scholarly journals GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

2022 ◽  
Author(s):  
Raquel Guillamat-Prats ◽  
Daniel Hering ◽  
Martina Rami ◽  
Carmen Haerdner ◽  
Donato Santovito ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Knockout Mice ◽  
Adaptive Immune Response ◽  
Cell Maturation ◽  
Cell Phenotype ◽  
Sequencing Analysis ◽  
Adaptive Immune

Abstract Identifying novel pathways regulating the adaptive immune response in chronic inflammatory diseases such as atherosclerosis is of particular interest in view of developing new therapeutic drugs. Here we report that the lipid receptor GPR55 is highly expressed by splenic B cells and inversely correlates with atheroma plaque size in mice. In human carotid endarterectomy specimen, GPR55 transcript levels were significantly lower in unstable compared to stable carotid plaques. To study the impact of GPR55 deficiency in atherosclerosis, we crossed Gpr55 knockout mice with apolipoprotein E (ApoE) knockout mice and subjected the mice to Western diet for 4 to 16 weeks. Compared to ApoE-/- controls, ApoE-/-Gpr55-/- mice developed larger plaques with increased necrotic core size, associated with elevated circulating and aortic leukocyte counts. Flow cytometry, immunofluorescence and RNA-sequencing analysis of splenic B cells in these mice revealed a hyperactivated B cell phenotype with disturbed plasma cell maturation and immunoglobulin (Ig)G antibody overproduction. The specific contribution of B cell GPR55 in atherosclerosis was further studied in mixed Gpr55-/-/µMT bone marrow chimeras on low density receptor deficiency (Ldlr-/-) background, revealing that B-cell specific depletion of Gpr55 was sufficient to promote plaque development. Conversely, adoptive transfer of wildtype B cells into ApoE-/-Gpr55-/- mice blunted the proatherogenic phenotype. In vitro stimulation of splenocytes with the endogenous GPR55 ligand LPI promoted plasma cell proliferation and enhanced B cell activation marker expression, which was inhibited by the GPR55 antagonist CID16020046. Collectively, these discoveries provide new evidence for GPR55 as key modulator of the adaptive immune response in atherosclerosis. Targeting GPR55 could be useful to limit inflammation and plaque progression in patients suffering from atherosclerosis.

scholarly journals GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

2021 ◽  
Author(s):  
Raquel Guillamat-Prats ◽  
Daniel Hering ◽  
Martina Rami ◽  
Carmen Haerdtner ◽  
Donato Sanovito ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Knockout Mice ◽  
Adaptive Immune Response ◽  
Cell Maturation ◽  
Cell Phenotype ◽  
Sequencing Analysis ◽  
Adaptive Immune

Identifying novel pathways regulating the adaptive immune response in chronic inflammatory diseases such as atherosclerosis is of particular interest in view of developing new therapeutic drugs. Here we report that the lipid receptor GPR55 is highly expressed by splenic B cells and inversely correlates with atheroma plaque size in mice. In human carotid endarterectomy specimen, GPR55 transcript levels were significantly lower in unstable compared to stable carotid plaques. To study the impact of GPR55 deficiency in atherosclerosis, we crossed Gpr55 knockout mice with apolipoprotein E (ApoE) knockout mice and subjected the mice to Western diet for 4 to 16 weeks. Compared to ApoE-/- controls, ApoE-/-Gpr55-/- mice developed larger plaques with increased necrotic core size, associated with elevated circulating and aortic leukocyte counts. Flow cytometry, immunofluorescence and RNA-sequencing analysis of splenic B cells in these mice revealed a hyperactivated B cell phenotype with disturbed plasma cell maturation and immunoglobulin (Ig)G antibody overproduction. The specific contribution of B cell GPR55 in atherosclerosis was further studied in mixed Gpr55-/-/μMT bone marrow chimeras on low density receptor deficiency (Ldlr-/-) background, revealing that B-cell specific depletion of Gpr55 was sufficient to promote plaque development. Conversely, adoptive transfer of wildtype B cells into ApoE-/-Gpr55-/- mice blunted the proatherogenic phenotype. In vitro stimulation of splenocytes with the endogenous GPR55 ligand LPI promoted plasma cell proliferation and enhanced B cell activation marker expression, which was inhibited by the GPR55 antagonist CID16020046. Collectively, these discoveries provide new evidence for GPR55 as key modulator of the adaptive immune response in atherosclerosis. Targeting GPR55 could be useful to limit inflammation and plaque progression in patients suffering from atherosclerosis.

