Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice
UMass Chan Affiliations
Department of Molecular Genetics and MicrobiologyDocument Type
Journal ArticlePublication Date
2004-08-18Keywords
AgingAnimals
B-Lymphocytes
Bone Marrow
Bromodeoxyuridine
DNA-Binding Proteins
Flow Cytometry
Gene Expression Regulation
Immunity, Cellular
Mice
Mice, Inbred Strains
Time Factors
VDJ Recombinases
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
J Exp Med. 2004 Aug 16;200(4):411-23. Link to article on publisher's site
DOI
10.1084/jem.20040845Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38150PubMed ID
15314072Related Resources
ae974a485f413a2113503eed53cd6c53
10.1084/jem.20040845