Impaired germinal center maturation in adenosine deaminase deficiency.
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.
Aldrich
Melissa B
MB
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030, USA.
Chen
Wilma
W
Blackburn
Michael R
MR
Martinez-Valdez
Hector
H
Datta
Surjit K
SK
Kellems
Rodney E
RE
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
D003838:Deoxyadenine Nucleotides; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D000243:Adenosine Deaminase; C026600:2'-deoxyadenosine triphosphate