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Cited by 112T-cell and B-cell ImmunologyImmune Response and InflammationImmunotherapy and Immune Responses

The DOI matches its Crossref record; 74 of the 76 references it cites were found in a registry or an index.

Marginal Zone B-Cells, a Gatekeeper of Innate Immunity

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Zouali, Moncef, Richard, Yolande·2011·Frontiers in Immunology
DOI 10.3389/fimmu.2011.00063PMC PMC3341996
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Abstract

To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies - performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans - showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells - MZ B-cells and/or B1 B-cells - with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies.

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Figures

Figure 1 Organization of the follicular and MZ B-cell compartments in human. Sections of human spleens were stained with mAbs to CD20 or alpha smooth muscle actin (ASM). (A) The network of fibroblast-like cells stained by the anti-ASM mAb subdivides the outer and inner MZ around the follicles, and separates the T-cell zone from the red pulp. Original magnification ×10. (B) A ring of B-cells can be seen outside the ASM+ network in both the T and B-cell zones. Original magnification ×10. (C,D) Secondary B-cell follicles with a central germinal center, the mantle zone (intense blue in C, black arrow), the MZ, and the perifollicular zone (white arrow) with less dense accumulation of B-cells. Original magnification ×20. (E) Schematic representation of the T- and B-cell zones in human spleen. GC, germinal center; PALS, periarteriolar lymphatic sheath; MZ, marginal zone.
Figure 1 Organization of the follicular and MZ B-cell compartments in human. Sections of human spleens were stained with mAbs to CD20 or alpha smooth muscle actin (ASM). (A) The network of fibroblast-like cells stained by the anti-ASM mAb subdivides the outer and inner MZ around the follicles, and separates the T-cell zone from the red pulp. Original magnification ×10. (B) A ring of B-cells can be seen outside the ASM+ network in both the T and B-cell zones. Original magnification ×10. (C,D) Secondary B-cell follicles with a central germinal center, the mantle zone (intense blue in C, black arrow), the MZ, and the perifollicular zone (white arrow) with less dense accumulation of B-cells. Original magnification ×20. (E) Schematic representation of the T- and B-cell zones in human spleen. GC, germinal center; PALS, periarteriolar lymphatic sheath; MZ, marginal zone.CC BY-NC · PubMed Central
Figure 2 Loss of MZ B-cells and switched memory B-cells during the acute phase of SIV infection. Macaques were infected intravenously with the pathogenic SIVmac251 strain. For each macaque, blood samples were taken before infection and every 3 days post-infection (dpi). Three groups of five macaques were sacrificed 14, 21, and 28 dpi. At euthanasia, spleen, peripheral blood, and mesenteric lymph nodes (LN) were collected from SIV-Infected animals and from four non-infected control animals. (A) Plasma viral load was determined by real-time PCR as described (Peruchon et al., 2009). Horizontal bars indicate median values. (B) Absolute numbers of blood CD4 T-cells were determined in each animal as described (Peruchon et al., 2009) before infection and 11–12 dpi when they reached their lowest values (nadir). Horizontal bars indicate median values. (C) CD27 and SIgD expression was studied by three-parameter immunofluorescence analysis on CD20-gated populations from various organs. Cells were gated on forward and side scatter (R1), and then on CD20 (R2) expression. CD27 and SIgD expression on CD20+ cells is shown on a representative dot plot of peripheral blood mononuclear cells staining. The percentage of positive cells is indicated in each quadrant. Flow cytometry plots depict log10 fluorescence. (D–F) Shown are the mean percentages of naïve (SIgD+CD27−, open area), switched memory (SIgD−CD27+, hatched area), and MZ (SIgD+CD27+, black area) B-cells for each group of animals (n = 3). (D) Shows data in peripheral blood before and after exposure to SIV. (E) Shows data from the spleen of non-infected animals (ctl, n = 4) and SIV-infected animals (n = 3 for all groups). (F) shows data from LN of non-infected animals (ctl, n = 4) and SIV-infected animals (n = 5 for all groups). (G) Spleen sections from non-infected macaques (Ctl) and from SIV-infected animals collected 14, 21, and 28 dpi were stained with alpha smooth muscle actin (ASM) mAb for visualization of the MZ. Shown are staining for one representative animal from each group. White bars indicate the MZ region width as measured in 19–22 ASM-stained regions in each spleen. Mean values ± SEM are 132 ± 14 μm for Ctl, and 114 ± 23, 136 ± 27, 106 ± 17 μm for macaques infected for 14, 21, and 28 dpi, respectively.
