1610Pervasive B cell Activation during Viremic HIV-1 Infection but Effective Responses with Appropriate Stimulation in vitro

Background:Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including B lymphocytes) in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod in relapsing forms of multiple sclerosis, supporting this therapeutic concept for the treatment of autoimmune disorders.Objectives:Although the effect of S1P-receptor modulators in reducing peripheral B cells is well documented1,2, the role of the S1P1 receptor on this cell type is only incompletely understood. In this study, the mode of action of cenerimod on primary human B cells was investigated in a series of in vitro experiments, including S1P1 receptor cell surface expression and chemotaxis towards S1P. Moreover, S1P1 expression following B cell activation in vitro was studied. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GC on the mode of action of cenerimod was evaluated.Methods:Primary human B lymphocytes from healthy donors were isolated from whole blood. In one set of experiments, cells were treated with different concentrations of cenerimod to measure S1P1 receptor internalization by flow cytometry. In a second set of experiments, isolated B cells were activated using different stimuli or left untreated. Cells were then analysed for S1P1 and CD69 cell surface expression and tested in a novel real-time S1P-mediated migration assay. In addition, the effect of physiological concentrations of GCs (prednisolone and prednisone) on cenerimod activity in preventing S1P mediated migration was tested.Results:In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human B lymphocytes. Cenerimod also blocked migration of nonactivated and activated B lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Upon B cell activation, which was monitored by CD69 upregulation, a simultaneous downregulation of S1P1 expression was detected, leading to less efficient S1P-directed cell migration. Importantly, physiological concentrations of GC did not affect the inhibitory activity of cenerimod on B cell migration.Conclusion:These results show that cenerimod, by modulating S1P1, blocks B lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod with GC. These results are consistent with results of comparable experiments done previously using primary human T lymphocytes.References:[1]Nakamura M et al., Mult Scler. 2014 Sep; 20(10):1371-80.[2]Strasser DS et al., RMD Open 2020;6:e001261.Disclosure of Interests:None declared

Download Full-text

Association of interleukin-10 promoter genetic variants with T-cell and B-cell activation in HIV-1 infection

Retrovirology ◽

10.1186/1742-4690-9-s2-p168 ◽

2012 ◽

Vol 9 (S2) ◽

Author(s):

D Naicker ◽

B Julg ◽

C McClurg ◽

M Ghebremichael ◽

F Porichis ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Genetic Variants ◽

Cell Activation ◽

Interleukin 10 ◽

B Cell Activation ◽

Hiv 1

Download Full-text

OP0167 A low molecular weight baff signallinginhibitor, bik-13, ameliorates b cell activation in vitro and in vivo autoimmune models and consequently suppresses production of igg and cytokines

10.1136/annrheumdis-2018-eular.4132 ◽

2018 ◽

Author(s):

K. Yoshimoto ◽

N. Seki ◽

K. Suzuki ◽

K. Sugahara ◽

K. Chiba ◽

...

Keyword(s):

Molecular Weight ◽

B Cell ◽

Cell Activation ◽

Low Molecular Weight ◽

B Cell Activation

Download Full-text

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

Nucleic Acids Research ◽

10.1093/nar/gky281 ◽

2018 ◽

Vol 46 (11) ◽

pp. 5547-5560 ◽

Cited By ~ 9

Author(s):

Kuo-Hsuan Hung ◽

Yong H Woo ◽

I-Ying Lin ◽

Chin-Hsiu Liu ◽

Li-Chieh Wang ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

De Novo ◽

Epigenetic Mechanism ◽

B Cell Activation ◽

Motif Analysis ◽

Follicular Helper

Abstract T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.

Download Full-text

APRIL-Deficient Mice Have Normal Immune System Development

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.997-1006.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 997-1006 ◽

Cited By ~ 128

Author(s):

Eugene Varfolomeev ◽

Frank Kischkel ◽

Flavius Martin ◽

Dhaya Seshasayee ◽

Hua Wang ◽

...

Keyword(s):

B Cell ◽

Cell Activation ◽

System Development ◽

Physiological Role ◽

B Cell Activation ◽

Tnf Superfamily ◽

Immune System Development ◽

Humoral Responses

ABSTRACT APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL−/− mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.

Download Full-text

Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins

Science Signaling ◽

10.1126/scisignal.aao7194 ◽

2019 ◽

Vol 12 (571) ◽

pp. eaao7194 ◽

Cited By ~ 6

Author(s):

Isabel Wilhelm ◽

Ella Levit-Zerdoun ◽

Johanna Jakob ◽

Sarah Villringer ◽

Marco Frensch ◽

...