Graphene Oxide Modulates B Cell Surface Phenotype and Impairs Immunoglobulin Secretion in Plasma Cell

2016 ◽  
Vol 16 (4) ◽  
pp. 4205-4215 ◽  
Author(s):  
Shaohai Xu ◽  
Shengmin Xu ◽  
Shaopeng Chen ◽  
Huadong Fan ◽  
Xun Luo ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Graphene Oxide ◽  
Immune System ◽  
Cell Surface ◽  
B Cell ◽  
Plasma Cell ◽  
Adaptive Immune System ◽  
Surface Phenotype ◽  
Adaptive Immune

Since discovery, graphene oxide (GO) has been used in all aspects of human life and revealed promising applications in biomedicine. Nevertheless, the potential risks of GO were always being revealed. Although GO was found to induce immune cell death and innate immune response, little is known regarding its toxicity to the specific adaptive immune system that is crucial for protecting against exotic invasion. The B-cell mediated adaptive immune system, which composed of highly specialized cells (B and plasma cell) and specific immune response (antibody response) is the focus in our present study. Using diverse standard immunological techniques, we found that GO modulated B cell surface phenotype, both costimulatory molecules (CD80, CD86 and especially CD40) and antigen presenting molecules (both classical and nonclassical) under the condition without causing cell death. Meanwhile, the terminal differentiated immunoglobulin (Ig) secreting plasma cell was affected by GO, which displayed a less secretion of Ig and more severe ER stress caused by the retention of the secreted form of Ig in cell compartment. The combined data reveal that GO has a particular adverse effect to B cell and the humoral immunity, directly demonstrating the potential risk of GO to the specific adaptive immunity.

scholarly journals Hypoxia stimulus: An adaptive immune response during dendritic cell maturation

2008 ◽  
Vol 73 (7) ◽  
pp. 816-825 ◽  
Author(s):  
I. Rama ◽  
B. Bruene ◽  
J. Torras ◽  
R. Koehl ◽  
J.M. Cruzado ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Adaptive Immune Response ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Adaptive Immune

scholarly journals Giving blood: a new role for CD40 in tumorigenesis

2006 ◽  
Vol 203 (11) ◽  
pp. 2409-2412 ◽  
Author(s):  
Stephan Bergmann ◽  
Pier Paolo Pandolfi
Keyword(s):  
Immune Response ◽  
Endothelial Cells ◽  
B Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Early Stage ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Novel Therapeutic

CD40 was initially identified as a receptor expressed by B cells that is crucial for inducing an effective adaptive immune response. CD40 was subsequently shown to be expressed by endothelial cells and to promote angiogenesis. New data now show that in tumor-prone transgenic mice, CD40-mediated neovascularization is essential for early stage tumorigenicity. This suggests, at least in this mouse model, that CD40 has an important role in the angiogenic process that is coupled to carcinogenesis, a finding that could lead to novel therapeutic opportunities.

scholarly journals In severe COVID-19, SARS-CoV-2 induces a chronic, TGF-β-dominated adaptive immune response

2020 ◽  
Author(s):  
Marta Ferreira-Gomes ◽  
Andrey Kruglov ◽  
Pawel Durek ◽  
Frederik Heinrich ◽  
Caroline Tizian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
B Cells ◽  
Immune Reaction ◽  
Adaptive Immune Response ◽  
Gene Expression Signature ◽  
Adaptive Immune ◽  
Activated B Cells ◽  
Peripheral B Cells

Here we have analyzed the dynamics of the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, as reflected by activated B cells egressing into the blood, at the single cell level. Early on, before seroconversion in response to SARS-CoV-2 spike protein, activated peripheral B cells displayed a type 1 interferon-induced gene expression signature. After seroconversion, activated B cells lost this signature, expressed IL-21- and TGF-β-induced gene expression signatures, and mostly IgG1 and IgA1. In the sustained immune reaction of the COVID-19 patients, until day 59, activated peripheral B cells shifted to expression of IgA2, reflecting instruction by TGF-β. Despite the continued generation of activated B cells, those cells were not found in the lungs of deceased COVID-19 patients, nor did the IgA2 bind to dominant antigens of SARS-CoV-2. In severe COVID-19, SARS-CoV-2 thus triggers a chronic immune reaction distracted from itself and instructed by TGF-β.

scholarly journals B cells lacking RelB are defective in proliferative responses, but undergo normal B cell maturation to Ig secretion and Ig class switching.

