Adenosine Deaminase deficiency - immunodeficiency in humans, autoimmunity in flies? T. Dolezal¹, M. Zurovec², P.J. Bryant¹. 1) Developmental and Cell Biology, University of California, Irvine, CA; 2) Institute of Entomology and University of South Bohemia, Ceske Budejovice, Czech Republic.

   Adenosine Deaminase (ADA) deficiency in humans causes severe combined immunodeficiency disease (SCID) with impaired lymphocyte differentiation. The exact molecular mechanisms of lymphotoxicity remain obscure however, and the relative effects of intracellular lymphotoxicity versus signaling properties of extracellular adenosine on ADA SCID have not been sufficiently explored. We have recently found a functional homolog of ADA in flies ADGF-A (Adenosine Deaminase-related Growth Factor-A) and have demonstrated that a loss-of-function mutation in ADGF-A causes larval lethality. We have shown that the catalytic activity of ADGF-A is required for its function both in vitro and in vivo and that mutant larvae have an elevated level of extracellular adenosine in larval hemolymph similar to the higher adenosine levels found in the blood of SCID patients. In contrast to SCID, ADGF-A mutant larvae express significant hyperproliferation of blood cells with differentiation into podocytes and lamellocytes with melanotic tumor formation. Mutant larvae also show extensive fat body disintegration. The mutant phenotype is completely rescued by the expression of transgenically provided ADGF-A in the lymph glands. This suggests that inappropriate blood cell development due to lack of ADA causes an autoimmune reaction towards self tissues in flies. In humans, the effects of ADA deficiency are quite different: the reason for this is likely due to the existence of a mechanism of negative selection in the adaptive immunity of vertebrates. Nevertheless, further studies of the ADGF-A mutant phenotype in flies can significantly contribute to the understanding of SCID pathogenesis and the role of extracellular adenosine in cell differentiation.