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Cited by 211T-cell and B-cell ImmunologyImmune responses and vaccinationsMonoclonal and Polyclonal Antibodies Research

The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.

Plasma cell survival in the absence of B cell memory

Open access
Hammarlund, Erika, Thomas, Archana, Amanna, Ian J., Holden, Lindsay A., Slayden, Ov D., Park, Byung, Gao, Lina, Slifka, Mark K.·2017·Nature Communications
DOI 10.1038/s41467-017-01901-wPMC PMC5701209
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Abstract

Pre-existing serum antibodies play an important role in vaccine-mediated protection against infection but the underlying mechanisms of immune memory are unclear. Clinical studies indicate that antigen-specific antibody responses can be maintained for many years, leading to theories that reactivation/differentiation of memory B cells into plasma cells is required to sustain long-term antibody production. Here, we present a decade-long study in which we demonstrate site-specific survival of bone marrow-derived plasma cells and durable antibody responses to multiple virus and vaccine antigens in rhesus macaques for years after sustained memory B cell depletion. Moreover, BrdU + cells with plasma cell morphology can be detected for 10 years after vaccination/BrdU administration, indicating that plasma cells may persist for a prolonged period of time in the absence of cell division. On the basis of these results, long-lived plasma cells represent a key cell population responsible for long-term antibody production and serological memory.

