{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Adenosine deaminase 2 (ADA2), encoded by the "}, {"type": "i", "children": [{"type": "t", "text": "CECR1"}]}, {"type": "t", "text": " gene, is a unique secreted enzyme that plays dual roles as both a catalytic modulator of extracellular adenosine levels and a growth factor influencing immune cell behavior and vascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Unlike the intracellular ADA1 isoenzyme, ADA2 is released primarily by cells of the myeloid lineage – in particular, monocytes undergoing differentiation into macrophages and dendritic cells – and binds to cell surfaces via proteoglycans and adenosine receptors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Its enzymatic activity converts extracellular adenosine into inosine, thereby modulating adenosine‐mediated signaling pathways that govern inflammatory responses, angiogenesis, and tissue repair. In addition, ADA2 exerts growth factor–like actions that stimulate proliferation of activated CD4⁺ T cells and drive T cell–dependent differentiation and proliferation of monocytes into macrophages; such activities contribute to the balance between proinflammatory (M1) and anti‐inflammatory (M2) macrophage phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies have revealed that ADA2 exists as a glycosylated dimer with distinct substrate-binding properties and unique domains that mediate cell-surface interactions, providing a molecular basis for its specialized extracellular functions as compared with ADA1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In contexts of inflammation, hypoxia, or oncogenesis, ADA2 activity is upregulated and can influence the tumor microenvironment by promoting M2-like polarization of tumor-associated macrophages, enhancing paracrine signaling (for example, via PDGF-B) that supports angiogenesis and tumor cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Conversely, loss-of-function mutations in "}, {"type": "i", "children": [{"type": "t", "text": "CECR1"}]}, {"type": "t", "text": " lead to ADA2 deficiency (DADA2), a monogenic disorder characterized by systemic vasculopathy, recurrent strokes, autoinflammation, immunodeficiency, and, in some cases, hematologic abnormalities – a spectrum of clinical manifestations that underscores the essential role of ADA2 in maintaining endothelial integrity and balanced immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " \n Collectively, these findings establish ADA2 as a multifunctional extracellular mediator whose catalytic conversion of adenosine and growth factor–like activities are critical for modulating inflammation, vascular stability, and immune cell differentiation.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qing Zhou, Dan Yang, Amanda K Ombrello, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early-onset stroke and vasculopathy associated with mutations in ADA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1307361"}], "href": "https://doi.org/10.1056/NEJMoa1307361"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24552284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24552284"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Paulina Navon Elkan, Sarah B Pierce, Reeval Segel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1307362"}], "href": "https://doi.org/10.1056/NEJMoa1307362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24552285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24552285"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Andrey V Zavialov, Eduard Gracia, Nicolas Glaichenhaus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.1109764"}], "href": "https://doi.org/10.1189/jlb.1109764"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20453107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20453107"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Anton V Zavialov, Xiaodi Yu, Dorothe Spillmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for the growth factor activity of human adenosine deaminase ADA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.083527"}], "href": "https://doi.org/10.1074/jbc.M109.083527"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20147294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20147294"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Roberta Caorsi, Federica Penco, Francesca Schena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Monogenic polyarteritis: the lesson of ADA2 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Rheumatol Online J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12969-016-0111-7"}], "href": "https://doi.org/10.1186/s12969-016-0111-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27609179"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27609179"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Alexandre Belot, Evangeline Wassmer, Marinka Twilt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in CECR1 associated with a neutrophil signature in peripheral blood."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Rheumatol Online J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1546-0096-12-44"}], "href": "https://doi.org/10.1186/1546-0096-12-44"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25278816"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25278816"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lin Wang, Luz M Londono, Jessica Cowell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-21-0340"}], "href": "https://doi.org/10.1158/0008-5472.CAN-21-0340"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33863778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33863778"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Benzeeta Pinto, Prateek Deo, Susmita Sharma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Rheumatol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10067-021-05711-w"}], "href": "https://doi.org/10.1007/s10067-021-05711-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33791889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33791889"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Isabelle Meyts, Ivona Aksentijevich "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10875-018-0525-8"}], "href": "https://doi.org/10.1007/s10875-018-0525-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29951947"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29951947"}]}]}]}