scholarly journals 701 Activating CD73 on B cells as a target for immunotherapy of COVID-19 and viral associated cancers: clinical activity in human papilloma virus positive (HPV) head and neck squamous cell cancers (HNSCC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A729-A729
Author(s):  
Jason Luke ◽  
Jaime Merchan ◽  
Brett Hughes ◽  
Jeffrey Sosman ◽  
Abhishek Tripathi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Head And Neck ◽  
Cell Activation ◽  
Phase 1 ◽  
Clinical Activity ◽  
List Type ◽  
B Cell Activation ◽  
Phase 1 Trial ◽  
Cd73 Expression

BackgroundMupadolimab (mupa) is a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that has agonistic properties.1 CD73 is involved in production of adenosine and in cellular trafficking. Mupa reacts with the majority of circulating B cells leading to activation and expression of differentiation markers CD69, CD138 and CD38, and transformation into plasmablasts with secretion of IgM and IgG. B cell activation provided the rationale to develop mupa for immunotherapy of cancer and Covid-19. Intratumor HPV specific B cells have been reported in HNSCC.2 This report describes properties of mupa and the early signs of clinical activity in HPV+ HNSCC.MethodsELISA and flow cytometry were used to measure binding of anti-CD73. Humanized NSG-SGM3 mice were used to evaluate effects of Mupa on human anti-SARS CoV2 spike protein (SP) response. CD73 expression in biopsies was measured by immunohistochemistry. Mupa (IV q 3 weeks) with or without pembrolizumab is being evaluated in an ongoing phase 1 trial in patients with refractory cancers.ResultsMupa binding to CD73 was blocked by APCP, an analog of adenosine diphosphate that locks CD73 in the closed conformation, indicating mupa binding to the open conformation. Cross blocking and cellular internalization studies showed that mupa is distinct from other anti-CD73 antibodies such as MEDI9447 and AD2. NSG-SGM3 mice were immunized with 50 µg SP subcutaneously and treated with mupa 10mg/kg or control IgG IP. Mupa treated animals mounted an antigen specific human anti-SP response; no antibody responses were seen in controls (P=0.02). In the dose-escalation portion of the phase 1 trial, mupa doses of ≥12 mg/kg saturated CD73 sites on circulating B cells. High stromal CD73 expression was observed in HPV+ HNSCC biopsies from 5 evaluable patients with chemotherapy and anti-PD1 refractory disease, and tumor regression was seen in 2 of these patients receiving 7 and 16 cycles of ≥12 mg/kg mupa without pembrolizumab. Safety of mupa+pembrolizumab was evaluated in 16 patients with no MTD reached and no changes in serum immunoglobulins. Transient reductions in circulating CD73 B cells were observed consistent with redistribution to lymphoid tissues.ConclusionsCD73 plays a role in B cell activation and differentiation. Mupa is an antibody with agonistic activity that stimulates B cells and enhances antigen specific antibody production. This activity supports a strategy to combine mupa with pembrolizumab to enhance both humoral and cellular immunity in the treatment of viral associated cancers such as HPV+HNSCC, and viral infections.Trial RegistrationNCT03454451ReferencesWillingham S, Criner G, Hill C, Hu S, Rudnick J, Daine-Matsuoka B, Hsieh J, Mashhedi H, Hotson A, Brody J, Marron T, Piccione E, Buggy J, Mahabhashyam S, Jones W, Mobasher M, Miller R. Characterization and Phase 1 trial of a B cell activating anti-CD73 antibody for the immunotherapy of COVID-19. medRxiv, 2020; https://doi.org/10.1101/2020.09.10.20191486.Wieland A, Patel M, Cardenas M, Eberhardt C, Hudson W, Obeng R, Griffith C, Wang X, Chen Z, Kissick H, Saba N, Ahmed R. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 2020; https://doi.org/10.1038/s41586-020-2931-3.Ethics ApprovalThe study was approved by Western IRB, approval number 1-1066703-1. Participants gave informed consent before taking part.

scholarly journals 476 AK119, a humanized anti-CD73 monoclonal antibody, as Immunotherapy for COVID-19

