Gene expression dynamics during germinal center transit in B cells.

The germinal center (GC) reaction in T cell dependent antibody responses is crucial for the generation of B cell memory and plays a critical role in B cell lymphomagenesis. To gain insight into the physiology of this reaction, we identified the transcriptional changes that occur in B cells during the GC-transit (naïve B cells --> CD77(+) centroblasts (CBs) --> CD77(-) centrocytes (CCs) --> memory B cells) by DNA microarray experiments and the subsequent data analysis employing unsupervised and supervised hierarchical clustering. The naïve B cell is characterized by a nonproliferative, anti-apoptotic phenotype and the expression of various chemokine and cytokine receptors. The transition from naïve B cells to CBs is associated with (1) the up-regulation of genes associated with cellular proliferation, DNA-repair, and chromatin remodeling; (2) the acquisition of a pro-apoptotic phenotype; (3) the down-regulation of cytokine, chemokine, and adhesion receptors expressed in the naïve cells; and (4) the expression of a distinct adhesion repertoire. The CB and the CC revealed surprisingly few gene expression differences, suggesting that the CC is heterogeneous in its cellular composition. The CB/CC to memory B cell transition shows a general reversion to the profile characteristic for the naïve B cells, with the exception of the up-regulation of several surface receptors, including CD27, CD80, and IL-2Rbeta, and the simultaneous expression of both anti- and pro-apoptotic genes. These gene expression profiles of the normal B cell subpopulations are being used to identify the signals occurring during GC development, the cellular derivation of various types of B cell malignancies, and the genes deregulated in GC-derived tumors.

Transcriptional analysis of the B cell germinal center reaction.

The germinal center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during GC transit (naive B cells --> centroblasts --> centrocytes --> memory B cells) by gene expression profiling. Naive B cells, characterized by the expression of cell cycle-inhibitory and antiapoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naive cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor beta. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies.