scholarly journals Sphingosine-1-Phosphate Receptor Type 4 (S1P4) Is Differentially Regulated in Peritoneal B1 B Cells upon TLR4 Stimulation and Facilitates the Egress of Peritoneal B1a B Cells and Subsequent Accumulation of Splenic IRA B Cells under Inflammatory Conditions

2021 ◽  
Vol 22 (7) ◽  
pp. 3465
Author(s):  
Janik Riese ◽  
Alina Gromann ◽  
Felix Lührs ◽  
Annabel Kleinwort ◽  
Tobias Schulze
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peritoneal Cavity ◽  
Lymphoid Organs ◽  
Receptor Expression ◽  
Inflammatory Conditions ◽  
Sphingosine 1 Phosphate ◽  
Secondary Lymphoid Organs

Background: Gram-negative infections of the peritoneal cavity result in profound modifications of peritoneal B cell populations and induce the migration of peritoneal B cells to distant secondary lymphoid organs. However, mechanisms controlling the egress of peritoneal B cells from the peritoneal cavity and their subsequent trafficking remain incompletely understood. Sphingosine-1-phosphate (S1P)-mediated signaling controls migratory processes in numerous immune cells. The present work investigates the role of S1P-mediated signaling in peritoneal B cell trafficking under inflammatory conditions. Methods: Differential S1P receptor expression after peritoneal B cell activation was assessed semi‑quantitatively using RT-PCR in vitro. The functional implications of differential S1P1 and S1P4 expression were assessed by transwell migration in vitro, by adoptive peritoneal B cell transfer in a model of sterile lipopolysaccharide (LPS)‑induced peritonitis and in the polymicrobial colon ascendens stent peritonitis (CASP) model. Results: The two sphingosine-1-phosphate receptors (S1PRs) expressed in peritoneal B cell subsets S1P1 and S1P4 are differentially regulated upon stimulation with the TLR4 agonist LPS, but not upon PMA/ionomycin or B cell receptor (BCR) crosslinking. S1P4 deficiency affects both the trafficking of activated peritoneal B cells to secondary lymphoid organs and the positioning of these cells within the functional compartments of the targeted organ. S1P4 deficiency in LPS-activated peritoneal B cells results in significantly reduced numbers of splenic innate response activator B cells. Conclusions: The S1P-S1PR system is implicated in the trafficking of LPS-activated peritoneal B cells. Given the protective role of peritoneal B1a B cells in peritoneal sepsis, further experiments to investigate the impact of S1P4-mediated signaling on the severity and mortality of peritoneal sepsis are warranted.

CD40 Ligand Activation Alters B Cell Migration to Secondary Lymphoid Organs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 935-935
Author(s):  
Yvonne A. Efebera ◽  
Tahamtan Ahmadi ◽  
Amanda Flies ◽  
David H. Sherr
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cd40 Ligand ◽  
Lymphoid Organs ◽  
Cell Populations ◽  
Secondary Lymphoid Organs ◽  
Activated B Cells

