scholarly journals B Cell Subset Analysis and Gene Expression Characterization in Mid-Luteal Endometrium

2021 ◽  
Vol 9 ◽  
Author(s):  
Mengni Shen ◽  
Tim Child ◽  
Monica Mittal ◽  
Geet Sarodey ◽  
Rehan Salim ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Subset ◽  
Active Role ◽  
Host Immune Responses ◽  
Follicular Helper ◽  
Epithelial Layers ◽  
Expression Characterization

The human endometrium is the innermost mucosal membrane of the uterus and is the first point of contact for an implanting blastocyst. A wide variety of immune cells are found amongst the endometrial epithelial layers and stromal cells which both provide host immune responses against pathogens and also assist with placentation and pregnancy establishment, however, B cells have not been characterized, despite being a vital player in both adaptive and mucosal immunity. Through analysis of mid-luteal endometrial biopsies, we find 1–5% of endometrial immune cells are B cells, the majority were naïve or memory B cells, with few plasma cells. Compared with circulating B cells, endometrial B cells had an activated phenotype, with increased expression of CD69, HLA-DR, CD74, and CD83, and IL-10 production capacities. PD1+CXCR5+ICOS+ T follicular helper-like cells and FAS+IgD–BCL6+ germinal center B cells were also present in the endometrium, which may indicate that endometrial B cells are playing an active role through germinal center reactions in the human endometrial environment.

scholarly journals Intrinsic properties of human germinal center B cells set antigen affinity thresholds

2018 ◽  
Vol 3 (29) ◽  
pp. eaau6598 ◽  
Author(s):  
Kihyuck Kwak ◽  
Nicolas Quizon ◽  
Haewon Sohn ◽  
Avva Saniee ◽  
Javier Manzella-Lapeira ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Synapse Formation ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Intrinsic Properties ◽  
High Affinity ◽  
Follicular Helper ◽  
Bcr Signaling ◽  
Engagement And Disengagement

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.

scholarly journals Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells

2017 ◽  
Vol 214 (5) ◽  
pp. 1259-1267 ◽  
Author(s):  
Nike J. Kräutler ◽  
Dan Suan ◽  
Danyal Butt ◽  
Katherine Bourne ◽  
Jana R. Hermes ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Protective Immunity ◽  
Plasma Cells ◽  
Discrete Subset ◽  
Autoantibody Production ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.

scholarly journals A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Zhao Wang ◽  
Mingming Li ◽  
Ming Zhou ◽  
Yajing Zhang ◽  
Jie Yang ◽  
...  
Keyword(s):  
B Cells ◽  
Rabies Virus ◽  
Humoral Immunity ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Gm Csf ◽  
Follicular Helper ◽  
The World

ABSTRACT Rabies remains a public health threat in most parts of the world, and approximately 99% of the cases are transmitted by dogs. There is an urgent need to develop an efficacious and affordable vaccine to control canine-transmitted rabies in developing countries. Our previous studies demonstrate that overexpression of chemokines/cytokines such as CCL-3 (MIP-1α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the immunogenicity of rabies vaccines. In the present study, the chemokine CXCL13 was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, and the effect of the chemokine CXCL13 on the immunogenicity of RABV was investigated. It was found that LBNSE-CXCL13 recruited follicular helper T (Tfh) and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice. Further studies showed that mice immunized with LBNSE-CXCL13 produced more rabies virus-neutralizing antibodies (VNAs) and developed better protection than those immunized with the parent virus LBNSE or the GM-CSF-expressing RABV (LBNSE-GM-CSF). Collectively, these findings provide a better understanding of the role of CXCL13 expression in the immunogenicity of the RABV, which may help in designing more-efficacious rabies vaccines. IMPORTANCE Rabies is endemic in most parts of the world, and more effort is needed to develop affordable and effective vaccines to control or eliminate this disease. The chemokine CXCL13 recruits both Tfh and B cells, which is essential for the homing of Tfh cells and the development of B cell follicles. In this study, the effect of the overexpression of CXCL13 on the immunogenicity of the RABV was evaluated in a mouse model. We found that CXCL13 expression promoted humoral immunity by recruiting Tfh and GC B cells, facilitating the formation of GCs, and increasing the number of plasma cells. As expected, the overexpression of CXCL13 resulted in enhanced virus-neutralizing antibody (VNA) production and protection against a virulent RABV challenge. These findings provide a better understanding of the role of CXCL13 in RABV-induced immune responses, which will help in designing more efficacious rabies vaccines.

scholarly journals The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression but not CD4+ Tfh cells

2019 ◽  
Author(s):  
Gretchen Harms Pritchard ◽  
Akshay T. Krishnamurty ◽  
Jason Netland ◽  
E. Nicole Arroyo ◽  
Kennidy K. Takehara ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Effector Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

SummaryHumoral immunity depends upon the development of long-lived, antibody-secreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

scholarly journals Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival

2012 ◽  
Vol 109 (38) ◽  
pp. 15401-15406 ◽  
Author(s):  
Xijun Ou ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Cell Compartments ◽  
Follicular Helper ◽  
Inducible Costimulator ◽  
Ligand Expression

