Germinal centres: role in B-cell physiology and malignancy

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Abstract
The germinal centre (GC) of lymphoid organs is the main structure where antigen-activated B cells diversify their immunoglobulin genes by somatic hypermutation (SHM) to generate high-affinity antibodies. Most of the cells also undergo class-switch recombination (CSR) to generate antibodies with specialized effector functions. The processes of SHM and CSR are associated with DNA-strand breaks. GC B cells use specialized mechanisms that allow for the activity of those DNA-modifying processes without inducing a DNA-damage response, foremost by inhibiting the p53-dependent and p53-independent responses. Centroblasts, which are GC B cells that undergo active SHM, are programmed to proliferate extremely rapidly and thereby generate a large number of immunoglobulin mutations in a short time from which high-affinity antibodies can be selected. Moreover, these cells have a pro-apoptotic programme that ensures the rapid elimination of B cells expressing newly generated antibodies with suboptimal binding characteristics. The transcription factor BCL-6 (B-cell lymphoma 6) is the master regulator of GC B-cell differentiation, as it mediates the repression of genes involved in negative cell cycle regulation as well as the inhibition of genes involved in B-cell activation, plasma-cell and memory B-cell differentiation, and in the response to genotoxic stress. GC B cells that produce high-affinity antibodies are selected to differentiate into plasma cells and memory B cells through specific gene expression changes that coordinately regulate proliferation, apoptosis and differentiation. Essential for these processes are several major transcriptional regulators that, besides BCL-6, include PAX5 (paired box protein 5), NF-κB (nuclear factor-κB), IRF4 (interferon-regulatory factor 4), BLIMP1 (B-lymphocyte-induced maturation protein 1), and XBP1 (X-box binding protein 1). Genes critically involved in the regulation of proliferation, apoptosis and differentiation during the GC response are occasionally dysregulated by genomic alterations — such as chromosomal translocations or aberrant SHM in regulatory regions — resulting from errors during antibody gene modifications. Therefore, the production of high-affinity antibodies comes at the risk of oncogenic transformation.