Abstract Background: An increased understanding of the requirements for antigen presentation has encouraged development of cell-based cancer vaccines. Trials using dendritic cells (DC) as antigen presenting cells (APC) for immunotherapy of several malignancies have shown considerable success. However, the difficulty in generating large numbers of DC required for these immunizations has led to the search for alternative APC. One such candidate is the CD40 ligand (CD40L)-activated B cell, populations of which can readily be expanded in vitro. To be an effective vehicle for antigen presentation to T cells, CD40L-activated B cells must be capable of migrating to secondary lymphoid organs. Therefore, CD40L-activated B cell migration following subcutaneous or intravenous injection was evaluated. Methods: Splenic B cells from GFP transgenic mice were activated with CD40L + IL-4 and expanded in vitro prior to i.v. or s.c. injection of 3–4 x 107 into C57BL/6 mice. Recipient mice were sacrificed 2 hrs or 1–14 days thereafter and the percentage of GFP+/B220+ B cells quantified in spleens and lymph nodes by flow cytometry. Localization of these cells within lymphoid organs was determined by immunohistochemistry. In some experiments, activated C57BL/6 B cells were labeled with carboxy fluorescein succinimidyl ester (CFSE) to evaluate cell growth in vivo. Results: Murine B cell populations were readily expanded by culture on CD40L-transfected L cells in the presence of IL-4. CD40L-activated B cells expressed high levels of CD80, CD86, and LFA-1 but decreased levels of L-selectin relative to naive cells. Following i.v. injection, activated B cells were detected in spleens and lymph nodes within 1 day. Peak concentrations of activated B cells were noted in spleens and lymph nodes on days 7 (4.8% of injected cells) and 10 (1.25% of injected cells) respectively, suggesting expansion of the activated B cell population in vivo. Naive B cells injected i.v. were detected within 1 day but their number declined precipitously thereafter. Following s.c. injection, peak levels of CD40L-activated B cells were noted on day 5 (spleens) and day 7 (lymph nodes). As determined by immunohistochemistry, both CD40L-activated and naïve B cells injected i.v. appeared in B cell regions of spleens and lymph nodes. While the kinetics of accumulation of CD40L-activated B cells injected s.c. or i.v. were similar, s.c. injected CD40L-activated B cells homed to the T cell regions of spleens and lymph nodes. CFSE experiments indicated that these activated B cells continue to grow in vivo. In contrast, naïve B cells injected s.c. only appeared in B cell regions. Conclusion: CD40L-activated B cell populations can readily be expanded in vitro, CD40L-activated B cells migrate to secondary lymphoid organs even when injected s.c., activated B cell populations expand in vivo, and s.c. injected, CD40L-activated B cells preferentially home to T cell regions of secondary lymphoid organs. These results suggest that this effective APC may serve as an important vehicle for delivery and presentation of exogenous (e.g. tumor) antigens to T cells in vivo.

scholarly journals α4-integrin deficiency in B cells does not affect disease in a T-cell–mediated EAE disease model

2019 ◽  
Vol 6 (4) ◽  
pp. e563
Author(s):  
Rehana Z. Hussain ◽  
Petra D. Cravens ◽  
William A. Miller-Little ◽  
Richard Doelger ◽  
Valerie Granados ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Adoptive Transfer ◽  
Lymphoid Organs ◽  
Pathogenic Role ◽  
Genetic Ablation ◽  
Secondary Lymphoid Organs ◽  
The Brain

ObjectiveThe goal of this study was to investigate the role of CD 19+ B cells within the brain and spinal cord during CNS autoimmunity in a peptide-induced, primarily T-cell–mediated experimental autoimmune encephalomyelitis (EAE) model of MS. We hypothesized that CD19+ B cells outside the CNS drive inflammation in EAE.MethodsWe generated CD19.Cre+/− α4-integrinfl/fl mice. EAE was induced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOGp35-55). Multiparameter flow cytometry was used to phenotype leukocyte subsets in primary and secondary lymphoid organs and the CNS. Serum cytokine levels and Ig levels were assessed by bead array. B-cell adoptive transfer was used to determine the compartment-specific pathogenic role of antigen-specific and non–antigen-specific B cells.ResultsA genetic ablation of α4-integrin in CD19+/− B cells significantly reduced the number of CD19+ B cells in the CNS but does not affect EAE disease activity in active MOGp35-55-induced disease. The composition of B-cell subsets in the brain, primary lymphoid organs, and secondary lymphoid organs of CD19.Cre+/− α4-integrinfl/fl mice was unchanged during MOGp35-55-induced EAE. Adoptive transfer of purified CD19+ B cells from CD19.Cre+/− α4-integrinfl/fl mice or C57BL/6 wild-type (WT) control mice immunized with recombinant rMOG1-125 or ovalbumin323-339 into MOGp35-55-immunized CD19.Cre+/− α4-integrinfl/fl mice caused worse clinical EAE than was observed in MOGp35-55-immunized C57BL/6 WT control mice that did not receive adoptively transferred CD19+ B cells.ConclusionsObservations made in CD19.Cre+/− α4-integrinfl/fl mice in active MOGp35-55-induced EAE suggest a compartment-specific pathogenic role of CD19+ B cells mostly outside of the CNS that is not necessarily antigen specific.

scholarly journals Human Dendritic Cells Skew Isotype Switching of CD40-activated Naive B Cells towards IgA1 and IgA2

1997 ◽  
Vol 185 (11) ◽  
pp. 1909-1918 ◽  
Author(s):  
Jérôme Fayette ◽  
Bertrand Dubois ◽  
Stéphane Vandenabeele ◽  
Jean-Michel Bridon ◽  
Béatrice Vanbervliet ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Culture Conditions ◽  
Lymphoid Organs ◽  
Cell Growth And Differentiation ◽  
Secondary Lymphoid Organs

Within T cell–rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on ∼10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-β, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40–50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-β. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-β. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell–dependent B cell growth and differentiation, by inducing the IgA isotype switch.

