title: Impaired germinal center maturation in adenosine deaminase deficiency.
abstract: Mice deficient in the enzyme adenosine deaminase (ADA) have small lymphoid organs that contain reduced numbers of peripheral lymphocytes, and they are immunodeficient. We investigated B cell deficiency in ADA-deficient mice and found that B cell development in the bone marrow was normal. However, spleens were markedly smaller, their architecture was dramatically altered, and splenic B lymphocytes showed defects in proliferation and activation. ADA-deficient B cells exhibited a higher propensity to undergo B cell receptor-mediated apoptosis than their wild-type counterparts, suggesting that ADA plays a role in the survival of cells during Ag-dependent responses. In keeping with this finding, IgM production by extrafollicular plasmablast cells was higher in ADA-deficient than in wild-type mice, thus indicating that activated B cells accumulate extrafollicularly as a result of a poor or nonexistent germinal center formation. This hypothesis was subsequently confirmed by the profound loss of germinal center architecture. A comparison of levels of the ADA substrates, adenosine and 2'-deoxyadenosine, as well resulting dATP levels and S-adenosylhomocysteine hydrolase inhibition in bone marrow and spleen suggested that dATP accumulation in ADA-deficient spleens may be responsible for impaired B cell development. The altered splenic environment and signaling abnormalities may concurrently contribute to a block in B cell Ag-dependent maturation in ADA-deficient mouse spleens.
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030, USA.
authors: Melissa B
authors: MB
authors: Aldrich
authors: Wilma
authors: W
authors: Chen
authors: Michael R
authors: MR
authors: Blackburn
authors: Hector
authors: H
authors: Martinez-Valdez
authors: Surjit K
authors: SK
authors: Datta
authors: Rodney E
authors: RE
authors: Kellems
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001202:Ascitic Fluid / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003838:Deoxyadenine Nucleotides / Q000096:biosynthesis / Q000502:physiology; D018858:Germinal Center / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007075:Immunoglobulin M / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D003838:Deoxyadenine Nucleotides; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D000243:Adenosine Deaminase; C026600:2'-deoxyadenosine triphosphate