1996 ◽  
Vol 184 (4) ◽  
pp. 1537-1541 ◽  
Author(s):  
C M Snapper ◽  
F R Rosas ◽  
P Zelazowski ◽  
M A Moorman ◽  
M R Kehry ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Knockout Mice ◽  
Cd40 Ligand ◽  
Cell Maturation ◽  
Nf Kappa B ◽  
B Cell Maturation ◽  
Activation Conditions ◽  
Ig Heavy Chain ◽  
Regulatory Sites

A number of distinct functional abnormalities have been observed in B cells derived from p50/ NF-kappa B or c-rel knockout mice. RelB, another member of the NF-kappa B/Rel family of transcription factors, is expressed during the latter stages of B cell maturation and can bind to regulatory sites within the Ig heavy chain locus. Therefore, we tested the ability of B cells from relB knockout mice (relB-/-) to proliferate, undergo maturation to IgM secretion, and switch to the expression of downstream Ig isotypes in response to distinct activators including LPS, anti-CD40 mAb or CD40 ligand, and/or dextran anti-IgD antibodies in combination with various cytokines, including IL-4, IL-5, IFN-gamma, and TGF-beta. B cells lacking RelB showed up to 4-fold reductions in DNA synthesis in response to LPS, CD40, and membrane Ig-dependent activation relative to controls. However, relB-/- B cells were comparable to control B cells in their ability to undergo maturation to IgM secretion and switch to the expression of IgG3, IgG1, IgG2b, IgG2a, IgE, and/or IgA under all activation conditions tested. Thus, RelB, like c-Rel and p50/NF-kappa B, plays a role in B cell proliferation. However, in contrast to c-Rel and p50/ NF-kappa B, it is not critically involved in maturation to Ig secretion or expression of Ig isotypes.

scholarly journals GABP Transcription Factor Is Required for B Lymphocyte Maturation and Plasma Cell Development

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1179-1179
Author(s):  
Zhongfa Yang ◽  
Yu Zhu ◽  
Rachel Gerstein ◽  
Alan G. Rosmarin
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Rectal Prolapse ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Maturation ◽  
B Cell Maturation

Abstract B lymphocytes develop in the bone marrow and later encounter antigen in lymph nodes, where they complete their development as plasma cells or B memory cells. Several key transcription factors have been identified that are required for B cell development, including Pax5, BCL6, C-MYC, and others. GABP is a tetrameric ets transcription factor that includes the DNA-binding GABP alpha protein, and the unrelated protein, GABP beta, which contains multimerization and transcriptional activation domains. GABP plays key roles in cell cycle control and mitochondrial biogenesis. It is also required for lineage specific gene expression, and it was previously shown to control gene expression of the IL-7 receptor and Pax5, both of which are required for lymphocyte development. Disruption of mouse Gabpα caused cell cycle arrest in hematopoietic stem cells (HSC), profound loss of progenitor cells, and aberrant myeloid differentiation. We created a conditional knockout model of Gabpα in B lymphocytes by breeding mice with lox-P flanked Gabpa to mice that bear Cre recombinase knocked into the B-cell specific CD19 locus; the mice also carry the Rosa 26 lox-STOP-lox YFP transgene, which permits identification and isolation of individual Gabpα null cells, based on expression of YFP. Loss of Gabpα was highly lineage specific for B lymphocytes. Gabpa null mice were healthy and vigorous through young adulthood, but some developed rectal prolapse by nine months of age, and necropsy demonstrated thinning of the intestinal wall and loss of Peyer's Patches and other lymphoid tissue. We immunologically characterized mice between 6 and 8 weeks of age, in order to minimize secondary effects of the inflammatory process associated with rectal prolapse. There was no deletion of Gabpα in T lymphocytes, and no discernable effect on T-cell subpopulations. We observed a significant reduction in Gabpα null (YFP+) B cells, in comparison with the Gabpα replete (YFP-) B cells in bone marrow and spleen. Gabpα null cells contributed to the pro-B cell population, but there was a progressively reduced contribution of Gabpα null cells to later stages of B cell maturation. We detected no Gabpα null cells among mature naive IgD+/IgM+ B cells, indicating a profound block in B cell maturation in cells that lack Gabpα. Importantly, no YFP+ CD138+ cells were detected, indicating that Gabpα null cells could not contribute to plasma cell development. We conclude that Gabp is required for full B cell maturation and plasma cell development in mice, and that its deletion is associated with loss of Peyer's Patches and rectal prolapse. GABP was previously shown to regulate expression of IL-7R and Pax5, which are expressed in lymphoid progenitor cells long before activation of CD19 expression. Thus, failure of B cell development and plasma cell formation in this CD19-Cre Gabpα null model is independent of the effect of GABP on those other B cell factors, and indicates a new, critical role for GABP in later stages of B cell and plasma cell development. Although rectal prolapse has been observed in mice with T cell defects, this represents the first demonstration that B cell defects cause such a phenotype. Disclosures Gerstein: Vertex Pharmaceuticals: Other: employer of spouse.