Keyword(s):

B Cells ◽

Cell Surface ◽

B Cell ◽

Cell Activation ◽

Surface Expression ◽

Cell Surface Expression ◽

B Cell Activation ◽

Intracellular Ca ◽

Bacterial Lectins

Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL fromBurkholderia ambifariaand LecB fromPseudomonas aeruginosa, on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its co-receptor CD19, as well as on spleen tyrosine kinase (Syk) activity. The resulting release of intracellular Ca2+was followed by an increase in the cell surface abundance of the activation marker CD86, augmented cytokine secretion, and subsequent cell death, replicating all of the events that are observed in vitro upon canonical and antigen-mediated B cell activation. Moreover, injection of BambL in mice resulted in a substantial, BCR-independent loss of B cells in the bone marrow with simultaneous, transient enlargement of the spleen (splenomegaly), as well as an increase in the numbers of splenic B cells and myeloid cells. Together, these data suggest that bacterial lectins can initiate polyclonal activation of B cells through their sole capacity to bind to fucose.

Download Full-text

Telomerase Activity Is Induced in Human Peripheral B Lymphocytes by the Stimulation to Antigen Receptor

Blood ◽

10.1182/blood.v89.4.1299 ◽

1997 ◽

Vol 89 (4) ◽

pp. 1299-1307 ◽

Cited By ~ 73

Author(s):

Hideya Igarashi ◽

Nobuo Sakaguchi

Keyword(s):

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Cell Activation ◽

Interleukin 2 ◽

Antigen Receptor ◽

Telomerase Activity ◽

B Cell Activation ◽

Molecular Events

Abstract To understand the molecular events for the proliferation of B cells, we studied the induction of telomerase activity in vitro after stimulation to B-cell antigen receptor (BCR) on human peripheral B cells. Although unstimulated purified B cells of tonsils and peripheral blood from healthy volunteers do not express detectable telomerase activity, anti-IgM beads induce telomerase activity in these B cells. Soluble anti-IgM antibody (Ab) alone does not induce telomerase activity, but the second signal, given by either one of the cytokines of interleukin-2 (IL-2), IL-4, and IL-13 or by anti-CD40 monoclonal Ab (MoAb), is effective as the costimulation for the induction of the activity. Stimulation with antiIgM Ab and anti-CD40 MoAb induces telomerase activity in most mature B cells of the tonsils and peripheral blood. The stimuli to both IgM and IgD receptors similarly induce the activity. Induction of telomerase activity is accompanied with the proliferation of B cells, but is not absolutely correlated with the extent of B-cell growth. Phorbol dibutylate (PDB) plus calcium (Ca) ionophore (PDB/Ca), which replace the activation through BCR and the costimulatory molecules, also induce telomerase activity. Moreover, it is suggested that phosphoinositide (PI) 3-kinase plays a role for the induction of telomerase activity in B cells stimulated with anti-IgM Ab and anti-CD40 MoAb. These results suggest that telomerase activity is induced in the B-cell activation of the antigen specific immune response.

Download Full-text

Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

Journal of Virology ◽

10.1128/jvi.00839-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12525-12534 ◽

Cited By ~ 10

Author(s):

Anne Woods ◽

Fanny Monneaux ◽

Pauline Soulas-Sprauel ◽

Sylviane Muller ◽

Thierry Martin ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Type I Interferon ◽

Type I ◽

Interferon Production ◽

B Cell Activation ◽

B Cell Tolerance

ABSTRACT The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F1] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.

Download Full-text

Enhanced B Cell Activation in the Absence of CD81

Blood ◽

10.1182/blood.v112.11.2578.2578 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2578-2578

Author(s):

Mrinmoy Sanyal ◽

Rosemary Fernandez ◽

Shoshana Levy

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Receptor ◽

Free Calcium ◽

B Cell Activation ◽

Membrane Reorganization ◽

A Cell

Abstract CD81 is a component of the CD19/CD21 coreceptor complex in B cells. This tetraspanin molecule was previously shown to enable membrane reorganization in B cells responding to complement-bound antigens. Here we stimulated B cells via their B cell receptor (BCR) and demonstrate that Cd81−/− B cells fluxed higher intracellular free calcium ion along with increased phosphorylation of PLCγ2 and Syk. The stimulated Cd81−/− B cells also proliferated faster and secreted higher amounts of antibodies. Moreover, activation of the TLR4 pathway in Cd81−/− B cells induced increased proliferation and antibody secretion. Furthermore, Cd81−/− mice mounted a significantly higher immune response to T-cell independent antigens than their wildtype counterparts. Finally, analysis of Cd81−/− B cells that were generated by bone marrow transplantation into Rag1−/− mice confirmed a cell intrinsic hyperactive phenotype. Taken together, these results indicate that CD81 plays a negative role in B cell activation in vitro and in vivo.

Download Full-text