CpG DNA and LPS induce distinct patterns of activation in human monocytes

Hartmann, Gunther; Krieg, Arthur Μ.

doi:10.1038/sj.gt.3300880

Cited by 178 publications

(111 citation statements)

References 51 publications

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“…In contrast to TLR2, TLR4, TLR6, and TLR7/8 ligands, the TLR9 ligand CpG ODN 2006 was weak at inducing TNF-␣ in PBMC (Fig. 1B) as previously described (38).…”

Section: Peripheral Blood B Cells Show Strong Polyclonal Proliferatiomentioning

confidence: 99%

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

Berkeredjian-Ding

Wagner

Hornung

et al. 2005

The Journal of Immunology

301

215

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Detailed information of human B cell activation via TLR may lead to a better understanding of B cell involvement in autoimmunity and malignancy. In this study we identified a fundamental difference in the regulation of TLR7- and TLR9-mediated B cell stimulation: whereas the induction of polyclonal naive B cell proliferation by the TLR7 ligands resiquimod (R848) and loxoribine required the presence of plasmacytoid dendritic cells (PDCs), activation via the TLR9 ligand CpG was independent of PDCs. We found that PDC-derived type I IFN enhanced TLR7 sensitivity of B cells by selectively up-regulating TLR7 expression. In contrast the expression levels of TLR9 and of other TLRs studied remained unchanged. In the presence of type I IFN, TLR7 ligation triggered polyclonal B cell expansion and B cell differentiation toward Ig-producing plasma cells; notably, this occurred independently of T cell help and B cell Ag. Human B cells did not respond to ligands of other TLRs including TLR2, TLR4 and TLR6 with and without type I IFN. In conclusion, our results reveal a distinct regulation of TLR7 and TLR9 function in human B cells and highlight TLR7 and TLR9 as unique targets for therapeutic intervention in B cell-mediated immunity and disease.

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“…In contrast to TLR2, TLR4, TLR6, and TLR7/8 ligands, the TLR9 ligand CpG ODN 2006 was weak at inducing TNF-␣ in PBMC (Fig. 1B) as previously described (38).…”

Section: Peripheral Blood B Cells Show Strong Polyclonal Proliferatiomentioning

confidence: 99%

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

Berkeredjian-Ding

Wagner

Hornung

et al. 2005

The Journal of Immunology

301

215

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“…9,10 Unmethylated CpG motifs, characteristic of bacterial DNA, are detected by TLR9 and many recent studies have focused on CpG oligodeoxynucleotides and their role as stimulators of immune cells. [11][12][13][14][15][16][17][18][19][20][21][22][23][24] These pathogen-associated molecular patterns (PAMPs) serve as effective signals of bacterial invasion and trigger the ensuing immune response. Engagement of the TLRs by their respective ligands triggers a multifaceted response involving antigen presentation, cell surface expression of costimulatory molecules, and synthesis and release of cytokines, which in turn stimulates specific adaptive responses involving T and B lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells

Bourke

Bosisio

Golay

et al. 2003

Blood

347

273

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“…We recently demonstrated that CpG DNA induces activation of human monocytes (31) and dendritic cells (32), effects which are distinct from LPS-mediated effects. The goal of the present study is to systematically search for an optimal human CpG motif, to determine its functional effects on human B cells, and to elucidate its molecular mechanism of action.…”

mentioning

confidence: 99%

Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

Hartmann

Krieg

2000

The Journal of Immunology

544

456

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The vertebrate immune system recognizes bacterial DNA based on the presence of unmethylated CpG-dinucleotides in particular base contexts (“CpG motifs”). In contrast to mice, knowledge about CpG-mediated effects on human B cells is poor. In the present study we identify and determine an optimal human CpG motif. A phosphodiester oligonucleotide containing this motif strongly stimulated CD86, CD40, CD54, and MHC class II expression, IL-6 synthesis, and proliferation of primary human B cells. These effects required internalization of the oligonucleotide and endosomal maturation. The molecular mechanism of action of this CpG motif was associated with the sustained induction of the NF-κB p50/p65 heterodimer and of the transcription-factor complex AP-1. Transcription-factor activation by CpG DNA was preceded by increased phosphorylation of the stress kinases c-Jun N-terminal kinase and p38, and of activating transcription factor-2. In contrast to CpG, signaling through the B cell receptor led to activation of extracellular receptor kinase and to phosphorylation of a different isoform of c-Jun N-terminal kinase. These studies define the structure of a highly active human CpG motif and characterize its molecular mechanism of action in primary human B cells.

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CpG DNA and LPS induce distinct patterns of activation in human monocytes

Cited by 178 publications

References 51 publications

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells

Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

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