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J. Exp. Med.,
Volume 188, Number 3, August 3, 1998 483-495
By
From Abgenix, Inc., Fremont, California 94555
The relationship between variable (V) gene complexity and the efficiency of B cell development was studied in strains of mice deficient in mouse antibody production and engineered
with yeast artificial chromosomes (YACs) containing different sized fragments of the human
heavy (H) chain and 
light (L) chain loci. Each of the two H and the two chain fragments
encompasses, in germline configuration, the same core variable and constant regions but contains different numbers of unique VH (5 versus 66) or V genes (3 versus 32). Although each of
these YACs was able to substitute for its respective inactivated murine counterpart to induce B cell development and to support production of human immunoglobulins (Igs), major differences in the efficiency of B cell development were detected. Whereas the YACs with great V
gene complexity restored efficient development throughout all the different recombination and
expression stages, the YACs with limited V gene repertoire exhibited inefficient differentiation
with significant blocks at critical stages of B cell development in the bone marrow and peripheral lymphoid tissues. Our analysis identified four key checkpoints regulated by VH and V
gene complexity: (a) production of functional µ chains at the transition from the pre B-I to the pre B-II stage; (b) productive VJ recombination at the small pre B-II stage; (c) formation of
surface Ig molecules through pairing of µ chains with L chains; and (d) maturation of B cells. These findings demonstrate that V gene complexity is essential not only for production of a diverse repertoire of antigen-specific antibodies but also for efficient development of the B cell
lineage.
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