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Human adenosine deaminase type 2 deficiency (<jats:styled-content style=\"fixed-case\">DADA<\/jats:styled-content>2), due to biallelic deleterious mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">ADA<\/jats:styled-content>2<\/jats:italic> gene, is the first described monogenic type of small\u2010 and medium\u2010size vessel vasculitis. The phenotype of <jats:styled-content style=\"fixed-case\">DADA<\/jats:styled-content>2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of <jats:styled-content style=\"fixed-case\">ADA<\/jats:styled-content>2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of <jats:styled-content style=\"fixed-case\">ADA<\/jats:styled-content>2, macrophage differentiation is skewed to a pro\u2010inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti\u2010<jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content> therapy with etanercept and that is the first\u2010line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (<jats:styled-content style=\"fixed-case\">HSCT<\/jats:styled-content>) has been shown to be a definitive cure in <jats:styled-content style=\"fixed-case\">DADA<\/jats:styled-content>2 patients who present with a severe cytopenia. <jats:styled-content style=\"fixed-case\">HSCT<\/jats:styled-content> can also cure the vascular phenotype and is the treatment modality for patients\u2019 refractory to anti\u2010cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of <jats:styled-content style=\"fixed-case\">DADA<\/jats:styled-content>2. Further research on the pathophysiology of this multifaceted condition is needed to fine\u2010tune and steer future therapeutic strategies.<\/jats:p>","DOI":"10.1111\/imr.12722","type":"journal-article","created":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T01:12:24Z","timestamp":1545181944000},"page":"62-72","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Human adenosine deaminase 2 deficiency: A multi\u2010faceted inborn error of immunity"],"prefix":"10.1111","volume":"287","author":[{"given":"Leen","family":"Moens","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Laboratory for Childhood Immunology KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-8554","authenticated-orcid":false,"given":"Michael","family":"Hershfield","sequence":"additional","affiliation":[{"name":"Department of Medicine 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