In this issue of Blood, Hashem et al report a remarkable therapeutic result: all facets of the diverse spectrum of the rare disease adenosine deaminase 2 (ADA2) deficiency, which range from vasculopathy including stroke to severe anemia and immunodeficiency, can be corrected by hematopoietic stem cell transplantation (HSCT).1  What unites these diverse manifestations is the deregulation of the innate immune system. The rapidly expanding knowledge is gained from detailed analysis of the innate immune system and the genes that regulate the function of myeloid cells, macrophages, and antigen-presenting cells. This knowledge forms the basis for understanding many diseases.2-4  Thus, hyperinflammation is found in disorders including cancer, neurological diseases, bowel diseases, rheumatoid diseases, and vasculitis, with a strong contribution of the innate immune system to disease initiation and progression.

Immune regulation not only may be governed by genes that regulate specific genetic programs such as development, cytokine secretion, or signaling pathways, but it also is regulated by metabolism and small metabolites. Thus, one of the first immune defects discovered was the deficiency of ADA1, which causes T-cell deficiency by intracellular accumulation of toxic compounds that cannot be removed because of the defect of this enzyme; however, “poisoning” of cells is not the only feature. ADA1 is an intracellular enzyme. The metabolites are also extracellularly active and may interact with receptors on a variety of different cells, including cells of the specific and innate immune system. ADA1 is almost exclusively expressed in cells of the lymphoid system. In contrast, ADA2 is present in almost all cells, specifically in cells of the myeloid lineage. ADA2 is secreted, in contrast to ADA1, and acts as an extracellular mediator of cellular interactions, mostly activation of cells of the immune system. Thus, deficiency of ADA2 disturbs the balance of factors that stimulate and/or inhibit activation of immune cells. In 2014, the first patients with diseases ranging from cutaneous vasculitis with severe necrotizing features to stroke and pure red cell aplasia were described with ADA2 deficiency caused by mutations in the CREC1 gene.5,6  Although the majority of the ADA2 deficiency cases described so far present with vasculopathy, patients with defects exclusively in the hematopoietic system such as pure red cell aplasia or Diamond-Blackfan anemia have also been described.7  It is puzzling to understand the role of adenosine and the 2 deaminases in cellular cross talk in the pathophysiology of these patients.8  Cells carry adenosine receptors on the surface and adenosine may stimulate or inhibit cellular function. However, the 2 ADAs act both as enzymes that deaminate adenosine and as signal transduction molecules because all cells of the immune system express 1 or both ADA1and ADA2 receptors. The consequence of ADA2 deficiency in terms of its influence on the fine-tuning of the innate immune system is not well understood.

Overall, 8% of deficiency of ADA2 (DADA2) cases described have had a fatal outcome. Treatment of ADA2 deficiency-induced hyperinflammation and vasculitis may involve inhibition of effector molecules such as tumor necrosis factor and interleukin-1, but these treatments are only partially successful and may not treat the hematological defects. Because, at least in a subgroup of patients, the defect in hematopoiesis affects almost all lineages including immunodeficiency with hypogammaglobulinemia and T-cell function, HSCT has been considered as a treatment specifically for patients with this phenotype. Because DADA2 is a rare disease, experience with HSCT in a large series of patients is not available, although single case reports have been published.9 

Hashem et al now present data from 14 patients with DADA2 treated by HSCT in different centers. Almost all of the 14 patients transplanted had defects in the hematopoietic system as an indication for stem cell transplantation. The results of this treatment are remarkable. HSCT is able to not only cure the deficiency in hematopoiesis and immune function, as one might have expected, but also eliminate the vasculopathy. The results of this study are summarized as follows.

First, HSCT is the treatment of choice, especially for patients with primary hematological features of DADA2, and HSCT can cure all aspects of the disease. A total of 14/14 patients have been cured of their disease, including vasculopathy, and transplantation has been successful with respect to both engraftment and further clinical course. Second, probably because of the deficiency of DADA2 patients in both innate and specific immunity, graft failure did not occur and may enable reduced conditioning regimens, reducing short- and long-term toxicity. Third, matched allogeneic donors are the preferred donors of choice because siblings may have slight forms of the disease not easily detected. As a consequence, the use of sibling donors would require extensive genetic testing to ensure the donor is suitable.

This landmark paper adds new information to the growing field of diseases that exhibit common phenotypes ranging from vasculopathy/hyperinflammation to hematopoietic and immune dysfunction as a consequence of a deregulated innate immune system. That all vasculopathy features can also be cured by reconstitution of a functional myeloid system suggests that, rather than a dysfunction of endothelial cells, a deregulated monocyte/macrophage function is the cause of even severe features such as stroke. Although in the future, gene therapy (eg, by gene editing) may become available, HSCT is currently the treatment of choice, at least for patients with the hematopoietic phenotype.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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