scholarly journals In Vitro Comparison of Different TKI Activity in T-Cell Populations: Selective Sparing of Treg By Nilotinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5774-5774
Author(s):  
Elena Marinelli Busilacchi ◽  
Andrea Costantini ◽  
Nadia Viola ◽  
Benedetta Costantini ◽  
Antonella Poloni ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Population ◽  
Cell Cultures ◽  
Adaptive Immune Response ◽  
Dependent Manner ◽  
Adaptive Immune

Abstract Introduction Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation and is characterized by frequent multi-organ involvement that resembles the autoimmune diseases. Donor-derived CD4+ and CD8+ T lymphocytes have classically been considered to be the main effector cells mediating GVHD pathogenesis. Indeed, removal of T cells from transplant inocula almost completely prevents GVHD developing, at the price of increased incidences of graft rejection and disease recurrence. However recent studies suggest that B cells might also play an important role in the biology of cGVHD. The role of Treg lymphocytes in the pathogenesis of cGVHD is still controversial and the tyrosine kinase inhibitor′s (TKI) role in the modulation of this pathway is not yet fully characterized. In vitro data confirm that TKIs regulates both innate and adaptive immune response by interacting with many cell population such as T-cells, B-cells, dendritic cells, mast cells and macrophages. According to these observations, we investigated the TKI′s immunomodulatory effects (Nilotinib, Dasatinib, Imatinib, Ponatinib) on lymphocyte populations. Materials and Methods Peripheral blood mononuclear cells were isolated by density gradient centrifugation using Ficoll-Biocoll. Cells were cultured in RPMI 1640 at a concentration 1x106 cell/well. Nilotinib, Imatinib, Dasatinib and Ponatinib were added to cell cultures at serial concentration (Imatinib:1μM,10μM,50μM; Nilotinib:0.5μM,2μM,10μM; Dasatinib:50nM,100nM,200nM; Ponatinib:1nM,10nM,50nM,100nM) on the first day. Six-color flow cytometry analysis (Facs Canto II) was performed on the cells harvested after 96 h cultures using conjugated antibodies (CD3,CD4,CD16,CD56,CD3,CD25,CD19,CD45RA,FoxP3,CD127,7-Aminoactinomycin-D), for cell cycle analysis cells were stained with propidium iodide. For cytokine analysis, supernatants were collected and analyzed for cytokines according to the instruction of Bio-Plex Pro Human Cytokine 17-plex Assay with Bio-Plex (Bio-Rad). Results A significant decrease of cytotoxic T cells viability was observed when cells were cultured in presence of Imatinib (50μM,p<0.01), Ponatinib (10nM,p<0.05) and Dasatinib (100nM,p<0.01). On the contrary, exposure to Nilotinib didn′t induce cell death. Increasing concentrations of all the tested TKI significantly inhibited T cell proliferation in a dose-dependent manner; the effect become statistically significant starting from Imatinib (1μM,p<0.05), Dasatinib (50nM,p<0.01), Ponatinib (50nM,p<0.01) and Nilotinib (0.5μM,p<0.01). Exposure to Imatinib, Dasatinib and Ponatinib induced a statistically significant decrease (p<0.01) of Treg cells proportion, even at the lowest drug concentration in culture; Nilotinib induced Treg decrease only at concentrations exceeding 2μM (p<0.01), higher than those usually achieved in clinical practice. A significant increase of naive Treg apoptosis was observed after exposure to Dasatinib (50nmM,p<0.01), Ponatinib (50nM,p<0.01) and Imatinib (50μM,p<0.01); exposure to Nilotinib has no effect on this population. Both Nilotinib and Dasatinib induced a profound inhibition of pro-inflammatory cytokine production (in particular TNFα, IFNγ, IL13 and IL17) when added to the cell cultures (p<0.05); slower decrease in supernatant cytokine concentration was observed in presence of either Imatinib (50μM,p<0.05) and Ponatinib (50nM,p<0.05). Increasing concentrations of all TKIs except Nilotinib induced a significant decline of NK cells (p<0.01) and B cell (p<0.01). Conclusion The present study focuses the peculiar Nilotinib activity on lymphocyte′s regulation: this TKI, at therapeutic concentrations in vitro, interact with innate and adaptive immune response show anti-inflammatory properties. Unlike other TKIs, Nilotinib determine inflammatory cytokines reduction, preserving T cell population and Treg. These data support the potential use of Nilotinib in cGVHD Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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