The Selenoprotein Thioredoxin Reductase 1 Is Crucial for B-1 Cell but Dispensable for B-2 Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3691-3691
Author(s):  
Pankaj Kumar Mandal ◽  
Ursula Zimber-Strobl ◽  
Georg W. Bornkamm ◽  
Armin Gerbitz ◽  
Marcus Conrad
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
Peritoneal Cavity ◽  
Thioredoxin Reductase ◽  
Cell Development ◽  
Activation Induced Cell Death

Abstract Abstract 3691 Poster Board III-627 Introduction A growing body of evidence has implicated the role of reactive oxygen species (ROS) as second messengers in the signaling of various cytokines and growth factors that govern innate immunity and inflammation. For example, ROS is involved in TLR4-mediated activation of MAPK pathways. However, oxidative stress resulting from elevated ROS levels is involved in the etiology of many pathological conditions. Although immune cells generate ROS for signaling and microbicidal activity, they are extremely sensitive towards oxidative stress and therefore maintain high levels of antioxidants. The immunomodulatory and antioxidant function of selenium is in part due to the incorporation of selenium into selenoproteins, which are an important component of the antioxidant system. The selenoprotein thioredoxin reductase 1 (Txnrd1) and its major substrate thioredoxin 1 are essential for embryogenesis and are implicated in sustaining high proliferation rates due to provision of electrons for ribonucleotide reductase. The rapid turnover of immune cells upon activation and the extreme sensitivity towards ROS prompted us to address the role of Txnrd1 in B cell development and physiology. Methods Using the Cre-loxP system, we addressed the role of Txnrd1 in B cell development. B cell–specific Txnrd1 knockout mice were generated by breeding conditional Txnrd1 knockout mice (Txnrd1fl/fl; fl= loxP flanked allele) with mb-1 cre mice, in which expression of cre recombinase is driven by the murine mb-1 locus. Cells from bone marrow, spleen, lymph node and peritoneal cavity were isolated and analyzed by FACS using combinations of cell surface markers. For in vitro stimulation experiments, untouched B cells were isolated from spleen by MACS using CD43 microbeads and treated with various stimulants (α-CD40, α-CD40+IL4, LPS, LPS+IL4 and α-IgM). Results B-cell specific ablation of Txnrd1 leads to severly impaired development of peritoneal cavity B cells (PercB or B-1). The dramatic reduction in B-1 cells in mb-1 Cre; Txnrd1fl/fl mice indicated that Txnrd1 is required for the development and/or self-renewal of B-1 cells. Analysis of B220+ cells from bone marrow, spleen and lymph node revealed a normal distribution of different subpopulation of B-2 cells, demonstrating the dispensable role of Txnrd1 in B-2 cell development. In vitro stimulation of Txnrd1 deficient B-2 cells with various stimuli (stated above) revealed normal activation as shown by increased expression of activation markers CD86 and CD95. However, a higher percentage of dead cells was detected in Txnrd1 null B-2 cells as compared to control cells. This suggests that either Txnrd1 deficient B-2 cells fail to proliferate in response to various stimuli or undergo activation-induced cell death. Conclusions Our data provide first evidence that Txnrd1 is indispensable for the development and/or self-renewal of B-1 cells. As peritoneal cavity B-cells are responsible for producing natural antibodies, it is tempting to speculate that the compromised Txnrd1 function may lead to an increased susceptibility towards pathogens. Although Txnrd1 deficiency has little impact on the development of B-2 cells, they show compromised proliferation or activation-induced cell death upon stimulation. These findings could either be due to the essential role of Txnrd1 in sustaining high proliferation rates or the induction of cell death in response to massive oxidative stress resulting from receptor activation-induced signaling. Further studies will provide intriguing insight in to the downstream signaling cascades and in the immune response upon immunization. Disclosures: No relevant conflicts of interest to declare.

