Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2

Blood. 2019 Jul 25;134(4):395-406. doi: 10.1182/blood.2018892752. Epub 2019 Apr 23.


Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti-tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species- and peptidylarginine deiminase-dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine / metabolism*
  • Adenosine Deaminase / deficiency*
  • Adenosine Deaminase / metabolism
  • Agammaglobulinemia / etiology*
  • Agammaglobulinemia / metabolism*
  • Biomarkers / metabolism
  • Cytokines / metabolism
  • Enzyme Activation
  • Extracellular Traps / immunology*
  • Extracellular Traps / metabolism*
  • Female
  • Humans
  • Inflammation Mediators / metabolism
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • NF-kappa B / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Receptors, Purinergic P1 / metabolism
  • Severe Combined Immunodeficiency / etiology*
  • Severe Combined Immunodeficiency / metabolism*
  • Sex Factors
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • Receptors, Purinergic P1
  • Tumor Necrosis Factor-alpha
  • ADA2 protein, human
  • Adenosine Deaminase
  • Adenosine

Supplementary concepts

  • Severe combined immunodeficiency due to adenosine deaminase deficiency