual activity of AK2. Indeed, hypogammaglobulinemia was the only immunologic alteration found in all the patients, who presented with normal numbers of T and B cells and plasmablasts.…”