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Figures

Fig. 1 Tetanus-specific antibody responses following memory B cell depletion. Six Rhesus macaques received 4 intramuscular doses of Tripedia® vaccine (arrows, panel a) and tetanus-specific serum antibody responses were monitored closely for 15 months a to 10 years b. CD20+ B cells were depleted from 4 experimental animals (Experimental; E) at the indicated time points by administration of anti-CD20/Rituximab (b, c) and these animals also underwent splenectomy and surgical removal of draining lymph nodes (LN) at 3.5 years after primary vaccination. Two control animals (Control; C) were monitored in parallel throughout the experiment to compare tetanus-specific antibody levels and memory B cell frequencies. Efficiency of B cell depletion was determined by staining PBMC for CD22+ B cells c and tetanus-specific memory B cells were directly measured by flow cytometry either before or after memory B cell depletion performed at 1.5 years after vaccination d. The dashed line in a and b represents the tetanus-specific ELISA titer coinciding with 0.01 IU/ml calibrated based on the international serum standard, Tetanus Immunoglobulin TE-3. The dashed line in d indicates the limit of detection. Further details describing the statistical model for determining antibody decay rates and half-life estimates can be found in the Methods (Eqs. 1 and 2)
Fig. 1 Tetanus-specific antibody responses following memory B cell depletion. Six Rhesus macaques received 4 intramuscular doses of Tripedia® vaccine (arrows, panel a) and tetanus-specific serum antibody responses were monitored closely for 15 months a to 10 years b. CD20+ B cells were depleted from 4 experimental animals (Experimental; E) at the indicated time points by administration of anti-CD20/Rituximab (b, c) and these animals also underwent splenectomy and surgical removal of draining lymph nodes (LN) at 3.5 years after primary vaccination. Two control animals (Control; C) were monitored in parallel throughout the experiment to compare tetanus-specific antibody levels and memory B cell frequencies. Efficiency of B cell depletion was determined by staining PBMC for CD22+ B cells c and tetanus-specific memory B cells were directly measured by flow cytometry either before or after memory B cell depletion performed at 1.5 years after vaccination d. The dashed line in a and b represents the tetanus-specific ELISA titer coinciding with 0.01 IU/ml calibrated based on the international serum standard, Tetanus Immunoglobulin TE-3. The dashed line in d indicates the limit of detection. Further details describing the statistical model for determining antibody decay rates and half-life estimates can be found in the Methods (Eqs. 1 and 2)CC BY · PubMed Central
Fig. 2 Longitudinal analysis of antibody responses to multiple antigens after vaccination or infection. Serum antibody titers were measured at the indicated time points for a paramyxovirus that is antigenically related to measles virus (Measles), rhesus cytomegalovirus (RhCMV), adenovirus, pertussis toxin, filamentous hemagglutinin (FHA), and pertactin. Arrows indicate the dates when anti-CD20 administration was performed or when splenectomy and draining lymph nodes (LN) were surgically removed. Control animals, Rh#20923 and Rh#21169, did not have anti-CD20 treatment or surgeries performed and are represented by dashed lines. The gray shaded region below the dotted line (<200 ELISA units) represents the points in which ELISA titers become equivocal or are below the limit of detection. Control animal Rh#21169 was seronegative for measles virus antigen
Fig. 2 Longitudinal analysis of antibody responses to multiple antigens after vaccination or infection. Serum antibody titers were measured at the indicated time points for a paramyxovirus that is antigenically related to measles virus (Measles), rhesus cytomegalovirus (RhCMV), adenovirus, pertussis toxin, filamentous hemagglutinin (FHA), and pertactin. Arrows indicate the dates when anti-CD20 administration was performed or when splenectomy and draining lymph nodes (LN) were surgically removed. Control animals, Rh#20923 and Rh#21169, did not have anti-CD20 treatment or surgeries performed and are represented by dashed lines. The gray shaded region below the dotted line (<200 ELISA units) represents the points in which ELISA titers become equivocal or are below the limit of detection. Control animal Rh#21169 was seronegative for measles virus antigenCC BY · PubMed Central
Fig. 3 Antigen-specific and total IgG+ plasma cells in different bone marrow compartments. Quantitation of tetanus-specific, measles-specific, or total IgG-specific antibody-secreting cells (ASC) was determined directly ex vivo in 6-hour ELISPOT assays. a, b Samples of femoral bone marrow cells from a representative animal (Rh#21128) were assayed to determine the frequency of measles-specific and tetanus-specific ASC by ELISPOT from unfractionated bone marrow compared to the frequencies observed after MACS-based separation of a CD38− vs. CD38+ cell populations or b CD20− vs. CD20+ cell populations. The frequency of tetanus-specific ASC c, the frequency of total IgG-secreting ASC d and the frequency of tetanus-specific ASC as a percentage of total IgG-secreting ASC e was determined by ELISPOT analysis for each of the indicated bone marrow sites. The bars in c–e represent the mean ± S.E.M. Significant differences in plasma cell frequencies between the indicated bone marrow sites compared to the femur are indicated by Dunnett adjusted P values (c, d; mixed effect negative binomial regression, e; rank based mixed effect linear regression, n = 6, see also Supplementary Fig. 2). Symbols, *P < 0.05 and **P < 0.01
Fig. 3 Antigen-specific and total IgG+ plasma cells in different bone marrow compartments. Quantitation of tetanus-specific, measles-specific, or total IgG-specific antibody-secreting cells (ASC) was determined directly ex vivo in 6-hour ELISPOT assays. a, b Samples of femoral bone marrow cells from a representative animal (Rh#21128) were assayed to determine the frequency of measles-specific and tetanus-specific ASC by ELISPOT from unfractionated bone marrow compared to the frequencies observed after MACS-based separation of a CD38− vs. CD38+ cell populations or b CD20− vs. CD20+ cell populations. The frequency of tetanus-specific ASC c, the frequency of total IgG-secreting ASC d and the frequency of tetanus-specific ASC as a percentage of total IgG-secreting ASC e was determined by ELISPOT analysis for each of the indicated bone marrow sites. The bars in c–e represent the mean ± S.E.M. Significant differences in plasma cell frequencies between the indicated bone marrow sites compared to the femur are indicated by Dunnett adjusted P values (c, d; mixed effect negative binomial regression, e; rank based mixed effect linear regression, n = 6, see also Supplementary Fig. 2). Symbols, *P < 0.05 and **P < 0.01CC BY · PubMed Central
Fig. 4 Identification of BrdU+ plasma cells at 3.5 and 10 years after BrdU administration. Each panel shows a representative microscopic image of tissue samples from rhesus macaques after immunohistochemical staining for BrdU+ cells. Paraffin-embedded bone marrow and tissue samples were stained for BrdU and counterstained with Mayer’s hematoxylin. BrdU+ plasma cells were identified based on their size and their characteristic “clock face” nuclei (see inset images). Sections showing draining lymph node (LN) or spleen at 3.5 years after primary vaccination were obtained by surgical removal from experimental CD20-depleted animals (Rh#21139 and Rh#21131, respectively). LN and spleen samples examined at 10 years post-vaccination were obtained from one of the control animals (Rh#20923) whereas sections of humerus and femur came from experimental CD20-depleted animals (Rh#21128 and Rh#21131, respectively) at necropsy. A 20 μm scale bar is included in each panel
Fig. 4 Identification of BrdU+ plasma cells at 3.5 and 10 years after BrdU administration. Each panel shows a representative microscopic image of tissue samples from rhesus macaques after immunohistochemical staining for BrdU+ cells. Paraffin-embedded bone marrow and tissue samples were stained for BrdU and counterstained with Mayer’s hematoxylin. BrdU+ plasma cells were identified based on their size and their characteristic “clock face” nuclei (see inset images). Sections showing draining lymph node (LN) or spleen at 3.5 years after primary vaccination were obtained by surgical removal from experimental CD20-depleted animals (Rh#21139 and Rh#21131, respectively). LN and spleen samples examined at 10 years post-vaccination were obtained from one of the control animals (Rh#20923) whereas sections of humerus and femur came from experimental CD20-depleted animals (Rh#21128 and Rh#21131, respectively) at necropsy. A 20 μm scale bar is included in each panelCC BY · PubMed Central

