Toxic metabolite causes ADA immunosuppression

ADA immunosuppression is caused by mitochondrial cytochrome c release and T cell apoptosis

Aug 13, 2002
Tudor Toma(

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 authors. "We anticipate that continued use of in vitro models of thymocyte differentiation to study ADA deficiency will not only shed additional light on the pathogenesis of this immunodeficiency but will also further our understanding of normal programs of T cell development", they conclude.