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A508-A508
Author(s):  
Tingting Zhong ◽  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Na Chen ◽  
Konyew Kwek ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Enzymatic Activity ◽  
B Cell ◽  
Antibody Production ◽  
Cell Activation ◽  
Phase 1 ◽  
B Cell Activation ◽  
Internalization Rate ◽  
Interferon Activity

BackgroundCD73, an ecto-5’-nucleotidase involved in ATP metabolism, converts AMP into adenosine. ATP could induce production of interferon-beta1, which induces cellular resistance to viral infection and triggers apoptosis of virus-infected cells.2 In COVID-19, SARS-CoV-2 causes severe respiratory syndrome by effectively inhibiting interferon activity,3 4 leading to impaired anti-viral response. Moreover, lung injury seen in severe COVID-19 patients might be caused by excess adenosine.5 Inhibition of CD73 is believed to increase extracellular ATP, thereby countering COVID-19. Furthermore, independent of its inhibitory effects on CD73, preclinical results from other anti-CD73 mAb suggested CD73 blockade activates lymphocytes, induced antibody production from B cells and enhanced lymphocyte trafficking,6 thereby, stimulated the production of anti-SARS-CoV-2 antibodies leading to the rapid clearance of the virus.7 We developed AK119, a humanized monoclonal antibody targeting CD73, as an immunotherapy agent for the treatment of COVID-19.MethodsEvaluation of AK119 activity to bind to the CD73 antigen was performed by using ELISA, Fortebio, and FACS assay. The activity of AK119 to inhibit enzymatic activity of CD73 was evaluated by cell-based enzyme assay; and the activity of AK119 to induce internalization of CD73 and enhance CD69 and CD83 expression on B cell were performed by using FACS assays. We also investigated the potential of AK119 to promote immunoglobulin production from human B cells.ResultsAK119 could effectively bind to human CD73 with high affinity, which is comparable or superior to 10.3AA, a leading anti-CD73 antibody, in protein-based assays. AK119 inhibited CD73 enzymatic activity on MDA-MB-231 cells (IC50_AK119, 27.60 nM; IC50_10.3AA, 15.99 nM) and U87-MG cells (IC50_AK119, 0.2448 nM; IC50_10.3AA, 0.0691 nM), with a higher maximal inhibition rates of 108.26% in MDA-MB-231 cells and 96.24% in U87-MG cells compared with 10.3AA (77.02% and 75.77%, respectively). AK119 effectively induced CD73 internalization in MDA-MB-231 cells and U87-MG cells, and the internalization rate of CD73 was 60.75% and 82.39%, respectively; for 10.3AA, the internalization rate was 50.53% and 73.65%, respectively. Moreover, AK119 could stimulate approximately 4–5 fold up-regulation of CD69 (figure 1A) and CD83 (figure 1B) that are markers of B cell activation; and, AK119 significantly promoted IgG production from B cells.ConclusionsIn summary, in comparison to a leading CD73 antibody currently in clinical trial, AK119 demonstrated more complete CD73 inhibition; and more dramatic B cell activation and antibody production. Thus, A119 presented desirable preclinical bioactivities. The safety and pharmacokinetics of single ascending doses of AK119 will be evaluated in healthy volunteers in an upcoming Phase 1, First-in-Human study (NCT04516564).Trial RegistrationNCT04516564ReferencesZhang C, He H, Wang L, et al. Virus-Triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. J Immunol 2017;199:1372–1381.Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014;32:513–545.Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718–724.Yuen CK, Lam JY, Wong WM, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect 2020;9:1418–1428.Hoogendijk AJ, Pinhanços SS, van der Poll T, Wieland CW. AMP-activated protein kinase activation by 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR) reduces lipoteichoic acid-induced lung inflammation. J Biol Chem 2013;288:7047–7052.Luke, Jason J., et al. Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers. J Clin Oncol 2019;37: suppl 2505–2505.Corvus Pharmaceuticals, Inc. Corvus Pharmaceuticals Provides Business Update and Reports Second Quarter 2020 Financial Results. 30 July 2020. [https://corvuspharma.gcs-web.com/news-releases/news-release-details/corvus-pharmaceuticals-provides-business-update-and-reports-4].Abstract 476 Figure 1AK119 induces up-regulation of CD69 and CD83 expression on B cells. PBMCs were incubated overnight with AK119 or 10.3AA. Flow cytometry analysis was performed with gating on B cells (CD19+CD3-) and mean fluorescence intensity (MFI) is reported for antibody staining of (A) CD69 or (B) CD83. One-way ANOVA, **P<0.01, ***P<0.001, vs Human IgG1 group.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

