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  • Review Article
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Germinal centres: role in B-cell physiology and malignancy

Nature Reviews Immunology volume 8, pages 22–33 (2008)Cite this article

Key Points

  • 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.

Abstract

Over the past several years, studies on normal and malignant B cells have provided new insights into the unique physiology of the germinal centre (GC). In particular, advances in technology have allowed a more precise dissection of the phenotypes of GC B cells and the specific transcriptional programmes that are responsible for this phenotype. Furthermore, substantial progress has been made in the understanding of the mechanism controlling the exit of B cells from the GC and the decision to become a memory B cell or plasma cell. This Review focuses on these recent advances and discusses their implications for the pathogenesis of B-cell lymphomas.

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Figure 1: The germinal centre microenvironment.
Figure 2: Biological functions and regulating pathways: BCL-6 expression in the germinal centre.
Figure 3: Termination of the GC transcriptional programme and post-GC B-cell development.
Figure 4: DNA lesions in germinal centre B cells and their functional consequences.
Figure 5: Molecular mechanisms promoting B-cell lymphomagenesis.

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Acknowledgements

We wish to thank the members of the Dalla-Favera laboratory, and in particular L. Pasqualucci and M. Saito, for discussions.

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Authors and Affiliations

  1. Departments of Pathology and Genetics & Development, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St Nicholas Avenue, New York, 10032, New York, USA

    Ulf Klein & Riccardo Dalla-Favera

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  1. Ulf Klein
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Correspondence to Riccardo Dalla-Favera.

Glossary

Memory B cells

Antigen-experienced B cells that express high-affinity antibodies and quickly differentiate into plasma cells in antigen-recall responses.

Plasma cells

Non-dividing, terminally differentiated, antibody-secreting cells of the B-cell lineage.

Antibody-secreting cells

A term that denotes both proliferating plasmablasts and non-proliferating plasma cells. The term is used when both cell types might be present.

Plasmablast

The B-cell lineage precursor of non-dividing plasma cells, which has the capacity to divide and that has migratory potential.

Follicular dendritic cell

Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres. These cells possess long dendrites and carry intact antigen on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibody.

Centroblast

A proliferating germinal-centre B cell of which the rearranged variable-region immunoglobulin genes are undergoing somatic hypermutation.

Centrocyte

The progeny of a centroblast. These cells undergo immunoglobulin class switching and are selected on the basis of the improved affinity of their immunoglobulin for antigen following interaction with immune complexes that are associated with follicular dendritic cells, and on their ability to elicit help from follicular B helper T (TFH) cells.

Two-photon intravital microscopy

Laser-scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. The main advantage is deep tissue penetration of the infrared light, owing to the low level of light scattering within the tissue.

Telomerase

An enzyme that is capable of extending the ends of telomeres after replication by using an RNA template that is part of the enzyme complex.

Programmed cell death

A common form of cell death, which is also known as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, plasma-membrane blebbing and DNA fragmentation into segments of about 180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by neighbouring cells.

p53 tumour-suppressor gene.

The mutation of the p53 gene in cancer can lead to a lack of cell-cycle control and apoptosis.

Ubiquitin-mediated proteasomal degradation

An important proteolytic process that involves the tagging of unwanted proteins with ubiquitin, which allows their recognition by the proteasome — a large, multi-component protein-degrading complex.

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Klein, U., Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 8, 22–33 (2008). https://doi.org/10.1038/nri2217

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