scholarly journals THU0053 CONTRIBUTION OF DEFECTIVE NON-APOPTOTIC FAS SIGNALING TO IMMUNE DYSREGULATION IN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 238.3-238
Author(s):  
J. Staniek ◽  
T. Kalina ◽  
G. Andrieux ◽  
M. Boerries ◽  
I. Janowska ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathway ◽  
Germinal Center ◽  
Lymphoid Organs ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Fas Signaling ◽  
Secondary Lymphoid Organs

Background:ALPS patients show impaired generation of humoral memory for T independent antigens whereas they generate memory for self-antigens due to impaired FAS-dependent removal of autoreactive germinal center B cells. It is known that FAS signaling via caspase activation results in cell apoptosis. However, FAS ligation may also initiate or modulate non-apoptotic signaling as shown for example by its ability to activate NF-κB. Recent data implicate a regulatory role of FAS in the modulation of mTOR signaling in ALPS double-negative T cells. Moreover, a recently described C194V FAS mutation disturbs its post-translational modification leading to impaired apoptosis induction while non-apoptotic signalling is still intact. Consequently, C194V FAS protects from the autoimmune phenotype in the murine ALPS system. This supports the view that FAS may prevent autoimmunity with other mechanisms than inducing apoptosis.Objectives:We hypothesize that FAS mutations impair this modulatory signaling, leading to hyper-activation of B cells. Therefore we aim to investigate non apoptotic FAS signaling in B cells derived from healthy individuals and ALPS patients.Methods:We studied resting and activated B cells in ALPS patients in presence or absence of FAS ligand by flow cytometry analysing relevant molecules to the CD40 signaling pathway. We used mass cytometry to perform functional phenotyping of B cells isolated from secondary lymphoid organs. Proteomic studies were performed to identify potential signaling circuits and RNA sequencing to study the consequences of FAS signaling on B cell fate.Results:In CD40L activated B cells, FAS signaling results in specific modulation of the mTOR signaling pathway. This modulation is absent in ALPS derived B cells. In line with these data germinal center B cells and plasmablast from secondary lymphoid organs of ALPS patients show hyperactive mTOR signaling pathway. Proteomic studies identify a circuit that links FAS to the phosphatase PTEN via DAXX and the deubiquitinase USP7.Conclusion:We describe a new role of FAS in the regulation of B cell activation. Defects in FAS signaling in ALPS contribute to dysregulation of the mTOR signaling pathway and disturbed B cell development.Disclosure of Interests:None declared

scholarly journals Interleukin-13 in Combination With CD40 Ligand Potently Inhibits Apoptosis in Human B Lymphocytes: Upregulation of Bcl-xL and Mcl-1

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4415-4424 ◽  
Author(s):  
Jon Lømo ◽  
Heidi Kiil Blomhoff ◽  
Sten Eirik Jacobsen ◽  
Stanislaw Krajewski ◽  
John C. Reed ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Peripheral Blood ◽  
Cell Apoptosis ◽  
Cell Types ◽  
Cd40 Ligand ◽  
Interleukin 13

Abstract Interleukin-13 (IL-13) is a novel T-cell–derived cytokine with IL-4–like effects on many cell types. In human B lymphocytes, IL-13 induces activation, stimulates proliferation in combination with anti-IgM or anti-CD40 antibodies, and directs Ig isotype switching towards IgE and IgG4 isotypes. We show here that IL-13 also regulates human B-cell apoptosis. IL-13 reduced spontaneous apoptosis of peripheral blood B cells in vitro, as shown by measurement of DNA fragmentation using the TUNEL and Nicoletti assays. The inhibition of cell death by IL-13 alone was significant but modest, but was potently enhanced in combination with CD40 ligand (CD40L), a survival stimulus for B cells by itself. Interestingly, IL-13 increased the expression of CD40 on peripheral blood B cells, providing a possible mechanism for the observed synergy. IL-13 alone was a less potent inhibitor of apoptosis than IL-4. Moreover, there was no additive effect of combining IL-4 and IL-13 at supraoptimal concentrations, which is consistent with the notion that the IL-4 and IL-13 binding sites share a common signaling subunit. The combination of IL-13 with CD40L augmented the expression of the Bcl-2 homologues Bcl-xL and Mcl-1, suggesting this as a possible intracellular mechanism of induced survival. By contrast, levels of Bcl-2, and two other Bcl-2 family members, Bax and Bak, remained unaltered. Given the importance of the CD40-CD40L interaction in B-cell responses, these results suggest a significant role of IL-13 in the regulation of B-cell apoptosis.

