Toxic metabolite causes ADA immunosuppression

Congenital adenosine deaminase (ADA) deficiency results in a severe combined immunodeficiency, but the precise molecular mechanism triggered by ADA deficiency had remained unclear. In August 1 Journal of Clinical Investigation, Justin Van De Wiele and colleagues at the Oklahoma Medical Research Foundation, US, show that ADA deficiency causes dATP-induced mitochondrial cytochrome c release followed by apoptosis, leading to reduced thymic T cell production (J Clin Invest 2002, 110:395-402).

Van De Wiele et al. cultured fetal thymic organs from ADA-deficient mice and observed that thymocyte development could be rescued by normalization of dATP levels with an inhibitor of adenosine kinase. The cultures could also be rescued by introduction of a Bcl-2 transgene, suggesting that toxicity results from dATP-induced cytochrome c release from the mitochondria, triggering apoptosis of thymocytes beyond the double-negative stage.

"Our experiments provide a new perspective on the routes by which thymocytes die by apoptosis during development," write the ...