301 Increased population of myeloid dendritic cells and upregulated gene expression of TNF α is associated with poor response to hydroxychloroquine In cutaneous lupus

ABSTRACT Dendritic cells (DCs) respond to microbial infections by undergoing phenotypic maturation and by producing multiple cytokines. In the present study, we analyzed the ability of influenza A and Sendai viruses to induce DC maturation and activate tumor necrosis factor alpha (TNF-α), alpha/beta interferon (IFN-α/β), and IFN-like interleukin-28A/B (IFN-λ2/3) and IL-29 (IFN-λ1) gene expression in human monocyte-derived myeloid DCs (mDC). The ability of influenza A virus to induce mDC maturation or enhance the expression of TNF-α, IFN-α/β, interleukin-28 (IL-28), and IL-29 genes was limited, whereas Sendai virus efficiently induced mDC maturation and enhanced cytokine gene expression. Influenza A virus-induced expression of TNF-α, IFN-α, IFN-β, IL-28, and IL-29 genes was, however, dramatically enhanced when cells were pretreated with IFN-α. IFN-α priming led to increased expression of Toll-like receptor 3 (TLR3), TLR7, TLR8, MyD88, TRIF, and IFN regulatory factor 7 (IRF7) genes and enhanced influenza-induced phosphorylation and DNA binding of IRF3. Influenza A virus also enhanced the binding of NF-κB to the respective NF-κB elements of the promoters of IFN-β and IL-29 genes. In mDC IL-29 induced MxA protein expression and possessed antiviral activity against influenza A virus, although this activity was lower than that of IFN-α or IFN-β. Our results show that in human mDCs viruses can readily induce the expression of IL-28 and IL-29 genes whose gene products are likely to contribute to the host antiviral response.

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Involvement of Myeloid Dendritic Cells in the Development of Gastric Secondary Lymphoid Follicles in Helicobacter pylori-Infected Neonatally Thymectomized BALB/c Mice

Infection and Immunity ◽

10.1128/iai.71.4.2153-2162.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 2153-2162 ◽

Cited By ~ 44

Author(s):

Toshiki Nishi ◽

Kazuichi Okazaki ◽

Kimio Kawasaki ◽

Toshiro Fukui ◽

Hiroyuki Tamaki ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Dendritic Cells ◽

Epithelial Cells ◽

Lamina Propria ◽

Myeloid Dendritic Cells ◽

Lymphoid Follicles ◽

Inflammatory Protein ◽

H Pylori ◽

Antigen Presenting

ABSTRACT We previously described an animal model of Helicobacter pylori-induced follicular gastritis in neonatally thymectomized (nTx) mice. However, it is still not clear whether antigen-presenting dendritic cells (DCs) in the stomach have a role in the development of secondary follicles in H. pylori-infected nTx mice. We investigated the distribution of DC subsets using this model and examined their roles. To identify lymphoid and myeloid DCs, sections were stained with anti-CD11c (pan-DC marker) in combination with anti-CD8α (lymphoid DC marker) or anti-CD11b (myeloid DC marker) and were examined with a confocal microscope. Expression of macrophage inflammatory protein 3α (MIP-3α), which chemoattracts immature DCs, was analyzed by real-time PCR and immunohistochemistry. Follicular dendritic cells (FDCs) were stained with anti-SKY28 antibodies. In noninfected nTx mice, a few myeloid and lymphoid DCs were observed in the bottom portion of the lamina propria, whereas in H. pylori-infected nTx mice, there was an increased influx of myeloid DCs throughout the lamina propria. FDC staining was also observed in the stomachs of members of the infected group. MIP-3α gene expression was upregulated in the infected nTx group, and the immunohistochemistry analysis revealed MIP-3α-positive epithelial cells. These data suggest that H. pylori infection upregulates MIP-3α gene expression in gastric epithelial cells and induces an influx of myeloid DCs in the lamina propria of the gastric mucosa in nTx mice. Myeloid DCs and FDCs might contribute to the development of gastric secondary lymphoid follicles in H. pylori-infected nTx mice.