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Show all 67 references

Research works printed but not linked: 2

  1. Wolters, K. L. & Dehmel, H. Abschliessende untersuchungen uber die Tetanus Prophylaxe durch active Immunisierung. Zeitschrift fur Hyeitschrift 124, 326–332 (1942).
  2. Wassilak, S. G., Roper, M. H., Kretsinger, K. & Orenstein, W. A. in Vaccines (eds. Plotkin, S. A., Orenstein, W. A. & Offit, P. A.) (Saunders Elsevier, Amsterdam, The Netherlands, 2008).

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Metadata

Authors
Hammarlund, E., Thomas, A., Amanna, I. J., Holden, L. A., Slayden, O. D., Park, B., Gao, L., & Slifka, M. K.
Affiliations
  • Oregon National Primate Research Center (US)
  • Najít Technologies (United States) (US)
  • Portland State University (US)
  • OHSU Knight Cancer Institute (US)
Corresponding author
Slifka, Mark K.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-11-24
Volume
8
Issue
1
Pages
1781-1781
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01901-w
PMC
PMC5701209
OpenAlex
W2770797413
Cited by
210
References
67
Citations by year
2026: 20 · 2025: 20 · 2024: 15 · 2023: 23 · 2022: 28 · 2021: 36 · 2020: 32 · 2019: 22 · 2018: 14
FWCI
8.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PDXScholar (Portland State University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (P51OD011092)
  • Genentech
  • Oregon National Primate Research Center
  • National Institute on Aging (P01AG023664)
  • National Institute of Allergy and Infectious Diseases (U01AI082196)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Keywords
long-lived plasma cells, plasma cell survival, memory B cells, long-term antibody response, vaccine immunity, rhesus monkeys, BrdU labeling, bone marrow plasma cells
MeSH terms
Animals, Antibodies, Bacterial, Antibody Formation, B-Lymphocytes, Bacterial Vaccines, Cell Survival, Immunologic Memory, Macaca mulatta, Male, Plasma Cells, Vaccination

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