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Mechanisms of vascular inflammation in deficiency of adenosine deaminase 2 (DADA2)

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Abstract

Deficiency of adenosine deaminase 2 (DADA2) was first described as a monogenic form of systemic vasculitis that closely resembles polyarteritis nodosa (PAN). The phenotypic spectrum of DADA2 has vastly expanded in recent years and now includes pure red cell aplasia, bone marrow failure syndrome, lymphoproliferative disease, and humoral immunodeficiency. Vasculitis remains the most common presentation of DADA2, and treatment with tumor necrosis factor inhibitors (TNFi) has shown remarkable efficacy in preventing stroke and ameliorating features of systemic inflammation. The precise function of ADA2 has not been elucidated, and how absence of ADA2 ignites inflammation is an active area of research. In this review, we will discuss the current understanding of DADA2 from research and clinical perspectives. We will evaluate several proposed functions of ADA2, including polarization of monocyte phenotype, regulation of neutrophil extracellular trap formation, and modulation of innate immunity. We will also review the role of inflammatory cytokines including TNF and type I interferons. Lastly, we will provide future perspectives on understanding the phenotypic heterogeneity of DADA2 and discuss potential treatment options.

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Funding

This work is supported by National Institute of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant K08-AR074562, the Rheumatology Research Foundation K Supplement Award, Arthritis National Research Foundation All Arthritis Grant, and the Charles H. Hood Foundation Child Health Research Award (P.Y.L.). Q.Z. received the grants 2018YFC1004903 from National Key Research and Development Project, 31771548 and 81971528 from The National Natural Science Foundation of China, LR19H100001 from Zhejiang Provincial Natural Science Foundation of China.

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Authors and Affiliations

  1. Division of Immunology, Boston Childrens Hospital, Harvard Medical School, Boston, MA, USA

    Pui Y. Lee

  2. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, USA

    Ivona Aksentijevich

  3. The MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Qing Zhou

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This article is a contribution to the special issue on: Inflammation in vascular diseases—Guest Editors: Mariana Kaplan & Peter Grayson

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Lee, P.Y., Aksentijevich, I. & Zhou, Q. Mechanisms of vascular inflammation in deficiency of adenosine deaminase 2 (DADA2). Semin Immunopathol 44, 269–280 (2022). https://doi.org/10.1007/s00281-022-00918-8

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