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Dendritic Cells Pulsed with Intact Streptococcus pneumoniae Elicit both Protein- and Polysaccharide-specific Immunoglobulin Isotype Responses In Vivo through Distinct Mechanisms

Journal of Experimental Medicine ◽

10.1084/jem.20011432 ◽

2001 ◽

Vol 195 (1) ◽

pp. 1-14 ◽

Cited By ~ 98

Author(s):

Jesus Colino ◽

Yi Shen ◽

Clifford M. Snapper

Keyword(s):

Dendritic Cells ◽

Streptococcus Pneumoniae ◽

Myeloid Dendritic Cells ◽

Bacterial Proteins ◽

Histocompatibility Complex ◽

Tnf Α ◽

Necrosis Factor ◽

Igg1 Isotype

Immature bone marrow–derived myeloid dendritic cells (BMDCs) are induced to undergo phenotypic maturation and secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, and IL-10 when pulsed in vitro with intact Streptococcus pneumoniae. After transfer to naive mice, pulsed BMDCs induce immunoglobulin (Ig) isotype responses specific for both protein and polysaccharide pneumococcal antigens, having in common the requirement for viable BMDCs, T cells, and B7-dependent costimulation in the recipient mice. Whereas primary Ig isotype responses to bacterial proteins uniformly require BMDC expression of major histocompatibility complex class II, CD40, and B7, and the secretion of IL-6, but not IL-12, similar requirements for antipolysaccharide Ig responses were only observed for the IgG1 isotype.

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Polymorphisms in the Interleukin 4, Interleukin 13, and Corresponding Receptor Genes Are Not Associated with Systemic Sclerosis and Do Not Influence Gene Expression

The Journal of Rheumatology ◽

10.3899/jrheum.110235 ◽

2011 ◽

Vol 39 (1) ◽

pp. 112-118 ◽

Cited By ~ 8

Author(s):

JASPER C.A. BROEN ◽

PHILLIPE DIEUDE ◽

MADELON C. VONK ◽

LORENZO BERETTA ◽

FRANCISCO D. CARMONA ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Systemic Sclerosis ◽

Peripheral Blood ◽

Pulmonary Complications ◽

Interleukin 4 ◽

Nucleotide Polymorphisms ◽

Myeloid Dendritic Cells ◽

Blood Leukocytes ◽

Interleukin 13

Objective.Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes.Methods.We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France. Taqman assays were used to genotype single-nucleotide polymorphisms (SNP) in the following genes: (1) IL4 (−590C>T/rs2243250); (2) IL4 receptor alpha (IL4RA) (Q576R/rs1801275); (3) IL13 (R130Q/rs20541 and −1112C>T/rs1800925); and (4) IL13RA1 (43163G>A/rs6646259). The effect of these polymorphisms on expression of the corresponding genes was assessed using quantitative RT-PCR on RNA derived from peripheral blood B cells, T cells, plasmacytoid dendritic cells, monocytes, and myeloid dendritic cells. We investigated whether these polymorphisms influenced development of pulmonary complications over 15 years in patients with SSc.Results.None of the investigated polymorphisms was associated with SSc or any SSc clinical subtype. We did not observe any effect on transcript levels in the cell subtypes or on development of pulmonary complications.Conclusion.Our data showed that polymorphisms in IL4, IL13, and their receptors do not play a role in SSc and do not influence the expression of their corresponding transcript in peripheral blood cells.

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Ly49Q defines 2 pDC subsets in mice

Blood ◽

10.1182/blood-2004-09-3388 ◽

2005 ◽

Vol 105 (7) ◽

pp. 2787-2792 ◽

Cited By ~ 59

Author(s):

Yumiko Kamogawa-Schifter ◽

Jun Ohkawa ◽

Sahori Namiki ◽

Naoko Arai ◽

Ken-ichi Arai ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Specific Marker ◽

Primary Role ◽

Myeloid Dendritic Cells ◽

Tnf Α ◽

Simplex Virus ◽

Factor Α ◽

Antiviral Innate Immunity

AbstractPlasmacytoid dendritic cells (pDCs) play an important primary role for antiviral innate immunity by rapidly producing large amounts of type 1 interferon (IFN) upon viral infection. To study pDC biology, we generated a monoclonal antibody, termed 2E6, that recognizes pDCs. Molecular cloning of a cDNA encoding the 2E6 antigen revealed that it is a type II C-type lectin, Ly49Q, that consists of 247 amino acids with high homology to the natural killer (NK) receptor family Ly49, with an immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic domain. Ly49Q is expressed on pDCs but not on NK cells or myeloid dendritic cells. B220+, CD11c+, CD11b– pDCs in bone marrow were divided into Ly49Q+ and Ly49Q– subsets. While both subsets produced IFN-α upon cytosine-phosphate-guanosine (CpG) and herpes simplex virus stimulation, Ly49Q– pDCs responded poorly to influenza virus. In addition, Ly49Q– pDCs produced inflammatory cytokines such as interleukin 6 (IL-6), IL-12, and tumor necrosis factor α (TNF-α) upon stimulation at lower levels than those produced by Ly49Q+ pDCs. In contrast to bone marrow, Ly49Q+ pDCs were only found in peripheral blood, lymph nodes, and spleen. These results indicate that Ly49Q is a specific marker for peripheral pDCs and that expression of Ly49Q defines 2 subsets of pDCs in bone marrow.

