Title

Mechanisms of altered B lymphopoiesis in senescence

Date of Award

2000

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Richard L. Riley, Committee Chair

Abstract

Advancing age is accompanied by a decrease in the numbers of bone marrow pre-B cells in mice. Using information and technologies developed in the more recent past, this study has re-examined the stages of B cell developmental impairment and addressed possible mechanisms responsible for the aging phenomenon. Ex vivo analysis of bone marrow B cell precursors revealed two distinct patterns of disruption of B cell lymphopoiesis. In the first pattern, moderate decreases (∼50%) were seen in the late pre-B cell compartment only. The second pattern revealed severe decreases (>80%) in late pre-B cells, and this was accompanied by a decrease in pro-B cells. In both types of altered B cell lymphopoiesis, the frequencies of cells in active cell cycle was normal among all subsets of precursors. Of interest, aged mice with severely reduced pre-B cell numbers show increased susceptibility to apoptosis of both pro-B and pre-B cells. Expression of the surrogate light (SL) chain components is decreased at both the mRNA and protein levels in aged pro-B/early pre-B cells. Since the decreases seen in SL expression occur at the mRNA level, we examined the status of transcription factors important for SL expression in particular, and B lymphopoiesis in general, in aged B cell precursors. Aged B cell precursors expanded in culture with IL-7 showed decreased expression of the transcription factors Pax-5/BSAP and E2A/E47. Notably, diminished E2A/E47 correlated with lambda5 expression, which, in turn, correlated with ex vivo pre-B cell numbers. Both microenvironmental and cell "intrinsic" factors contributed to reduced expansion of aged pro-B/early pre-B cells in response to IL-7. We propose a model of impaired B cell lymphopoiesis in aging, as follows. In cases with moderate pre-B cell depletion, recruitment into the late pre-B cell compartment is diminished. This is possibly due to decreased expression of the SL chain components, leading to insufficient levels of the preBCR to mediate differentiation into the late pre-B cell stage. However, once selected for further maturation, the cells proliferate normally. Additionally, in cases with severe pre-B cell depletion, decreases in the earliest precursors, the pro-B cells, leads to further depletion in the subsequent precursor compartments. Thus, decreases in B cell precursors manifest as a failure of selection into differentiation, in all cases at the pre-B cell level, and in severely depleted mice, also at the pro-B cell stage.

Keywords

Health Sciences, Immunology

Link to Full Text

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