The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency

Current Rheumatology Reports (2020) 22:64 https://doi.org/10.1007/s11926-020-00944-1 VASCULITIS (L ESPINOZA, SECTION EDITOR) The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency Jennifer Lee Kendall 1 & Jason Michael Springer 1 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review We aim to describe the pathophysiology, clinical findings, diagnosis, and treatment of deficiency of adenosine deaminase 2 (DADA2). Recent Findings DADA2 is a multi-organ disease of children and less often adults, which can present with wide-ranging manifestations including strokes, medium vessel vasculitis, hematologic disease, and immunodeficiency. Diagnosis is through detection of reduced activity level of the adenosine deaminase 2 (ADA2) enzyme and/or identification of bi-allelic mutations in the ADA2 gene. Outside of high-dose glucocorticoids, conventional immunosuppression has been largely ineffective in treating this relapsing and remitting disease. Vasculitic-predominant manifestations respond extremely well to tumor necrosis factor-α inhibition. Hematopoietic stem cell transplantation can lead to normalization of enzyme activity, as well as resolution of vasculitic, hematologic, and immunologic manifestations, although treatment-related adverse effects are not uncommon. Summary Early detection of this disease across multiple disciplines could prevent devastating clinical outcomes, especially in genetically pre-disposed populations. Keywords Adenosine . Adenosine deaminase 2 deficiency . Vasculitis . Polyarteritis nodosa . Monogenic disease Introduction Pathophysiology of DADA2 Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder that affects multiple organ systems with highly variable clinical presentations. First described in 2014 by two separate groups as a mimic of polyarteritis nodosa (PAN), there have been over 260 cases of DADA2 identified to date [1••, 2••]. Abnormalities in adenosine breakdown play a key role in the pathogenesis. Adenosine is formed by the breakdown of adenine nucleotides, with increased concentrations seen in the setting of cellular damage [3, 4]. The effect of adenosine is mediated by four G protein-coupled cell surface receptors (A1, A2A, A2B, and A3), present on many different cell types [5••]. Receptor activation triggers either a decrease (A1 and A3) or increase (A2A and A2B) in intracellular cyclic AMP, which then mediates a change in cellular activation [3]. The varying effect of adenosine on cellular activity and local inflammation seems to be determined by the interplay between the local adenosine concentration, degree of cellular receptor expression, receptor type, and the receptor affinity; most of which can be affected by environmental factors [5••]. Drugs that manipulate the adenosine pathway can be effective in inflammatory diseases [4]. The adenosine deaminases catalyze the deamination of adenosine to inosine, and deoxyadenosine to deoxyinosine, a key part of the purinergic pathway [6••] (Fig. 1). There are two primary isoforms of adenosine deaminase in humans, adenosine deaminase (ADA) 1 and 2. The major adenosine deaminase in humans is ADA1, a 40-kDa monomer present in This article is part of the Topical Collection on Vasculitis * Jason Michael Springer Jennifer Lee Kendall 1 Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine University of Kansas Medical Center, 3901 Rainbow Blvd MS 2026, Kansas City, KS 66160, USA 64 Page 2 of 10 Curr Rheumatol Rep (2020) 22:64 Fig. 1 Proposed pathophysiology of deficiency of adenosine deaminase 2 (DADA2). Adenosine deaminase 2 (ADA2) is produced by myeloid cells with a reduction in enzyme level and/or enzyme activity level. Insufficient ADA2 activity leads to reduction in deamination of adenosine to deoxyadenosine, and an accumulation of extracellular adenosine. Dysregulation of NETosis, chronic neutrophil activation, and polarization from the M2 macrophage subtype to the pro- inflammatory M1 subtype leads to increased inflammatory cytokine production including Tumor Necrosis Factor-α (TNF-α), Interferon (IFN), and (in smaller cohorts) interleukin (IL)-6, IL-8, and IL-10. Dysregulation of NETosis and chronic neutrophil activation may also contribute toward decreased endothelial cell integrity. Increased numbers of naïve B cells with decreased mature B cells have been noted in DADA2 almost all cells, functioning to reduce levels of adenosine in the intracellular space, as high levels are cytotoxic [6••]. Known as severe combined immunodeficiency (SCID), lossof-function mutations in the ADA1 gene lead to increased apoptosis of T and B cells, resulting in recurrent infections [7]. ADA2 is present only at low levels in the physiologic state, increasing during periods of stress [6••]. Unlike ADA1, ADA2 is a 57-kDa homodimer, secreted into the extracellular space, with low affinity for adenosine in physiologic conditions, although this can change based on temperature and pH [6••]. Structurally, while ADA1 and ADA2 have somewhat similar catalytic domains, ADA2 has additional domains allowing it to mediate protein dimerization and cell surface binding in the extracellular space [8••]. The protein dimerization domain is structurally homologous with a family of adenosine deaminase growth factors [6••], which have been shown to be critical in the development of frog [9] and fly [10] embryos. ADA2 has been proposed to have a role in endothelial cell and hematopoietic cell development, although this enzyme is not present within human endothelial cells [2••, 6••, 8••]. Endothelial cell instability in patients with DADA2 is felt to predispose to an underlying vasculitic phenotype [1••, 2••]. ADA2 is predominantly expressed by monocytes undergoing T cell-dependent differentiation into macrophages and dendritic cells [11••]. ADA2 seems to also have cytokine-like growth factor properties, namely by activating CD4+ T cells and monocytes via cell surface binding and formation of the immunological synapse [11••]. ADA2 is also felt to have autocrine-type growth factor properties by stimulating macrophage proliferation and inducing T cell-dependent differentiation of monocytes to macrophages [11••]. ADA2 binds to different cell types via cell surface proteoglycans, but can bind specifically to T cells via the adenosine receptors [11••]. ADA2 binds preferentially to specific lymphocyte subsets without receptors more specific to ADA1 [5••]. Neutrophils have adenosine receptors. A chronic upregulation of neutrophil activity has been proposed to also be behind the vasculopathy component of DADA2 based on findings of upregulated interferon-stimulated gene transcripts in peripheral blood and overexpression of neutrophil-derived genes in two DADA2 patients. Neutrophil activation could contribute to reduced endothelial cell integrity [12]. Changes in the adenosine metabolism p (...truncated)