Key Points
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Humoral memory is provided by long-lived plasma cells.
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Plasmablasts that are competent to become long-lived plasma cells are generated from memory B cells, but it has not been excluded that they might be generated from other B-cell subtypes.
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The survival of plasma cells requires cell-intrinsic competence, as well as signals from an extrinsic survival niche.
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Plasma-cell survival niches are located in the bone marrow, secondary lymphoid organs and inflamed tissue.
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Competent plasmablasts can migrate to survival niches, whereas plasma cells cannot.
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The resolution of inflammation destroys plasma-cell survival niches in inflamed tissue and therefore eliminates these plasma cells, which are immobile and tissue resident, after an immune response.
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Humoral memory adapts to new antigens by successful competition between newly generated plasmablasts (which have a migratory capacity) and previously generated ('old') resident bone-marrow plasma cells (which are immobile) for survival niches in the bone marrow.
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Long-lived plasma cells can drive chronic autoimmunity and allergy and are a candidate target for curative therapies of these diseases.
Abstract
Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.
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Acknowledgements
We thank C. Raulfs for critical reading of the manuscript and the members of the Berlin B Cell Club for helpful discussions. We are especially grateful to R. A. Manz for helpful comments. This work was supported by the Deutsche Forschungs-gemeinschaft (Germany).
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Glossary
- Plasma cell
-
A non-dividing, terminally differentiated, immobile antibody-secreting cell of the B-cell lineage.
- Unfolded-protein response
-
A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, and causes the arrest of the cell cycle and apoptosis.
- Plasmablast
-
A dividing antibody-secreting cell of the B-cell lineage that has migratory potential. These cells can further mature into plasma cells, which do not divide.
- Marginal-zone B cell
-
A mature B cell that is enriched mainly in the marginal zone of the spleen, which is located at the border of the white pulp.
- Germinal centre
-
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, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.
- Class-switch recombination
-
A molecular alteration of the constant-region gene of the antibody heavy chain (CH) that leads to a switch in expression from the Cμ (or Cδ) region to one of the other CH genes. This leads to a switch in the class of the antibody that is displayed on the cell surface of the B cell (and that plasma cells subsequently produce) — from IgM (or IgD) to IgG, IgA or IgE — without altering the specificity of the antibody. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of the antibody classes to activate the appropriate downstream effector mechanisms.
- Somatic hypermutation
-
A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, somatic hypermutation leads to affinity maturation of B cells in germinal centres.
- (NZB × NZW)F1 mice
-
The F1 generation of the cross between NZB mice and NZW mice. (NZB × NZW)F1 mice have a disease that closely resembles the human disease systemic lupus erythematosus.
- Systemic lupus erythematosus
-
(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.
- Rheumatoid arthritis
-
An immune disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation, with acute-phase reactants — as well as rheumatoid factor (antibodies specific for IgG), which forms immune complexes that are deposited in many tissues — being present in the peripheral blood.
- Antibody-secreting cells
-
A term that encompasses both plasmablasts, which proliferate, and plasma cells, which do not proliferate. It is used when both cell types might be present.
- Aiolos
-
A lymphoid-regulatory protein that is a member of the Ikaros family. It is a haematopoietic-cell-specific transcription factor that is involved in B-cell development and function.
- Ikaros family
-
A family of zinc-finger-containing transcription factors. These factors are pleiotropic regulators of haematopoiesis and are required for the generation of lymphocyte and dendritic-cell lineages, as well as lymph nodes and Peyer's patches.
- Stromal cells
-
Cells of non-lymphoid origin that form the framework of each organ. By expressing various molecules, these cells can support adhesion, proliferation and survival of distinct cell subsets.
- Flow-cytometric analysis
-
A method that allows simultaneous detection of cell-surface and intracellular molecules on single cells, through the use of fluorescently labelled antibodies.
- Type 1 allergy
-
An allergy or hypersensitivity of type 1 is an abnormal immune response that involves IgE specific for otherwise harmless proteins.
- Autoreactive antibody
-
An antibody that is specific for a self-antigen.
- Citrullinated peptide
-
A peptide that incorporates the amino acid citrulline. These peptides are generated post-translationally by peptidylarginine deiminases. The citrulline moiety is the essential part of the antigenic determinant towards which characteristic autoantibodies in patients with rheumatoid arthritis are generated.
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Radbruch, A., Muehlinghaus, G., Luger, E. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6, 741–750 (2006). https://doi.org/10.1038/nri1886
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DOI: https://doi.org/10.1038/nri1886
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Nature Medicine (2024)
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Association between body fat distribution and B-lymphocyte subsets in peripheral blood
Immunity & Ageing (2023)
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Adjuvant effects of combination monophosphoryl lipid A and poly I:C on antigen-specific immune responses and protective efficacy of influenza vaccines
Scientific Reports (2023)
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Prediction of long-term humoral response induced by the two-dose heterologous Ad26.ZEBOV, MVA-BN-Filo vaccine against Ebola
npj Vaccines (2023)
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Autoimmune encephalitis: recent clinical and biological advances
Journal of Neurology (2023)