Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes

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Item Type:	Article
Title:	Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes
Creators Name:	Ehlers, L., Wouters, M., Pillay, B., Delafontaine, S., Dzhus, M., Baggio, M., Niehues, T., Dückers, G., Sevenants, L., Casteels, K., De Somer, L., Schrijvers, R., Vanderschueren, S., Jacquemyn, M., Daelemans, D., Hombrouck, A., Chambers, E.P., Tousseyn, T., Bucciol, G., Agostinis, P., Moens, L. and Meyts, I.
Abstract:	BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity causing vasculitis and bone marrow failure. Bone marrow failure is mostly unresponsive to tumor necrosis factor-alpha inhibitors. The limited understanding of the pathomechanisms driving the disease impedes the development of new treatment options. Unlike cellular model systems expressing pathogenic ADA2 variants, primary monocytes from DADA2 patients lack ADA2 protein expression. OBJECTIVES: This study aimed to analyze the role of protein degradation in the pathogenesis of DADA2 and the therapeutic potential of the lysosomotropic drug hydroxychloroquine in the treatment of DADA2 patients. METHODS: ADA2 protein expression in CD14+ monocytes from healthy controls (n=8) and DADA2 patients (n=11) was determined by western blot after inhibition of lysosomal and proteasomal degradation as well as after hydroxychloroquine treatment in vivo in one DADA2 patient. Lipidation of microtubule associated protein 1 light chain 3 beta (LC3B) was analyzed as a measure of autophagic activity. Clinical and laboratory data were recorded in two cytopenic DADA2 patients treated with 200 mg/day hydroxychloroquine. RESULTS: We demonstrated that inhibition of lysosomal degradation restores ADA2 protein expression in DADA2 monocytes in vitro. DADA2 monocytes exhibited increased autophagic activity. We observed clinical improvement in two cytopenic DADA2 patients treated with hydroxychloroquine and showed a concomitant increase in ADA2 protein levels in monocytes from one of these patients in vivo. CONCLUSION: We identify lysosomal protein degradation of ADA2 as a pathomechanism of DADA2 and introduce hydroxychloroquine as a potential treatment option in DADA2 patients with refractory cytopenia.
Keywords:	Deficiency of ADA2, Cytopenia, Hydroxychloroquine, Lysosomal Degradation, TLR9 Signaling
Source:	Journal of Allergy and Clinical Immunology
ISSN:	0091-6749
Publisher:	Elsevier
Date:	20 June 2025
Official Publication:	https://doi.org/10.1016/j.jaci.2025.06.009
PubMed:	View item in PubMed

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