Mutations in TNFRSF13B, better known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), contribute to common variable immunodeficiency and autoimmunity in humans. How TACI regulates these two opposing conditions is unclear, however. TACI binds the cytokines BAFF and APRIL, and previous studies using gene KO mice indicated that loss of TACI affected only T-cell–independent antibody responses. Here we demonstrate that Taci−/− mice have expanded populations of T follicular helper (Tfh) and germinal center (GC) B cells in their spleens when immunized with T-cell–dependent antigen. The increased numbers of Tfh and GC B cells in Taci−/− mice are largely a result of up-regulation of inducible costimulator (ICOS) ligand on TACI-deficient B cells, given that ablation of one copy of the Icosl allele restores normal levels of Tfh and GC B cells in Taci−/− mice. Interestingly, despite the presence of increased Tfh and antigen-specific B cells, immunized Taci−/− mice demonstrate defective antigen-specific antibody responses resulting from significantly reduced numbers of antibody-secreting cells (ASCs). This effect is attributed to the failure to down-regulate the proapoptotic molecule BIM in Taci−/− plasma cells. Ablation of BIM could rescue ASC formation in Taci−/− mice, suggesting that TACI is more important for the survival of plasma cells than for the differentiation of these cells. Thus, our data reveal dual roles for TACI in B-cell terminal differentiation. On one hand, TACI modulates ICOS ligand expression and thereby limits the size of Tfh and GC B-cell compartments and prevents autoimmunity. On the other hand, it regulates the survival of ASCs and plays an important role in humoral immunity.

scholarly journals Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 985-993 ◽  
Author(s):  
Suresh Pallikkuth ◽  
Anita Parmigiani ◽  
Sandra Y. Silva ◽  
Varghese K. George ◽  
Margaret Fischl ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Function ◽  
Cell Loss ◽  
H1n1 Influenza ◽  
Pbmc Culture ◽  
Tfh Cells ◽  
Follicular Helper ◽  
2009 H1n1

Abstract The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5+ CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.

scholarly journals Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice

2010 ◽  
Vol 207 (12) ◽  
pp. 2767-2778 ◽  
Author(s):  
Thomas Tiller ◽  
Juliane Kofer ◽  
Cornelia Kreschel ◽  
Christian E. Busse ◽  
Stefan Riebel ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Compartment ◽  
Fc Gamma Receptor ◽  
Gamma Receptor ◽  
Systemic Autoimmunity ◽  
Bone Marrow Plasma ◽  
Ig G ◽  
Deficient Mice

Abnormalities in expression levels of the IgG inhibitory Fc gamma receptor IIB (FcγRIIB) are associated with the development of immunoglobulin (Ig) G serum autoantibodies and systemic autoimmunity in mice and humans. We used Ig gene cloning from single isolated B cells to examine the checkpoints that regulate development of autoreactive germinal center (GC) B cells and plasma cells in FcγRIIB-deficient mice. We found that loss of FcγRIIB was associated with an increase in poly- and autoreactive IgG+ GC B cells, including hallmark anti-nuclear antibody–expressing cells that possess characteristic Ig gene features and cells producing kidney-reactive autoantibodies. In the absence of FcγRIIB, autoreactive B cells actively participated in GC reactions and somatic mutations contributed to the generation of highly autoreactive IgG antibodies. In contrast, the frequency of autoreactive IgG+ B cells was much lower in spleen and bone marrow plasma cells, suggesting the existence of an FcγRIIB-independent checkpoint for autoreactivity between the GC and the plasma cell compartment.

scholarly journals T-independent antigen induces humoral memory through germinal centers

2022 ◽  
Vol 219 (3) ◽  
Author(s):  
Xin Liu ◽  
Yongshan Zhao ◽  
Hai Qi
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Plasma Cells ◽  
Underlying Mechanism ◽  
Memory B Cells ◽  
Antigen B ◽  
Per Se ◽  
Humoral Responses ◽  
Human And Mouse

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.

scholarly journals Highly Sensitive Flow Cytometry Allows Monitoring of Changes in Circulating Immune Cells in Blood After Tdap Booster Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Annieck M. Diks ◽  
Indu Khatri ◽  
Liesbeth E.M. Oosten ◽  
Bas de Mooij ◽  
Rick J. Groenland ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Immune Cells ◽  
Plasma Cells ◽  
Booster Vaccination ◽  
Added Value ◽  
Maximum Expansion ◽  
Specific Serum ◽  
Circulating T Cells ◽  
Time Changes

Antigen-specific serum immunoglobulin (Ag-specific Ig) levels are broadly used as correlates of protection. However, in several disease and vaccination models these fail to predict immunity. In these models, in-depth knowledge of cellular processes associated with protective versus poor responses may bring added value. We applied high-throughput multicolor flow cytometry to track over-time changes in circulating immune cells in 10 individuals following pertussis booster vaccination (Tdap, Boostrix®, GlaxoSmithKline). Next, we applied correlation network analysis to extensively investigate how changes in individual cell populations correlate with each other and with Ag-specific Ig levels. We further determined the most informative cell subsets and analysis time points for future studies. Expansion and maturation of total IgG1 plasma cells, which peaked at day 7 post-vaccination, was the most prominent cellular change. Although these cells preceded the increase in Ag-specific serum Ig levels, they did not correlate with the increase of Ig levels. In contrast, strong correlation was observed between Ag-specific IgGs and maximum expansion of total IgG1 and IgA1 memory B cells at days 7 to 28. Changes in circulating T cells were limited, implying the need for a more sensitive approach. Early changes in innate immune cells, i.e. expansion of neutrophils, and expansion and maturation of monocytes up to day 5, most likely reflected their responses to local damage and adjuvant. Here we show that simultaneous monitoring of multiple circulating immune subsets in blood by flow cytometry is feasible. B cells seem to be the best candidates for vaccine monitoring.

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