The Proto-Oncogene LRF Is Essential for Normal Mature B Cell Development and Germinal Center Formation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1788-1788
Author(s):  
Nagisa Sakurai ◽  
Manami Maeda ◽  
Sung-UK Lee ◽  
Julie Teruya-Feldstein ◽  
Takahiro Maeda
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Transitional B Cells ◽  
Notch Pathways ◽  
Secondary Lymphoid Organs

Abstract LRF (Leukemia/Lymphoma Related Factor, also known as Pokemon, FBI-1, OCZF and ZBTB7a) was originally identified as an interaction partner of the oncoprotein BCL6. LRF can act as a proto-oncogene by repressing the tumor suppressor ARF and cooperates with BCL6 in MEF (mouse embryonic fibroblasts) immortalization. It is highly expressed in human Non-Hodgkin Lymphoma (NHL) cases, in the pathogenesis of which BCL6 is known to be involved (Maeda et al. Nature 2005). Inducible inactivation of the LRF gene in mouse Hematopoietic Stem Cells (HSCs) results in complete block of early B cell development at the HSC/progenitor stages and concomitant development of double positive (DP) T cells in the bone marrow (BM) (Maeda et al. Science 2007). While these findings clearly illustrate key roles of LRF in normal and malignant B cell development, it is not fully identified as to which B cell stages LRF is required during normal B cell development. To elucidate the role of LRF in B cells in vivo, we established and characterized B cell-specific LRF conditional knockout (KO) mice. We took advantage of mb-1 Cre knock-in mice, in which Cre expression is restricted to the B cells after the ProB cell stage. B cell compartments in the BM (PreProB, ProB, PreB and immatureB) are grossly normal in LRFF/ Fmb1-Cre mice. The LRF gene was efficiently eliminated in BM CD19+ B cells revealed by quantitative real-time PCR assay. Furthermore, LRF protein was not detected in purified CD19+ B cells, but seen in CD19-non-B cells, confirming the specific inactivation of the LRF gene in B cells. Thus, despite its critical role at the HSC/progenitor stages, LRF was found to be dispensable for the survival of normal BM B cells. These findings are consistent with the fact that GSI treatment (Maeda et al. Science 2007) or Notch1 loss (Lee and Maeda, unpublished) rescues the defects in early B cell development seen in LRFF/FMx1-Cre+ mice. Notch signaling is necessary for the transitional B cells to commit to the marginal zone B cells (MZB). Inactivation of the component of the Notch pathways in mice results in no MZB development. On the contrary, deletion of the MINT/SHARP gene, a suppressor of Notch signaling, leads to increase of MZB cells and concomitant reduction of follicular B (FOB) cells, indicating that Notch induces MZB cell fate at the transitional B cell stage. Given that LRF is a potent Notch suppressor at the HSC/progenitor stages, we hypothesized that LRF opposes Notch pathway in mature B cells as well. To test this hypothesis, we characterized mature B cell development in LRFF/Fmb1-Cre mice. While transitional B cells were largely unaffected in LRFF/Fmb1-Cre mice, we observed a slight but statistically significant reduction of follicular (FO) B cells (B220+CD19+AA4.1-CD1d-CD23+) and concomitant increase of MZB cells (B220+CD19+AA4.1-CD1d+CD23-) as seen in MINT/SHARP knockout mice. Thus, LRF may also oppose Notch pathways at the branching point for the FOB vs. MZB fate decision. Finally, to determine the role of LRF in Germinal Center (GC) formation in vivo, we characterized secondary lymphoid organs of LRFF/Fmb1-Cre mice after antigen stimulation. Both spleen and Peyer’s Patches were analyzed two weeks after immunization with Chicken Gamma Globulin (NP-CGG). While a GC reaction was robustly induced in control mice upon immunization, GC formation was significantly impaired in LRFF/Fmb1-Cre mice as revealed by immuno-histochemical analysis (IHC) and FACS. Only few GC cells (B220+CD19+FAS+CD38-PNA+) were observed in spleens, and the absolute numbers of GC cells were drastically reduced in LRFF/Fmb1-Cre mice. Residual LRF-deficient GC B cells were mostly negative for CXCR4, which is predominantly expressed in proliferating centroblasts within GCs, suggesting that LRF-deficient GC B cells may have defects in cellular proliferation in response to antigen stimuli. Our data indicates that LRF plays key roles in mature B cell development in the secondary lymphoid organs, but dispensable for the maintenance of early BM B cells.

scholarly journals Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody.

