Function of murine adenosine deaminase in the gastrointestinal tract.
Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency characterized by severe T and B cell lymphopenia. ADA-deficient humans also display defective development of gut-associated lymphoid tissues (GALT). They lack lymphoid cells, and the Peyer's patches are without germinal centers. In mice, ADA-deficient fetuses die perinatally due to liver damage, but they also exhibit pathology in the thymus, spleen, and the small intestine. The GI phenotype associated with ADA-deficient humans prompted us to examine the effect of ADA-deficiency on mouse small intestine tissue. The work presented here focuses on understanding the physiological role of ADA in the GI tract, using ADA-deficient mice rescued from perinatal lethality by restoring Ada expression to trophoblast cells. Histologically and immunologically, the GALT was compromised at all sites in ADA-/- mice, with the most dramatic changes seen in the Peyer's patches. Profound disturbances in purine metabolism were detected in all the gastrointestinal tissues. In particular, adenosine and deoxyadenosine, the ADA substrates, increased markedly while the product inosine decreased. The activity of S-adenosylhomocysteine hydrolase decreased throughout the GI tract, indicating a possible disruption of cellular transmethylation and activation of apoptotic pathways. There were also disturbances in the purine metabolic pathway with a decrease in the production of downstream nucleosides hypoxanthine and xanthine.
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Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Kellems
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D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D043383:Adenosylhomocysteinase; D000818:Animals; D003433:Crosses, Genetic; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000201:enzymology* / Q000473:pathology; D016511:Severe Combined Immunodeficiency / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase