Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

Abstract

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder presenting with a broad spectrum of clinical manifestations, including immunodeficiency, vasculopathy and hematologic disease. Biallelic mutations in ADA2 gene have been associated with a decreased ADA2 activity, leading to reduction in deamination of adenosine and deoxyadenosine into inosine and deoxyinosine and subsequent accumulation of extracellular adenosine. In the early reports, the pivotal role of innate immunity in DADA2 pathogenic mechanism has been underlined, showing a skewed polarization from the M2 macrophage subtype to the proinflammatory M1 subtype, with an increased production of inflammatory cytokines such as TNF-α. Subsequently, a dysregulation of NETosis, triggered by the excess of extracellular Adenosine, has been implicated in the pathogenesis of DADA2. In the last few years, evidence is piling up that adaptive immunity is profoundly altered in DADA2 patients, encompassing both T and B branches, with a disrupted homeostasis in T-cell subsets and a B-cell skewing defect. Type I/type II IFN pathway upregulation has been proposed as a possible core signature in DADA2 T cells and monocytes but also an increased IFN-β secretion directly from endothelial cells has been described. So far, a unifying clear pathophysiological explanation for the coexistence of systemic inflammation, immunedysregulation and hematological defects is lacking. In this review, we will explore thoroughly the latest understanding regarding DADA2 pathophysiological process, with a particular focus on dysregulation of both innate and adaptive immunity and their interacting role in the development of the disease.

Keywords: DADA2; TNF-α; adaptive immunity; adenosine deaminase 2 (ADA 2); innate immunity; interferon.

Figure 1

Schematic overview of DADA2 alterations in immune cells and the described related clinical signs and laboratory findings. DADA2 is associated with a wide variety of clinical manifestations. Here is a summary of clinical and immunological features, grouped in the two branches of the immune system; innate (A) and adaptive (B). LDG, Low Density Granulocytes; Treg, regulatory T cells; cTfh, circulating Tfh; MAIT, mucosal-associated invariant T; MAS, macrophage activation syndrome; ALPS; Autoimmune Lymphoproliferative Syndrome.

Figure 2

The interplay between innate and adaptive immune cells in DADA2. The insufficient or absent ADA2 enzymatic activity leads to a reduction of adenosine conversion into inosine and to an accumulation of adenosine in the extracellular space. In the innate immune system this leads to a chronic neutrophils activation and NETosis dysregulation with spontaneous NETs formation. Macrophages show a polarization towards the M1 subtype with consequent hypersecretion of inflammatory cytokines, especially TNF-α Dysregulation of NETosis and IFN-β secreted in large amount by endothelium also contribute to the M1 polarization. TNF-α acts on neutrophils contributing to maintaining their chronic activation state. CD56bright immature NK cells are increased. Dendritic cells present an altered subsets distribution. TNF-α, together with adenosine, acts also on Treg cells, that result diminished. In the T cell compartment, Tfh cells show an increased frequency but an impaired secretion of IL-21, crucial for B-cell function. Furthermore, T cells present a reduced proportion of the memory subsets and an alteration of CD40L expression. This defect is associated with an impaired B cell proliferation, differentiation and switching with consequent lower levels of immunoglobulins. CD8+ T cells show an exhausted phenotype and produce low amounts of granzyme A. Both T cells and monocytes show an upregulation of JAK – STAT1 – IFN pathways. In monocytes this activation contributes to the M1 macrophage polarization. TNF-α, Tumor necrosis factor α; IFN β, Interferon β; NETs, Neutrophils extracellular traps.