Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, NSW, Australia.
J Clin Immunol. 2021 Nov;41(8):1915-1935. doi: 10.1007/s10875-021-01141-0. Epub 2021 Oct 17.
Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes.
In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls.
The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4 and CD8 memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8 T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2 γδT) were diminished whereas pro-inflammatory monocytes and CD56 immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients.
Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.
腺苷脱氨酶 2 型（ADA2）（DADA2）缺陷是一种由 ADA2 双等位基因有害突变引起的罕见遗传性免疫缺陷。临床表现多种多样，从严重的血管病变伴腔隙性中风到免疫缺陷伴病毒感染、低丙种球蛋白血症和骨髓衰竭。关于 DADA2 患者白细胞的表型和功能，目前仅有有限的数据。本研究旨在对 DADA2 患者进行深入的免疫表型分析和功能分析，以研究其对人类淋巴细胞的影响。
对 10 名确诊的 DADA2 患者进行深入的免疫表型分析和功能分析，并与致病性 ADA2 突变的杂合携带者和健康正常对照进行比较。
患者的中位年龄为 10 岁（平均 20.7 岁，范围 1-44 岁）。10 名患者中有 4 名正在接受类固醇和/或依那西普或其他免疫抑制剂治疗。我们证实 DADA2 存在末端 B 细胞分化缺陷，并揭示骨髓中 B 细胞发育在原 B 细胞至前 B 细胞阶段受阻。我们还发现 CD4 和 CD8 记忆 T 细胞分化受损、加速衰竭/衰老、以及 ADA2 缺陷 CD8 T 细胞的存活和颗粒酶产生受损。非常规 T 细胞（即 iNKT、MAIT、Vδ2 γδT）减少，而促炎单核细胞和 CD56 幼稚 NK 细胞增加。与健康供体相比，DADA2 患者的所有单核细胞亚群中 IFN 诱导的凝集素 SIGLEC1 的表达增加。有趣的是，健康杂合携带者的淋巴细胞表型和功能通常介于健康供体和 ADA2 缺陷患者之间。
对 DADA2 患者进行扩展免疫表型分析显示出复杂的免疫表型。我们的研究结果为 DADA2 一些复杂和异质临床特征的细胞机制提供了深入的了解。需要进一步的研究来设计靶向治疗，以预防这些过度炎症患者的病毒感染，这是其主要的表型。
