Department of Pediatrics, Department of Microbiology and Immunology, University Hospitals Leuven, Leuven, Belgium.
Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, USA.
J Clin Immunol. 2018 Jul;38(5):569-578. doi: 10.1007/s10875-018-0525-8. Epub 2018 Jun 27.
Deficiency of ADA2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by biallelic hypomorphic mutations in the ADA2 gene that encodes the adenosine deaminase 2 (ADA2) protein. Over 60 disease-associated mutations have been identified in all domains of ADA2 affecting the catalytic activity, protein dimerization, and secretion. Vasculopathy ranging from livedo reticularis to polyarteritis nodosa (PAN) and life-threatening ischemic and/or hemorrhagic stroke dominate the clinical features of DADA2. Vasculitis and inflammation can affect many organs, explaining the intestinal, hepatological, and renal manifestations. DADA2 should be primarily considered in patients with early-onset fevers, rashes, and strokes even in the absence of positive family history. Hematological manifestations include most commonly hypogammaglobulinemia, although pure red cell aplasia (PRCA), immune thrombocytopenia, and neutropenia have been increasingly reported. Thus, DADA2 may unify a variety of syndromes previously not thought to be related. The first-line treatment consists of TNF-inhibitors and is effective in controlling inflammation and in preserving vascular integrity. Hematopoietic stem cell transplantation (HSCT) has been successful in a group of patients presenting with hematological manifestations. ADA2 is highly expressed in myeloid cells and plays a role in the differentiation of macrophages; however, its function is still largely undetermined. Deficiency of ADA2 has been linked to an imbalance in differentiation of monocytes towards proinflammatory M1 macrophages. Future research on the function of ADA2 and on the pathophysiology of DADA2 will improve our understanding of the condition and promote early diagnosis and targeted treatment.
ADA2 缺乏症（DADA2）是首个分子描述的单基因血管炎综合征。DADA2 是由 ADA2 基因的双等位基因功能降低突变引起的，该基因编码腺苷脱氨酶 2（ADA2）蛋白。在 ADA2 的所有结构域中已经发现了超过 60 种与疾病相关的突变，这些突变影响催化活性、蛋白二聚化和分泌。从网状青斑到结节性多动脉炎（PAN）和危及生命的缺血性和/或出血性中风的血管病变是 DADA2 的主要临床特征。血管炎和炎症可能影响许多器官，这解释了肠道、肝脏和肾脏的表现。即使没有阳性家族史，也应主要考虑 DADA2 患者的早发性发热、皮疹和中风。血液学表现最常见的是低丙种球蛋白血症，尽管纯红细胞再生障碍（PRCA）、免疫性血小板减少症和中性粒细胞减少症也越来越多地报道。因此，DADA2 可能统一了以前认为不相关的多种综合征。一线治疗包括 TNF 抑制剂，可有效控制炎症和维持血管完整性。造血干细胞移植（HSCT）在一组出现血液学表现的患者中取得了成功。ADA2 在髓样细胞中高度表达，并在巨噬细胞分化中发挥作用；然而，其功能仍在很大程度上未确定。ADA2 缺乏与单核细胞向促炎 M1 巨噬细胞分化失衡有关。对 ADA2 功能和 DADA2 病理生理学的未来研究将提高我们对该疾病的理解，并促进早期诊断和靶向治疗。
