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Aldrich, MB, Chen, W, Blackburn, MR, Martinez-Valdez, H, Datta, SK and Kellems, RE (2003) Impaired germinal center maturation in adenosine deaminase deficiency. J. Immunol. 171:5562-70
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.
Adenosine Deaminase/deficiency; Adenosine Deaminase/genetics; Adenosine Deaminase/metabolism; Animals; Apoptosis/genetics; Apoptosis/immunology; Ascitic Fluid/cytology; Ascitic Fluid/enzymology; Ascitic Fluid/immunology; Ascitic Fluid/pathology; B-Lymphocyte Subsets/cytology; B-Lymphocyte Subsets/enzymology; B-Lymphocyte Subsets/metabolism; B-Lymphocyte Subsets/pathology; Bone Marrow Cells/cytology; Bone Marrow Cells/enzymology; CD4-Positive T-Lymphocytes/cytology; CD4-Positive T-Lymphocytes/enzymology; Cell Differentiation/genetics; Cell Differentiation/immunology; Cell Division/genetics; Cell Division/immunology; Deoxyadenine Nucleotides/biosynthesis; Deoxyadenine Nucleotides/physiology; Germinal Center/enzymology; Germinal Center/immunology; Germinal Center/metabolism; Germinal Center/pathology; Immunoglobulin M/biosynthesis; Lymphocyte Activation/genetics; Lymphocyte Count; Lymphopenia/enzymology; Lymphopenia/genetics; Lymphopenia/immunology; Lymphopenia/pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Antigen, B-Cell/physiology; Spleen/enzymology; Spleen/immunology; Spleen/metabolism; Spleen/pathology
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