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Anti-inflammatory effects ofSaccharomyces boulardiimediated by myeloid dendritic cells from patients with Crohn's disease and ulcerative colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00217.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. G1083-G1092 ◽

Cited By ~ 22

Author(s):

Saskia Thomas ◽

Diana Metzke ◽

Jürgen Schmitz ◽

Yvonne Dörffel ◽

Daniel C. Baumgart

Keyword(s):

Ulcerative Colitis ◽

Dendritic Cells ◽

Crohn’S Disease ◽

T Cell ◽

Crohn's Disease ◽

Transforming Growth Factor ◽

Mucosal Healing ◽

Cell Phenotype ◽

Myeloid Dendritic Cells ◽

Tnf Α

Saccharomyces boulardii ( Sb) is a probiotic yeast that has demonstrated efficacy in pilot studies in patients with inflammatory bowel disease (IBD). Microbial antigen handling by dendritic cells (DC) is believed to be of critical importance for immunity and tolerance in IBD. The aim was to characterize the effects of Sb on DC from IBD patients. Highly purified (>95%), lipopolysaccharide-stimulated CD1c+CD11c+CD123−myeloid DC (mDC) from patients with ulcerative colitis (UC; n = 36), Crohn's disease (CD; n = 26), or infectious controls (IC; n = 4) were cultured in the presence or absence of fungal supernatant from Sb ( SbS). Phenotype and cytokine production and/or secretion of IBD mDC were measured by flow cytometry and cytometric bead arrays, respectively. T cell phenotype and proliferation were assessed in a mixed lymphocyte reaction (MLR) with allogenic CD4+CD45RA+naïve T cells from healthy donors. Mucosal healing was investigated in epithelial wounding and migration assays with IEC-6 cells. SbS significantly decreased the frequency of CD40-, CD80-, and CD197 (CCR7; chemokine receptor-7)-expressing IBD mDC and reduced their secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-6 while increasing IL-8. In the MLR, SbS significantly inhibited T cell proliferation induced by IBD mDC. Moreover, SbS inhibited TH1 (TNF-α and interferon-γ) polarization induced by UC mDC and promoted IL-8 and transforming growth factor-β-dependent mucosal healing. In summary, we provide novel evidence of synergistic mechanisms how Sb controls inflammation (inhibition of T cell costimulation and inflammation-associated migration and mobilization of DC) and promotes epithelial restitution relevant in IBD.

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Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation

Blood ◽

10.1182/blood.v98.5.1512 ◽

2001 ◽

Vol 98 (5) ◽

pp. 1512-1523 ◽

Cited By ~ 172

Author(s):

Adrian E. Morelli ◽

Alan F. Zahorchak ◽

Adriana T. Larregina ◽

Bridget L. Colvin ◽

Alison J. Logar ◽

...

Keyword(s):

Dendritic Cells ◽

Transforming Growth Factor ◽

De Novo ◽

Transforming Growth Factor Β1 ◽

Th2 Cells ◽

Myeloid Dendritic Cells ◽

Cd40 Ligation ◽

Murine Bone Marrow ◽

Protein Levels ◽

Tnf Α

Although it is known that dendritic cells (DCs) produce cytokines, there is little information about how cytokine synthesis is regulated during DC development. A range of cytokine mRNA/proteins was analyzed in immature (CD86−) or mature (CD86+) murine bone marrow (BM)- derived DCs. Highly purified, flow-sorted, immature DCs exhibited higher amounts of interleukin-1α (IL-1α), IL-1β, tumor necrosis factor-α (TNF-α), transforming growth factor β1 (TGF-β1), and macrophage migration inhibitory factor (MIF) mRNA/protein than mature DCs. After differentiation, DC up-regulated the levels of IL-6 and IL-15 mRNA/protein and synthesized de novo mRNA/protein for IL-12p35, IL-12p40, and IL-18. Although immature BM-derived DCs did not stimulate naive allogeneic T cells, mature DCs elicited a mixed population of T helper (Th) 1 (mainly) and Th2 cells in 3d-mixed leukocyte reactions. CD86+ BM DCs switched to different cytokine patterns according to whether they were terminally differentiated by lipopolysaccharide (LPS) or CD40 ligation. Although both stimuli increased IL-6, IL-12p40, IL-15, and TNF-α mRNA/protein levels, only LPS up-regulated transcription of IL-1α, IL-1β, IL-12p35, and MIF genes. Although LPS and CD40 cross-linking increased the T-cell allostimulatory function of BM DCs, only LPS stimulation shifted the balance of naive Th differentiation to Th1 cells, a mechanism dependent on the up-regulation of IL-12p35 and not of IL-23. These results demonstrate that, depending on the stimuli used to terminally mature BM DCs, DCs synthesize a different pattern of cytokines and exhibit distinct Th cell–driving potential.

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