Department of Molecular Genetics and Microbiology
Aging; Animals; B-Lymphocytes; Bone Marrow; Bromodeoxyuridine; DNA-Binding Proteins; Flow Cytometry; Gene Expression Regulation; Immunity, Cellular; Mice; Mice, Inbred Strains; Time Factors; VDJ Recombinases
Microbiology | Molecular Genetics
During aging, adaptive immunity is severely compromised, due in part to decreased production of B lymphocytes and loss of immunoglobulin (Ig) diversity. However, the molecular mechanisms that underlie age-associated diminished B cell production remain unclear. Using in vivo labeling, we find that this reduction in marrow pre-B cells reflects increased attrition during passage from the pro-B to pre-B cell pool. Analyses of reciprocal bone marrow chimeras reveal that the magnitude and production rates of pre-B cells are controlled primarily by microenvironmental factors, rather than intrinsic events. To understand changes in pro-B cells that could diminish production of pre-B cells, we evaluated rag2 expression and V(D)J recombinase activity in pro-B cells at the single cell level. The percentage of pro-B cells that express rag2 is reduced in aged mice and is correlated with both a loss of V(D)J recombinase activity in pro-B cells and reduced numbers of pre-B cells. Reciprocal bone marrow chimeras revealed that the aged microenvironment also determines rag2 expression and recombinase activity in pro-B cells. Together, these observations suggest that extrinsic factors in the bone marrow that decline with age are largely responsible for less efficient V(D)J recombination in pro-B cells and diminished progression to the pre-B cell stage.
DOI of Published Version
J Exp Med. 2004 Aug 16;200(4):411-23. Link to article on publisher's site
The Journal of experimental medicine
Labrie, Joseph E.; Sah, Alex P.; Allman, David M.; Cancro, Michael P.; and Gerstein, Rachel M., "Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice" (2004). Open Access Articles. 1033.