Figure 2 Loss of MZ B-cells and switched memory B-cells during the acute phase of SIV infection. Macaques were infected intravenously with the pathogenic SIVmac251 strain. For each macaque, blood samples were taken before infection and every 3 days post-infection (dpi). Three groups of five macaques were sacrificed 14, 21, and 28 dpi. At euthanasia, spleen, peripheral blood, and mesenteric lymph nodes (LN) were collected from SIV-Infected animals and from four non-infected control animals. (A) Plasma viral load was determined by real-time PCR as described (Peruchon et al., 2009). Horizontal bars indicate median values. (B) Absolute numbers of blood CD4 T-cells were determined in each animal as described (Peruchon et al., 2009) before infection and 11–12 dpi when they reached their lowest values (nadir). Horizontal bars indicate median values. (C) CD27 and SIgD expression was studied by three-parameter immunofluorescence analysis on CD20-gated populations from various organs. Cells were gated on forward and side scatter (R1), and then on CD20 (R2) expression. CD27 and SIgD expression on CD20+ cells is shown on a representative dot plot of peripheral blood mononuclear cells staining. The percentage of positive cells is indicated in each quadrant. Flow cytometry plots depict log10 fluorescence. (D–F) Shown are the mean percentages of naïve (SIgD+CD27−, open area), switched memory (SIgD−CD27+, hatched area), and MZ (SIgD+CD27+, black area) B-cells for each group of animals (n = 3). (D) Shows data in peripheral blood before and after exposure to SIV. (E) Shows data from the spleen of non-infected animals (ctl, n = 4) and SIV-infected animals (n = 3 for all groups). (F) shows data from LN of non-infected animals (ctl, n = 4) and SIV-infected animals (n = 5 for all groups). (G) Spleen sections from non-infected macaques (Ctl) and from SIV-infected animals collected 14, 21, and 28 dpi were stained with alpha smooth muscle actin (ASM) mAb for visualization of the MZ. Shown are staining for one representative animal from each group. White bars indicate the MZ region width as measured in 19–22 ASM-stained regions in each spleen. Mean values ± SEM are 132 ± 14 μm for Ctl, and 114 ± 23, 136 ± 27, 106 ± 17 μm for macaques infected for 14, 21, and 28 dpi, respectively.CC BY-NC · PubMed Central
Figure 3 B-cell apoptosis and antibody production in acutely SIV-infected macaques. (A) Spleen B-cells were purified from macaques using PE-conjugated anti-CD20 mAb and PE-conjugated magnetic beads. They were cultured for 24 h with medium or with 25 μg/ml rabbit anti Ig(H + L) Ab before staining with DAPI. Apoptotic cell percentages were determined in splenocyte cultures from four non-infected animals (Ctl, diamond symbols) and from two SIV-infected macaques sacrificed on 14, 21, or 28 dpi (circle symbols). Each point represents the percentage of hypodiploid B-cells from one animal. Bars represent the mean percentages. *p Value <0.05. (B) Plasma IgM and IgG concentrations were quantified before infection (Ctl, diamonds) and 7, 14, 21, and 28 dpi (filled circles). Horizontal bars indicate the median concentrations. Statistically significant differences are indicated (*p < 0.05; **p < 0.01; ***p < 0.001). (C) IgG, IgM, and IgA SIV-specific Ab concentrations in the plasma of SIV-infected macaques 14, 21, and 28 dpi. Horizontal bars indicate the median OD values. *p Value <0.05.
Figure 3 B-cell apoptosis and antibody production in acutely SIV-infected macaques. (A) Spleen B-cells were purified from macaques using PE-conjugated anti-CD20 mAb and PE-conjugated magnetic beads. They were cultured for 24 h with medium or with 25 μg/ml rabbit anti Ig(H + L) Ab before staining with DAPI. Apoptotic cell percentages were determined in splenocyte cultures from four non-infected animals (Ctl, diamond symbols) and from two SIV-infected macaques sacrificed on 14, 21, or 28 dpi (circle symbols). Each point represents the percentage of hypodiploid B-cells from one animal. Bars represent the mean percentages. *p Value <0.05. (B) Plasma IgM and IgG concentrations were quantified before infection (Ctl, diamonds) and 7, 14, 21, and 28 dpi (filled circles). Horizontal bars indicate the median concentrations. Statistically significant differences are indicated (*p < 0.05; **p < 0.01; ***p < 0.001). (C) IgG, IgM, and IgA SIV-specific Ab concentrations in the plasma of SIV-infected macaques 14, 21, and 28 dpi. Horizontal bars indicate the median OD values. *p Value <0.05.CC BY-NC · PubMed Central

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Metadata

Authors
Zouali, M., & Richard, Y.
Affiliations
  • Inserm (FR)
  • Université Paris Descartes (FR)
Corresponding author
Zouali, Moncef
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2011
Volume
2
Pages
63-63
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2011.00063
PMC
PMC3341996
OpenAlex
W2035855342
Cited by
112
References
76
Citations by year
2026: 5 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 9 · 2021: 15 · 2020: 12 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 1
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Frontiers in Immunology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Styrelsen för Internationellt Utvecklingssamarbete
  • Institut National de la Santé et de la Recherche Médicale
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
marginal zone B cells, B-1 cells, innate immunity, T cell-independent antibody response, T cell-dependent antibody response, superantigens, protein A, protein L, HIV-1, simian immunodeficiency virus, B-cell depletion, vaccination strategies

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