Adenosine and Adenosine Deaminase Contrary Manifestations in Immunity

Adenosine (Ado) is an important purine that regulates numerous physiological functions. Adenosine deaminase (ADA) catalyses the irreversible deamination of Ado and its derivatives. Ado and ADA are the essential players in the immune system, but their roles often are opposite, mutually exclusive and competitive. This work presents several critical immune system situations demonstrating the conflicts between the functions of Ado and ADA. Ado suppresses immunity and inflammation by inhibiting lymphocyte proliferation. ADA supports the development of the immune system by metabolising Ado. In infectious and inflamed diseases, the increased ADA levels in tissue exudates decrease Ado concentration, aggravating inflammation. ADA inhibition is required to protect Ado and mitigate inflammation. In hereditary ADA deficiency, cytotoxic metabolites of Ado accumulate in lymphocytes and suppress immunity. ADA deficiency became the second cause of severe combined immunodeficiency (SCID). Enzyme replacement therapy using PEGylated ADA and ADA gene therapy are recognised in ADA-SCID treatment. The human immunodeficiency virus (HIV) hyperactivates host immune cells, resulting in super-inflammation and acquired immunodeficiency syndrome (AIDS). Cytotoxic derivatives of Ado suppress HIV-1 growth, whereas ADA inactivates cytotoxic nucleosides. ADA inhibition is required to prolong the elimination time and reduce the effective doses of anti-AIDS drugs. Ado levels elevate in the tumour microenvironment, promote immunity suppression and condition tumour cell evasion of immune surveillance. ADA neutralises Ado and restores immunity. Furthermore, ADA can simultaneously bind to the CD26 protein on lymphocytes and the A_2AR receptors on antigen-presenting dendritic cells. Created CD26-ADA-A_2AR complex bridges T and dendritic cells, stimulating T lymphocyte function.