Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation.
Genetic deficiencies in the purine catabolic enzyme adenosine deaminase (ADA) in humans results primarily in a severe lymphopenia and immunodeficiency that can lead to the death of affected individuals early in life. The metabolic basis of the immunodeficiency is likely related to the sensitivity of lymphocytes to the accumulation of the ADA substrates adenosine and 2'-deoxyadenosine. Investigations using ADA-deficient mice have provided compelling evidence to support the hypothesis that T and B cells are sensitive to increased concentrations of 2'-deoxyadenosine that kill cells through mechanisms that involve the accumulation of dATP and the induction of apoptosis. In addition to effects on the developing immune system, ADA-deficient humans exhibit phenotypes in other physiological systems including the renal, neural, skeletal, and pulmonary systems. ADA-deficient mice develop similar abnormalities that are dependent on the accumulation of adenosine and 2'-deoxyadenosine. Detailed analysis of the pulmonary insufficiency seen in ADA-deficient mice suggests that the accumulation of adenosine in the lung can directly access cellular signaling pathways that lead to the development and exacerbation of chronic lung disease. The ability of adenosine to regulate aspects of chronic lung disease is likely mediated by specific interactions with adenosine receptor subtypes on key regulatory cells. Thus, the examination of ADA deficiency has identified the importance of purinergic signaling during lymphoid development and in the regulation of aspects of chronic lung disease.
Blackburn
Michael R
MR
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030 USA.
Kellems
Rodney E
RE
D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D051381:Rats; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology
D000243:Adenosine Deaminase