Increased Frequency of Pre–Pro B Cells in the Bone Marrow of New Zealand Black (NZB) Mice: Implications for aDevelopmental Block in B Cell Differentiation

Zhe-Xiong Lian,Kenneth Dorshkind,Tomoyuki Okada,Mitsuru Naiki,Susumu Ikehara,Hiroto Kita,Aftab A Ansari,Tom Hsu,Leonard D Shultz,M Eric Gershwin

doi:10.1080/1044667021000003961

Abstract

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor component Igα (mb-1). Furthermore, levels of expression of the Rug2, λ5 and Igβ (B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.

Highlights

Rapid progress is being made in defining lineage specific precursor cells that are intermediates in the pathway of B cell differentiation (Payne et al, 1999; Akashi et al, 2000)
We performed a detailed study of the ontogeny of each substage specific lineage of B cells from New Zealand black (NZB) mice
To further clarify the mechanisms responsible for the abnormal accumulation of Pre – Pro B cells in NZB mice, we examined the expression of key B cell lineage genes involved in the process of B cell maturation and differentiation using a highly enriched population of Pre –Pro B cells from the bone marrow of 2-month-old NZB and age matched control normal BALB/c mice prepared as described

Summary

INTRODUCTION

Rapid progress is being made in defining lineage specific precursor cells that are intermediates in the pathway of B cell differentiation (Payne et al, 1999; Akashi et al, 2000). Development of mature B cells from multipotential stem cells is accompanied by qualitative and/or quantitative differences in the expression of cell surface molecules. Such differences permit enumeration, depletion and enrichment of stage-specific precursor cells. The increased frequency of Pre – Pro B cells was secondary to a decreased rate of apoptosis. The decreased frequency of precursor B cells in NZB mice occurs at the most primitive stage of B cell differentiation may be secondary to abnormalities in the gene(s) that control B cell lineage differentiation

MATERIALS AND METHODS

RESULTS

Findings

DISCUSSION