Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells

Abstract

At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity. Here, we found that ADA2 binds to neutrophils, monocytes, NK cells and B cells that do not express CD26, a receptor for ADA1. Moreover, the analysis of CD4+ T-cell subset revealed that ADA2 specifically binds to regulatory T cells expressing CD39 and lacking the receptor for ADA1. Also, it was found that ADA1 binds to CD16- monocytes, while CD16+ monocytes preferably bind ADA2. A study of the blood samples from ADA2-deficient patients showed a dramatic reduction in the number of lymphocyte subsets and an increased concentration of TNF-α in plasma. Our results suggest the existence of a new mechanism, where the activation and survival of immune cells is regulated through the activities of ADA2 or ADA1 anchored to the cell surface.

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…This co‐stimulatory signal leads to augmented production of IFN‐gamma, TNF‐alpha, IL‐6 . In contrast, ADA2 has been found to bind preferentially to neutrophils, CD16 + monocytes, and to less extent to B cells and NK cells . It is secreted by monocytes differentiating into macrophages or dendritic cells and this secretion is down‐regulated by addition of IFN‐gamma .…”

“…60 In contrast, ADA2 has been found to bind preferentially to neutrophils, CD16 + monocytes, and to less extent to B cells and NK cells. 62 It is secreted by monocytes differentiating into macrophages or dendritic cells and this secretion is down-regulated by addition of IFNgamma. 32 Moreover, ADA2 but not ADA1 induces T cell-dependent differentiation of monocytes into macrophages and stimulates macrophage proliferation.…”

Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood

“…ADA2 is an enzyme that catalyzes the degradation of adenosine to inosine and is secreted by myeloid cells . The pathomechanism of DADA2 remains unclear, but ADA2 seems to have an immunomodulatory function . While DADA2 is primarily considered a vascular disease of childhood, recent evidence suggests that the clinical spectrum is not limited to vasculitis, arthralgias, and recurrent fevers, but can also include features of autoimmunity and immunodeficiency.…”

Evaluation of immune cellular enzymes, oxidative and nitrosative Stress in Saudi Patients with Cutaneous Leishmaniasis in Al-AHssa, before and after treatment

“…is widely distributed in human tissues and is higher in macrophages and lymphoid tissues. It is mediates deamination of the anti-in ammatory nucleoside adenosine to inosine and thus it has a role in maintenance of cellular immunity [9]. It was reported that high serum ADA activities were observed in patients with acute hepatitis, chronic active hepatitis, and in sera and lymphocytes of CL patients [10].…”