Marshall, Jennifer (2009)
Ph.D. thesis, University of Birmingham.
The early B cell response to antigen is analyzed, probing the mechanisms of divergent differentiation into plasmablasts or germinal centre (GC) B cells. Heterozygous QMxB6 mice, in which 5% of B cells are specific for the hapten 4-hydroxy-3-nitrophenol (NP), were immunized with NP-Ficoll. Varying the antigen dose altered the proportion of B cells that entered the extra follicular or GC responses and the amount of class switch recombination (CSR). The expression of phenotypic markers and switched antibody protein in parallel with gene array analysis and single cell real time RT-PCR in responding B cells was used to identify GC and plasmablast precursors and when and where CSR occurred. The results suggest CSR occurs in B blasts before GC B cells or plasmablasts emerge in both thymus dependent and thymus independent type II responses. The protein IRF4, which is essential for CSR and plasmablast differentiation, is expressed in all responding cells immediately after immunization and selectively upregulated to high levels in plasmablasts. A hierarchy of gene expression was identified as B cells differentiate into plasmablasts whereby high IRF4 mRNA expression precedes CD138 protein, which in turn precedes Blimp1 expression
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