scholarly journals The histone methyltransferase DOT1L is essential for humoral immune responses

2019 ◽  
Author(s):  
Liam Kealy ◽  
Andrea Di Pietro ◽  
Lauren Hailes ◽  
Sebastian Scheer ◽  
Lennard Dalit ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Biology ◽  
Influenza Infection ◽  
Humoral Response ◽  
Histone Methyltransferase ◽  
B Cell Differentiation ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Histone Modifiers

SUMMARYHistone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1lf/fMb1Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection of Dot1lf/fCd23Cre/+ mice, germinal centers failed to form and class-switched antibody-secreting cells were significantly attenuated. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.

scholarly journals BAFF Inhibition Effectively Suppresses the Development of Anti-HLA.A2 Antibody in the Highly Sensitized Mouse Model

2021 ◽  
Vol 22 (2) ◽  
pp. 861
Author(s):  
Ji Won Min ◽  
Yoo-Jin Shin ◽  
Hyeyoung Lee ◽  
Bo-Mi Kim ◽  
Ki Hyun Park ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Control Group ◽  
B Cell Differentiation ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Skin Allografts ◽  
Significant Difference ◽  
Desensitization Therapy

B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (Δ-13.62 vs. Δ27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (≤2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.

scholarly journals B-Cell Gene Expression and Microbiota Prior Immunization Profile Vaccine Humoral Responsiveness

2020 ◽  
Author(s):  
Elena Gonçalves ◽  
Yolanda Guillén ◽  
Javier R Lama ◽  
Jorge Sanchez ◽  
Christian Brander ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
B Cell Differentiation ◽  
Degree Of Protection ◽  
Randomized Clinical Study ◽  
Cell Gene Expression ◽  
New Biomarkers ◽  
Blood Transcriptome

Abstract Background: The identification of new biomarkers is essential to making it possible to predict the degree of protection following vaccination. Very few human studies have focused on baseline characteristics including microbiota and gene expression to underlie vaccine immune responsiveness. We investigated the host whole-blood transcriptome and microbiome before vaccination, to assess the likelihood of their involvement in an effective MVA-neutralizing antibody response (MVA-Nab) two months later. Results: We based our analyses on data obtained ­from a randomized clinical study in which participants (n=10) were vaccinated with the MVA-HIV clade B vaccine (MVA-B). Samples were collected at 2-time points prior vaccination (week-2, w0) to study blood transcriptome. Skin wrap (site of vaccination) and stool microbiota were analysed for diversity and abundance (16S rRNAseq). MVA-neutralizing antibody responses were measured at week 8. The levels of MVA-Nab responses were positively correlated with an abundance of Eubacterium in stool and Prevotella in skin. The simultaneous investigation of blood transcriptome and host microbiota before vaccination showed that genus diversity and bacterial abundance at that time correlated significantly with the expression of genes involved in B cell development stages. The combination of gene expression and microbiota makes it possible to forecast strong responders to MVA-B vaccination.Conclusion: To our knowledge, this is the first study integrating host blood gene expression and microbiota before vaccination to predict the intensity of humoral response months later. The genes identified are involved in B cell differentiation might open an avenue of research in this field to optimize vaccination strategies.

scholarly journals Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

2012 ◽  
Vol 109 (40) ◽  
pp. E2699-E2706 ◽  
Author(s):  
R. Ouchida ◽  
H. Mori ◽  
K. Hase ◽  
H. Takatsu ◽  
T. Kurosaki ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Cell Survival ◽  
Critical Role ◽  
Fc Receptor ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
B Cell Survival

scholarly journals Cutting Edge: Polycomb Gene Expression Patterns Reflect Distinct B Cell Differentiation Stages in Human Germinal Centers

2000 ◽  
Vol 164 (1) ◽  
pp. 1-4 ◽  
Author(s):  
Frank M. Raaphorst ◽  
Folkert J. van Kemenade ◽  
Elly Fieret ◽  
Karien M. Hamer ◽  
David P. E. Satijn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
B Cell ◽  
Expression Patterns ◽  
Germinal Centers ◽  
Cutting Edge ◽  
Gene Expression Patterns ◽  
B Cell Differentiation

scholarly journals mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralization of P.1 Brazilian variant

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Helen Parry ◽  
Gokhan Tut ◽  
Rachel Bruton ◽  
Sian Faustini ◽  
Christine Stephens ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cellular Response ◽  
Humoral Response ◽  
Antibody Responses ◽  
Vaccine Platform ◽  
Humoral Immune ◽  
Vaccine Responses ◽  
Cellular Immune Responses ◽  
Humoral Immune Responses ◽  
Cellular Immune

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80–96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.

scholarly journals A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum

2019 ◽  
Author(s):  
Amanda Chan ◽  
Alexis Dziedziech ◽  
Laura A Kirkman ◽  
Kirk W Deitsch ◽  
Johan Ankarklev
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Anion Channel ◽  
Histone Methyltransferase ◽  
Drug Uptake ◽  
Natural Setting ◽  
Membrane Expression ◽  
Acquired Drug Resistance ◽  
Histone Modifiers

AbstractMalaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.ImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.

scholarly journals Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhang Jiang ◽  
Cuifeng Li ◽  
Qian Wu ◽  
Peng An ◽  
Laiquan Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Immune Responses ◽  
B Cell ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Histone 3

scholarly journals TRAF6 Is Required for Generation of the B-1a B Cell Compartment as well as T Cell-Dependent and -Independent Humoral Immune Responses

PLoS ONE ◽  
2009 ◽  
Vol 4 (3) ◽  
pp. e4736 ◽  
Author(s):  
Takashi Kobayashi ◽  
Tae Soo Kim ◽  
Anand Jacob ◽  
Matthew C. Walsh ◽  
Yuho Kadono ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Cell Compartment ◽  
Humoral Immune ◽  
Humoral Immune Responses
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