Several studies point to elevated pools of adenosine and its metabolites as causal factors in the immunodeficiency of children with severe combined immunodeficiency disease (SCID) associated with the absence of adenosine deaminase (ADA). However, measurements of purine levels and purine metabolism have not led to a unifying hypothesis for the exact biochemical mechanism by which immune function is impaired. We wish to test a new hypothesis--that elevated levels of adenosine or adenosine metabolites interfere with RNA metabolism or function (i.e., protein synthesis) in the affected cells. In the mitogen-induced lymphocyte system, others have shown that protein synthesis is inhibited at lower levels (approximately 20-fold) of an ADA inhibitor than that required to inhibit DNA synthesis. A possible mechanism for this observation is inhibition of RNA methylation reactions by S-adenosyl homocysteine, levels of which may be increased by adenosine in lymphocytes of SCID:ADA patients. The elevation may occur due to the well-established product inhibition of S-adenosylhomocysteine cleavage reaction by adenosine. We propose to ivestigate effects of adenosine in the mitogen-induced lymphocyte system by measuring: 1) RNA maturation and protein synthesis in the lymphocytes or in cell-free systems derived therefrom: 2) the levels of S-adenosyl homocysteine, adenosine and other adenosine derivatives when lymphoblastogenesis is impaired; and 3) the extent of RNA methylation.
NIH ExPorter
NIH ExPorter