Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Nature ◽  
2002 ◽  
Vol 416 (6881) ◽  
pp. 603-607 ◽  
Author(s):  
Elizabeth A. Leadbetter ◽  
Ian R. Rifkin ◽  
Andreas M. Hohlbaum ◽  
Britte C. Beaudette ◽  
Mark J. Shlomchik ◽  
...  
Keyword(s):  
B Cells ◽  
Toll Like Receptors

Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms

2020 ◽  
Author(s):  
Tin Kyaw ◽  
Paula Loveland ◽  
Peter Kanellakis ◽  
Anh Cao ◽  
Axel Kallies ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
B Cells ◽  
B Cell ◽  
Immunoglobulin G ◽  
Cardiovascular Events ◽  
Cell Activation ◽  
Plasma Cells ◽  
B Cell Activation ◽  
Toll Like Receptors ◽  
Accelerated Atherosclerosis

Abstract Aims  Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. Methods and results  We used an apolipoprotein-E-deficient (ApoE−/−) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE−/− mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. Conclusion  Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4500-4504 ◽  
Author(s):  
Nadia L. Bernasconi ◽  
Nobuyuki Onai ◽  
Antonio Lanzavecchia
Keyword(s):  
B Cells ◽  
B Cell ◽  
Constitutive Expression ◽  
Human Memory ◽  
Cell Receptor ◽  
Primary Response ◽  
Memory B Cells ◽  
Toll Like Receptors ◽  
Polyclonal Activation ◽  
B Cell Subsets

Abstract Toll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity. In this study we investigated the expression of 10 TLRs in human naive and memory B-cell subsets. We report that in human naive B cells most TLRs are expressed at low to undetectable levels, but the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. The differential expression of TLR9 correlates with responsiveness to its agonist, CpG DNA. Thus, human memory B cells proliferate and differentiate to immunoglobulin (Ig)–secreting cells in response to CpG, while naive B do so only if simultaneously triggered through the BCR. The BCR-induced expression of TLRs in human naive B cells prevents polyclonal activation in a primary response, because it restricts stimulation to antigen-specific B cells. In contrast, the constitutive expression of TLRs in memory B cells allows polyclonal activation of the entire memory pool. Thus, in human B cells TLRs are downstream of BCR and play a role both in the primary response and in the memory phase.

scholarly journals Role of Intestinal Epithelial Cells in Immune Effects Mediated by Gram-Positive Probiotic Bacteria: Involvement of Toll-Like Receptors

2005 ◽  
Vol 12 (9) ◽  
pp. 1075-1084 ◽  
Author(s):  
Gabriel Vinderola ◽  
Chantal Matar ◽  
Gabriela Perdigon
Keyword(s):  
Small Intestine ◽  
B Cells ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Primary Cultures ◽  
Clonal Expansion ◽  
Probiotic Bacteria ◽  
Intestinal Epithelial ◽  
Toll Like Receptors

ABSTRACT The mechanisms by which probiotic bacteria exert their effects on the immune system are not completely understood, but the epithelium may be a crucial player in the orchestration of the effects induced. In a previous work, we observed that some orally administered strains of lactic acid bacteria (LAB) increased the number of immunoglobulin A (IgA)-producing cells in the small intestine without a concomitant increase in the CD4+ T-cell population, indicating that some LAB strains induce clonal expansion only of B cells triggered to produce IgA. The present work aimed to study the cytokines induced by the interaction of probiotic LAB with murine intestinal epithelial cells (IEC) in healthy animals. We focused our investigation mainly on the secretion of interleukin 6 (IL-6) necessary for the clonal expansion of B cells previously observed with probiotic bacteria. The role of Toll-like receptors (TLRs) in such interaction was also addressed. The cytokines released by primary cultures of IEC in animals fed with Lactobacillus casei CRL 431 or Lactobacillus helveticus R389 were determined. Cytokines were also determined in the supernatants of primary cultures of IEC of unfed animals challenged with different concentrations of viable or nonviable lactobacilli and Escherichia coli, previously blocked or not with anti-TLR2 and anti-TLR4. We concluded that the small intestine is the place where a major distinction would occur between probiotic LAB and pathogens. This distinction comprises the type of cytokines released and the magnitude of the response, cutting across the line that separates IL-6 necessary for B-cell differentiation, which was the case with probiotic lactobacilli, from inflammatory levels of IL-6 for pathogens.

scholarly journals Toll-like receptors: lessons to learn from normal and malignant human B cells

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2205-2213 ◽  
Author(s):  
David Chiron ◽  
Isabelle Bekeredjian-Ding ◽  
Catherine Pellat-Deceunynck ◽  
Régis Bataille ◽  
Gaëtan Jego
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lineage ◽  
Hematologic Malignancies ◽  
Toll Like Receptors ◽  
Chronic Infections ◽  
Humoral Immune ◽  
Human B Cells ◽  
Exact Function ◽  
And Function

Abstract The humoral immune system senses microbes via recognition of specific microbial molecular motifs by Toll-like receptors (TLRs). These encounters promote plasma cell differentiation and antibody production. Recent studies have demonstrated the importance of the TLR system in enhancing antibody-mediated defense against infections and maintaining memory B cells. These results have led the way to the design of vaccines that target B cells by engaging TLRs. In hematologic malignancies, cells often retain B cell–specific receptors and associated functions. Among these, TLRs are currently exploited to target different subclasses of B-cell leukemia, and TLR agonists are currently being evaluated in clinical trials. However, accumulating evidence suggests that endogenous TLR ligands or chronic infections promote tumor growth, thus providing a need for further investigations to decipher the exact function of TLRs in the B-cell lineage and in neoplastic B cells. The aim of this review is to present and discuss the latest advances with regard to the expression and function of TLRs in both healthy and malignant B cells. Special attention will be focused on the growth-promoting effects of TLR ligands on leukemic B cells and their potential clinical impact.

Expression of Toll-like Receptors and Their Signaling Pathways in Rheumatoid Synovitis

2011 ◽  
Vol 38 (5) ◽  
pp. 810-820 ◽  
Author(s):  
YASUNOBU TAMAKI ◽  
YUYA TAKAKUBO ◽  
TOMOYUKI HIRAYAMA ◽  
YRJÖ T. KONTTINEN ◽  
STUART B. GOODMAN ◽  
...  
Keyword(s):  
B Cells ◽  
Messenger Rna ◽  
Inflammatory Cells ◽  
Type A ◽  
Primary Response ◽  
Type B ◽  
Toll Like Receptors ◽  
Tir Domain ◽  
Cellular Markers ◽  
Molecular Patterns

Objective.Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters.Methods.TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining.Results.In RA, ß-actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells.Conclusion.RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.

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