scholarly journals AB0024 IN VITRO CHARACTERIZATION OF CENERIMOD, A POTENT AND SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 (S1P1) MODULATOR IN PREVENTING MIGRATION OF NON-ACTIVATED AND ACTIVATED PRIMARY HUMAN B CELLS IN THE PRESENCE OR ABSENCE OF GLUCOCORTICOIDS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.1-1046
Author(s):  
L. Schlicher ◽  
P. Kulig ◽  
M. Murphy ◽  
M. Keller
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
B Cell Activation ◽  
Human B Cells ◽  
Circulating Lymphocytes

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

scholarly journals 702 Dual blockade of the PD-1 checkpoint pathway and the adenosinergic negative feedback signaling pathway with a PD-1/CD73 bispecific antibody for cancer immune therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A744-A744
Author(s):  
Tingting Zhong ◽  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Negative Feedback ◽  
Immune Suppression ◽  
Specific Antibody ◽  
Cell Activation ◽  
Immune Therapy ◽  
B Cell Activation

BackgroundCD73 (ecto-5’-nucleotidase) is an ecto-nucleotidase that dephosphorylate AMP to form adenosine. Activation of adenosine signaling pathway in immune cells leads to the suppression of effector functions, down-regulate macrophage phagocytosis, inhibit pro-inflammatory cytokine release, as well as yield aberrantly differentiated dendritic cells producing pro-tumorigenic molecules.1 In the tumor microenvironment, adenosinergic negative feedback signaling facilitated immune suppression is considered an important mechanism for immune evasion of cancer cells.2 3 Combination of CD73 and anti-PD-1 antibody has shown promising activity in suppressing tumor growth. Hence, we developed AK119, an anti- human CD73 monoclonal antibody, and AK123,a bi-specific antibody targeting both PD-1 and CD73 for immune therapy of cancer.MethodsAK119 is a humanized antibody against CD73 and AK123 is a tetrameric bi-specific antibody targeting PD-1 and CD73. Binding assays of AK119 and AK123 to antigens, and antigen expressing cells were performed by using ELISA, Fortebio, and FACS assays. In-vitro assays to investigate the activity of AK119 and AK123 to inhibit CD73 enzymatic activity in modified CellTiter-Glo assay, to induce endocytosis of CD73, and to activate B cells were performed. Assay to evaluate AK123 activity on T cell activation were additionally performed. Moreover, the activities of AK119 and AK123 to mediate ADCC, CDC in CD73 expressing cells were also evaluated.ResultsAK119 and AK123 could bind to its respective soluble or membrane antigens expressing on PBMCs, MDA-MB-231, and U87-MG cells with high affinity. Results from cell-based assays indicated that AK119 and AK123 effectively inhibited nucleotidase enzyme activity of CD73, mediated endocytosis of CD73, and induced B cell activation by upregulating CD69 and CD83 expression on B cells, and showed more robust CD73 blocking and B cell activation activities compared to leading clinical candidate targeting CD73. AK123 could also block PD-1/PD-L1 interaction and enhance T cell activation.ConclusionsIn summary, AK119 and AK123 represent good preclinical biological properties, which support its further development as an anti-cancer immunotherapy or treating other diseases.ReferencesDeaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–65.Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997; 90:1600–10.Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I,Carbone DP, Feoktistov I, et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008; 112:1822–31.

scholarly journals Deep Phenotyping of CD11c+ B Cells in Systemic Autoimmunity and Controls

2021 ◽  
Vol 12 ◽  
Author(s):  
Hector Rincon-Arevalo ◽  
Annika Wiedemann ◽  
Ana-Luisa Stefanski ◽  
Marie Lettau ◽  
Franziska Szelinski ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Membrane Expression ◽  
Ki 67 ◽  
Inflammatory Conditions ◽  
Systemic Autoimmunity ◽  
Enhanced Expression

