The A/WySnJ mouse provides a model for studying B-cell selection into the stable peripheral B-cell pool. The investigators have shown that the A/WySnJ strain has a single, autosomal co-dominant defect, Bcmd-1, resulting in a profound peripheral B-cell deficiency and poor IgG responses. The Bcmd-1 defect is not present in the related A/J sub-line, is intrinsic to B-cells, and shortens the life span of peripheral B-cells by causing premature death at every maturation step after surface IgM acquisition. Two hypotheses can explain these observations: Bcmd-1 may be a loss-of-function mutation that either disrupts a life span lengthening pathway or disrupts a molecule that dampens a life span shortening pathway. The investigators propose biological, biochemical and genetic studies to distinguish these hypotheses and investigate the mechanism of Bcmd-1 action.
In Specific Aim one, the two genes that control B-cell deficiency in interspecies crosses, Bcmd-1 and Bcmd-2, will be mapped by analysis of simple sequence length polymorphisms in the extreme progeny of the (A/WySnJXCAST/Ei) F2 interspecific cross. A congenic strain will be constructed and used to map the Bcmd-1 locus that is polymorphic between strains A/WySnJ and A/J.
In Specific Aim two, the investigators test whether the steps in transit to the long-lived pool affected by Bcmd-1 comprise an """"""""all -or-none"""""""" event versus continuous signals. BrdU labeling studies of F1 individuals will be employed, since continuous signals predict an intermediate life span for all B-cells in F1 mice, whereas an all-or none event predicts separate pools of long-versus short-lived B-cells.
In Specific Aim three, assays will be established for B-cell life span, apoptosis, Bcl gene family induction, and cell division; then pathways that affect these parameters will be systematically probed in immature B-cells. When a pathway is found to affect A/J but not A/WySnJ B-cells, biochemical markers will be analyzed to determine whether Bcmd-1 disrupts the pathway.
In Specific Aim 4, the investigators assess Bcmd-1's effect on B-cell traffic, repertoire formation, and the germinal center reaction, through mixed marrow chimeras, limiting dilution and fine specificity analysis, and cytofluorimetric immunohistochemical studies in chimeric mice.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunobiology Study Section (IMB)
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Quill, Helen R
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University of Pennsylvania
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