Title

Expression of rag2 and V(D)J Recombinase Activity are Reduced in Aged Mice as a Result of Changes in the Bone Marrow Microenvironment: a Dissertation

Date

February 2004

UMMS Affiliation

Graduate School of Biomedical Sciences, Program in Immunology and Virology

Document Type

Dissertation, Doctoral

Subjects

B-Lymphocytes; Bone Marrow Cells; Cell Aging; Gene Rearrangement, B-Lymphocyte; Genes, RAG-1; Mice; VDJ Recombinases; Academic Dissertations

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Both humans and mice display an age-related decline in immunity. Reduced generation of mature B cells may be a contributing factor due to reduced entry of mature B cells with novel B cell receptors and specificity for pathogens into the mature B cell pool. In aged mice the numbers of B cell precursors within the bone marrow are diminished; there is a severe reduction in numbers of pre-B cells and an increase in numbers of re-circulated mature B cells. Other defects in developing B cells include reduced expression of rag1 and rag2 when measured in total bone marrow precursor populations. In the pro-B cell stage of development rag expression is essential to the process of V(D)J recombination and the generation of pre-B cells. It was not known prior to this work if rag levels were lower in pro-B cells. In Chapter 2 I show that rag2 expression is reduced in pro-B cells of aged mice. The reduction in rag2 expression is correlated with a loss of V(D)J recombinase activity in pro-B cells and reduced numbers of pre-B cells. This suggests that in aged mice the reduction in rag2 expression is sufficient to result in reduced V(D)J recombinase activity and reduced generation of pre-B cells, thus contributing to fewer pre-B cells in aged mice. Furthermore, I have shown that the loss of rag2 expression and recombinase activity in pro-B cells are the result of age-associated defects in the bone marrow-microenvironment as opposed to cell-intrinsic defects in developing precursors.

In Chapter 3 of this thesis I examine genetic influences on age-related defects in murine B cell development and correlations between bone marrow B cell subsets and peripheral T cell subsets. It was known that longevity and age-related defects in T cell subsets are influenced by genetic differences between strains of inbred mice. The impact of genetic polymorphisms on age-related defects in B cell development had not been previously assessed. Nor was it known if these defects were correlated with age-related changes in peripheral T cell subsets. Here I present evidence that B cell subsets in the bone marrow are influenced by genetic polymorphisms between mice strains. Genetic polymorphisms on Chromosomes 15 and 19 were found to influence the frequency of re-circulated and pre-B cells in the bone marrow of aged mice. Frequencies of bone marrow B cell subsets were compared with peripheral T cell subsets. Interestingly, an association between the frequency of pre-B cells was not observed with either re-circulated B cells in the bone marrow nor peripheral T cell subsets. However the frequency of pre-B cells was inversely correlated with the frequency of B220intIgM+ cells, a subset that was found to correlate with more advanced age-related T cell defects. In addition, frequencies of re-circulated B cells in the bone marrow were found to be associated with less advanced age-related defects in peripheral T cell subsets.

These observations indicate that defects in B cell development, including reduced rag2 expression and V(D)J recombinase activity, are the result of changes in the aged murine bone marrow microenvironment. In addition, a genetic polymorphism located on Chromosome 19 influences the frequency of pre-B cells in aged mice. Furthermore the frequencies of B cell precursors in aged mice are not correlated with peripheral T cell subsets, but are correlated with frequencies of B220intIgM+ cells in the bone marrow. These observations advance our understanding of age-related defects in murine B cell development and may lead to identification of genes that influence B cell development in aged mice and humans as well as to help devise therapeutics aimed at restoring humoral immunity in aged individuals.

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