1993 ◽  
Vol 178 (1) ◽  
pp. 257-264 ◽  
Author(s):  
K H Grabstein ◽  
T J Waldschmidt ◽  
F D Finkelman ◽  
B W Hess ◽  
A R Alpert ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Culture Methods ◽  
Cell Stage ◽  
Interleukin 7 ◽  
Slow Turnover

The effects of interleukin 7 (IL-7) on the growth and differentiation of murine B cell progenitors has been well characterized using in vitro culture methods. We have investigated the role of IL-7 in vivo using a monoclonal antibody that neutralizes IL-7. We find that treatment of mice with this antibody completely inhibits the development of B cell progenitors from the pro-B cell stage forward. We also provide evidence that all peripheral B cells, including those of the B-1 and conventional lineages, are derived from IL-7-dependent precursors. The results are consistent with the rapid turnover of B cell progenitors in the marrow, but a slow turnover of mature B cells in the periphery. In addition to effects on B cell development, anti-IL-7 treatment substantially reduced thymus cellularity, affecting all major thymic subpopulations.

Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Taoyong Chen ◽  
Jun Guo ◽  
Mingjin Yang ◽  
Chaofeng Han ◽  
Minghui Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Chemokine Receptor ◽  
Cyclooxygenase 2 ◽  
Lymphoid Organs ◽  
Receptor Expression ◽  
Chemokine Receptor Expression ◽  
Cox 2 ◽  
Secondary Lymphoid Organs

Abstract Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow–derived DCs toward macrophage inflammatory protein-3β (MIP-3β) and induces them to retain responsiveness to MIP-1α after lipopolysaccharide (LPS)–stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor–κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.

scholarly journals The impact of size on particle drainage dynamics and antibody response

2020 ◽  
Author(s):  
Simon Zinkhan ◽  
Anete Ogrina ◽  
Ina Balke ◽  
Gunta Reseviča ◽  
Andris Zeltins ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Lymphoid Organs ◽  
Cowpea Chlorotic Mottle Virus ◽  
Chlorotic Mottle Virus ◽  
Chlorotic Mottle ◽  
Secondary Lymphoid Organs ◽  
The Impact

AbstractVaccine-induced immune response can be greatly enhanced by mimicking pathogen properties. The size and the repetitive geometric shape of virus-like particles (VLPs) influence their immunogenicity by facilitating drainage to secondary lymphoid organs and enhancing interaction with and activation of B-cells and other innate humoral immune components. VLPs derived from the plant Bromovirus genus, specifically cowpea chlorotic mottle virus (CCMV), are T=3 icosahedron particles. They can be easily expressed in an E. coli host system and package ssRNA during the expression process. Recently, we have engineered CCMV-VLPs by incorporating the universal tetanus toxoid (TT) epitope at the N-terminus. The modified CCMVTT-VLPs successfully form icosahedral particles T=3, with a diameter of ∼30nm analogous to the parental VLPs. Interestingly, incorporating TT epitope at the C-terminus of CCMVTT-VLPs results in the formation of Rod-shaped VLPs, ∼1µm in length and ∼30nm in width. In this study, we have investigated the draining kinetics and immunogenicity of both engineered forms (termed as Round-shaped CCMVTT-VLPs and Rod-shaped CCMVTT-VLPs) as potential B cell immunogens using different in vitro and in vivo assays. Our results reveal that Round-shaped CCMVTT-VLPs are more efficient in draining to secondary lymphoid organs to charge antigen-presenting cells as well as B-cells. Furthermore, compared to Rod-shaped CCMVTT-VLPs, Round-shaped CCMVTT-VLPs led to more than 100-fold increased systemic IgG and IgA responses accompanied by prominent formation of splenic germinal centers. Round-shaped CCMVTT-VLPs could also polarize the induced immune response towards TH1. Up to our knowledge, this is the first study investigating and comparing the draining kinetics and immunogenicity of one and the same VLP monomer forming nano-sized icosahedrons or rods in the micrometer size.

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