Circulating CD11c+ B cells are a key phenomenon in certain types of autoimmunity but have also been described in the context of regular immune responses (i.e., infections, vaccination). Using mass cytometry to profile 46 different markers on individual immune cells, we systematically initially confirmed the presence of increased CD11c+ B cells in the blood of systemic lupus erythematosus (SLE) patients. Notably, significant differences in the expression of CD21, CD27, and CD38 became apparent between CD11c− and CD11c+ B cells. We observed direct correlation of the frequency of CD21−CD27− B cells and CD21−CD38− B cells with CD11c+ B cells, which were most pronounced in SLE compared to primary Sjögren's syndrome patients (pSS) and healthy donors (HD). Thus, CD11c+ B cells resided mainly within memory subsets and were enriched in CD27−IgD−, CD21−CD27−, and CD21−CD38− B cell phenotypes. CD11c+ B cells from all donor groups (SLE, pSS, and HD) showed enhanced CD69, Ki-67, CD45RO, CD45RA, and CD19 expression, whereas the membrane expression of CXCR5 and CD21 were diminished. Notably, SLE CD11c+ B cells showed enhanced expression of the checkpoint molecules CD86, PD1, PDL1, CD137, VISTA, and CTLA-4 compared to HD. The substantial increase of CD11c+ B cells with a CD21− phenotype co-expressing distinct activation and checkpoint markers, points to a quantitative increased alternate (extrafollicular) B cell activation route possibly related to abnormal immune regulation as seen under the striking inflammatory conditions of SLE which shows a characteristic PD-1/PD-L1 upregulation.

scholarly journals Antiviral Protection and Germinal Center Formation, But Impaired B Cell Memory in the Absence of CD19

1998 ◽  
Vol 188 (1) ◽  
pp. 145-155 ◽  
Author(s):  
Thomas Fehr ◽  
Robert C. Rickert ◽  
Bernhard Odermatt ◽  
Jürgen Roes ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antibody Responses ◽  
B Cell Activation ◽  
Protein Antigens ◽  
Cell Memory ◽  
B Cell Memory

Coligation of CD19, a molecule expressed during all stages of B cell development except plasmacytes, lowers the threshold for B cell activation with anti-IgM by a factor of 100. The cytoplasmic tail of CD19 contains nine tyrosine residues as possible phosphorylation sites and is postulated to function as the signal transducing element for complement receptor (CR)2. Generation and analysis of CD19 gene–targeted mice revealed that T cell–dependent (TD) antibody responses to proteinaceous antigens were impaired, whereas those to T cell–independent (TI) type 2 antigens were normal or even augmented. These results are compatible with earlier complement depletion studies and the postulated function of CD19. To analyze the role of CD19 in antiviral antibody responses, we immunized CD19−/− mice with viral antigens of TI-1, TI-2, and TD type. The effect of CD19 on TI responses was more dependent on antigen dose and replicative capacity than on antigen type. CR blocking experiments confirmed the role of CD19 as B cell signal transducer for complement. In contrast to immunization with protein antigens, infection of CD19−/− mice with replicating virus led to generation of specific germinal centers, which persisted for &gt;100 d, whereas maintenance of memory antibody titers as well as circulating memory B cells was fully dependent on CD19. Thus, our study confirms a costimulatory role of CD19 on B cells under limiting antigen conditions and indicates an important role for B cell memory.

scholarly journals Antigen Extraction and B Cell Activation Enable Identification of Rare Membrane Antigen Specific Human B Cells

2019 ◽  
Vol 10 ◽  
Author(s):  
Maria Zimmermann ◽  
Natalie Rose ◽  
John M. Lindner ◽  
Hyein Kim ◽  
Ana Rita Gonçalves ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Human B Cells

scholarly journals Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection

2019 ◽  
Vol 31 (12) ◽  
pp. 771-779 ◽  
Author(s):  
Sarah Leach ◽  
Ryo Shinnakasu ◽  
Yu Adachi ◽  
Masatoshi Momota ◽  
Chieko Makino-Okamura ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Influenza Infection ◽  
Memory B Cells ◽  
B Cell Activation ◽  
Memory B Cell

Memory B cells protect against heterologous influenza infection

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

2018 ◽  
Vol 46 (11) ◽  
pp. 5547-5560 ◽  
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.

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

2019 ◽  
Vol 12 (571) ◽  
pp. eaao7194 ◽  
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.

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