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Restoring immune cell protein through autophagy targeting revealed hydroxychloroquine’s potential in treating refractory cytopenia.  

A study published in June 2025 issue of Journal of Allergy and Clinical Immunology reported that Deficiency of adenosine deaminase 2 (DADA2), a genetic immune disorder marked by vasculitis and bone marrow failure, involved absent Adenosine deaminase 2 (ADA2) protein expression in primary monocytes despite its presence in cellular models.  

Researchers analyzed the involvement of protein degradation in DADA2 pathogenesis and evaluate the therapeutic potential of hydroxychloroquine (HCQ).  

They assessed ADA2 protein expression in CD14+ monocytes from healthy controls (HC) (n=8) and individuals with DADA2 (n=11) using western blot following inhibition of lysosomal and proteasomal degradation. The ADA2 levels were also evaluated after in vivo treatment with HCQ in 1 DADA2 case. Autophagic activity was measured by analyzing the lipidation of microtubule-associated protein 1 light chain 3 beta (LC3B). Clinical and laboratory findings were collected from 2 individuals with cytopenic DADA2 who received 200 mg/day HCQ.  

The results showed that lysosomal degradation inhibition restored ADA2 protein expression in DADA2 monocytes in vitro. Monocytes from individuals with DADA2 displayed elevated autophagic activity. Clinical improvement was noted in 2 individuals with cytopenic DADA2 treated with HCQ (200 mg/day), along with an in vivo increase in ADA2 protein levels in monocytes from 1 of these individuals.  

Investigators concluded that lysosomal degradation of ADA2 contributed to DADA2 pathogenesis and that HCQ showed potential as a treatment for the affected individuals with refractory cytopenia. 

Source: jacionline.org/article/S0091-6749(25)00651-7/fulltext