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The generation of antibody-secreting plasma cells

Key Points

  • The terminal differentiation of B cells generates short-lived plasmablasts and long-lived plasma cells, both of which secrete antibodies.

  • B cells and antibody-secreting cells display markedly divergent transcriptomes.

  • Differentiation of antibody-secreting cells from B cells is controlled by a network of antagonistic transcription factors.

  • Despite considerable heterogeneity, a simple probabilistic differentiation process can explain B cell terminal differentiation.

  • Transition from a short-lived plasmablast to a long-lived plasma cell requires homing to the bone marrow niche.

  • The plasma cell niche consists of a stromal component and a proliferation-inducing ligand (APRIL)-expressing haematopoietic cells.

Abstract

The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.

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Figure 1: The cellular stages of late B cell differentiation.
Figure 2: The gene-regulatory network controlling B cell terminal differentiation.
Figure 3: Model of the bone marrow plasma cell survival niche.

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Acknowledgements

This work is supported by the National Health and Medical Research Council (NHMRC) of Australia programme grant (APP1054925 to S.L.N., P.D.H., D.M.T. and L.M.C.) and fellowships (to P.D.H., D.M.T. and L.M.C.). S.L.N is supported by an Australian Research Council Future Fellowship. This work was made possible through Victorian State Government Operational Infrastructure Support, and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support.

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FURTHER INFORMATION

Immunological Genome Project

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Glossary

Plasmablasts

Dividing antibody-secreting cells of the B cell lineage that have migratory potential. These cells can further mature into plasma cells, which do not divide.

Plasma cells

Terminally differentiated quiescent B cells that develop from plasmablasts and are characterized by their capacity to secrete large amounts of antibodies.

Antibody-secreting cells

(ASCs). Refers to both proliferating plasmablasts and non-proliferating plasma cells. The term is used when both cell types might be present.

T cell-independent antigens

(TI antigens). Antigens that directly activate B cells, without the need for cognate T cell help.

Class-switch recombination

(CSR). The process by which proliferating B cells rearrange their DNA to switch from expressing IgM (or another class of immunoglobulin) to expressing a different immunoglobulin heavy chain constant region, thereby producing antibody with different effector functions.

Somatic hypermutation

(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Along with selection for B cells that produce high-affinity antibody, SHM leads to the affinity maturation of B cells in germinal centres.

Germinal centre

(GC). A highly specialized and dynamic microenvironment that gives rise to secondary B cell follicles during an immune response. It is the main site of B cell maturation, which leads to the generation of memory B cells and plasma cells that produce high-affinity antibody.

MicroRNA

A single-stranded RNA molecule of approximately 21–23 nucleotides in length that regulates the expression of genes by binding to the 3′ untranslated regions of specific mRNAs.

Multiple myeloma

A cancer of plasma cells that is characterized by an increased frequency of malignant cells in the bone marrow and high levels of monoclonal immunoglobulin in the serum.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase downstream of growth factors and nutrients, such as amino acids, glucose and oxygen.

Gene-regulatory network

Diagrams that are used to visualize the relationship between large numbers of genes and their regulators that are involved in distinct biological processes.

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Nutt, S., Hodgkin, P., Tarlinton, D. et al. The generation of antibody-secreting plasma cells. Nat Rev Immunol 15, 160–171 (2015). https://doi.org/10.1038/nri3795

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