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Publication Date

2009-08-21

Availability

UM campus only

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2009-07-30

First Committee Member

Bonnie Blomberg - Committee Member

Second Committee Member

Roland Jurecic - Committee Member

Third Committee Member

Thomas Malek - Committee Member

Fourth Committee Member

Nevis Fregien - Committee Member

Fifth Committee Member

Richard Riley - Mentor

Sixth Committee Member

Pamela Witte - Outside Committee Member

Abstract

B lymphopoiesis in aged mice is characterized by reduced B cell precursors and an altered antibody repertoire. Aged mice maintain an ordinarily minor pool of early c-kit+ pre-B cells, indicative of poor preBCR expression, even as preBCR competent early pre-B cells are significantly reduced. Therefore, in aged mice, preBCR-mediated B2 B lymphopoiesis is significantly diminished; likely as a consequence of poor surrogate light chain expression. Notably, the remnant B1 B cell lineage present in adult bone marrow is retained in aged mice as evidenced by normal numbers (~0.3%) of Lin-CD19+B220low/- B1 B cell precursors. Of interest, B1 progenitors express substantially less lambda 5 surrogate light chain protein than do B2 pro-B cells and the surrogate light chain levels are further reduced in aged mice. B cells derived from putatively preBCR-deficient precursors, either B2 c-kit+ B cell precursors or B1 B cell progenitors, from either young or aged mice, generate new B cells in vitro that are biased to larger size, higher levels of CD43/S7, and decreased kappa light chain expression. Notably, immature B cells in aged bone marrow exhibit a similar phenotype in vivo, consistent with the changes seen in B cell precursor subpopulations. In aged mice, the B2 pathway is partially blocked with limited preBCR expression and signaling; however, continued B cell development via preBCR-deficient pathways, including B1 pathways, is observed. Increased generation of new B cells by these alternative pathways may contribute to altered phenotype, repertoire, and function in senescence.

Keywords

B Cells; Aging; PreBCR; Surrogate Light Chain; Antibody Repertoire; Autoreactivity

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