U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3229-3234 ◽  
Author(s):  
Emina Savarese ◽  
Ohk-wha Chae ◽  
Simon Trowitzsch ◽  
Gert Weber ◽  
Berthold Kastner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Immune Complexes ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Dependent Manner ◽  
Stem Loop ◽  
Murine Bone Marrow ◽  
Small Nuclear Ribonucleoprotein ◽  
Nuclear Antigens

Abstract Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.

Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes

2015 ◽  
Vol 75 (9) ◽  
pp. 1728-1734 ◽  
Author(s):  
Dag Leonard ◽  
Maija-Leena Eloranta ◽  
Niklas Hagberg ◽  
Olof Berggren ◽  
Karolina Tandre ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Complexes ◽  
Serum Levels ◽  
Plasmacytoid Dendritic Cells ◽  
Interferon Α ◽  
Type I ◽  
Activated T Cells ◽  
Gm Csf

ObjectivesPatients with systemic lupus erythematosus (SLE) have an ongoing interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs). We investigated whether T cells can promote IFN-α production by pDCs.MethodsHuman pDCs were stimulated with immune complexes (ICs) containing U1 small nuclear ribonucleic proteins particles and SLE-IgG (RNA-IC) in the presence of T cells or T cell supernatants. T cells were activated by anti-CD3/CD28 antibodies or in a mixed leucocyte reaction. IFN-α and other cytokines were determined in culture supernatants or patient sera with immunoassays. The effect of interleukin (IL) 3 and granulocyte-macrophage-colony-stimulating factor (GM-CSF) on pDCs was examined by the use of antibodies, and the expression of CD80/CD86 was determined using flow cytometry.ResultsActivated T cells and supernatants from activated T cells increased IFN-α production by >20-fold. The stimulatory effect of T cell supernatants was reduced after depletion of GM-CSF (81%) or by blocking the GM-CSF receptor (55%–81%). Supernatant from activated T cells, furthermore, increased the frequency of CD80 and CD86 expressing pDCs stimulated with RNA-IC from 6% to 35% (p<0.05) and from 10% to 26% (p<0.01), respectively. Activated SLE T cells enhanced IFN-α production to the same extent as T cells from healthy individuals and a subset of patients with SLE had increased serum levels of GM-CSF.ConclusionsActivated T cells enhance IFN-α production by RNA-IC stimulated pDCs via GM-CSF and induce pDC maturation. Given the increased serum levels of GM-CSF in a subset of patients with SLE, these findings suggest that activated T cells may upregulate type I IFN production in SLE.

scholarly journals Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Autoimmune Disorders ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. Results We found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

scholarly journals Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine–Based Inhibitory Motif–Dependent Manner

2013 ◽  
Vol 190 (8) ◽  
pp. 3994-4004 ◽  
Author(s):  
Mir Munir A. Rahim ◽  
Lee-Hwa Tai ◽  
Angela D. Troke ◽  
Ahmad Bakur Mahmoud ◽  
Elias Abou-Samra ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn

scholarly journals Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

2020 ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Autoimmune Disorders ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.Results We found that treatment with 1-10 mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

scholarly journals Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells

2003 ◽  
Vol 198 (3) ◽  
pp. 513-520 ◽  
Author(s):  
Jennifer Lund ◽  
Ayuko Sato ◽  
Shizuo Akira ◽  
Ruslan Medzhitov ◽  
Akiko Iwasaki
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Plasmacytoid Dendritic Cells ◽  
Endocytic Pathway ◽  
Type I ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

Plasmacytoid dendritic cells (pDCs) have been identified as a potent secretor of the type I interferons (IFNs) in response to CpG as well as several viruses. In this study, we examined the molecular mechanism of virus recognition by pDCs. First, we demonstrated that the CD11c+Gr-1intB220+ pDCs from mouse bone marrow secreted high levels of IFN-α in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN-α secretion by pDCs required the expression of the adaptor molecule MyD88, suggesting the involvement of a Toll-like receptor (TLR) in HSV-2 recognition. To test whether a TLR mediates HSV-2–induced IFN-α secretion from pDCs, various knockout mice were examined. These experiments revealed a clear requirement for TLR9 in this process. Further, we demonstrated that purified HSV-2 DNA can trigger IFN-α secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN-α secretion by pDCs in a dose-dependent manner. The recognition of HSV-2 by TLR9 was mediated through an endocytic pathway that was inhibited by chloroquine or bafilomycin A1. The strict requirement for TLR9 in IFN-α secretion was further confirmed by the inoculation of HSV-2 in vivo. Therefore, these results demonstrate a novel mechanism whereby the genomic DNA of a virus can engage TLR9 and result in the secretion of IFN-α by pDCs.

scholarly journals Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Antonios Psarras ◽  
Adewonuola Alase ◽  
Agne Antanaviciute ◽  
Ian M. Carr ◽  
Md Yuzaiful Md Yusof ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I Interferon ◽  
Connective Tissue Diseases ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Interferon Production ◽  
Interferon Signature

AbstractAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

scholarly journals Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus

2014 ◽  
Vol 211 (10) ◽  
pp. 1969-1976 ◽  
Author(s):  
Vanja Sisirak ◽  
Dipyaman Ganguly ◽  
Kanako L. Lewis ◽  
Coline Couillault ◽  
Lena Tanaka ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Gene Dosage ◽  
Gene Expression Signature ◽  
Plasmacytoid Dendritic Cells ◽  
Genetic Evidence ◽  
Type I ◽  
Systemic Lupus ◽  
Autoantibody Production

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition, and tissue inflammation such as glomerulonephritis. Innate recognition of self-DNA and -RNA and the ensuing production of cytokines such as type I interferons (IFNs) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question by reducing gene dosage of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that global or DC-specific Tcf4 haplodeficiency ameliorated SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE nearly abolished key disease manifestations including anti-DNA antibody production and glomerulonephritis. Tcf4-haplodeficient SLE-prone animals showed a reduction of the spontaneous germinal center reaction and its associated gene expression signature. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis and autoantibody production, confirming their potential utility as therapeutic targets in the disease.

scholarly journals Mycophenolic Acid, Active Form of Mycophenolate Mofetil, Interferes With the IRF7 Nuclear Translocation and Type I IFN Production by Plasmacytoid Dendritic Cells

2020 ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Inhibitory Effect ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract BackgroundBoth humoral and cellular immune mechanisms are involved in the onset and progression of the autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLEvia the dysregulation of type I interferon (IFN) production;these cells act together with activated myeloid DCs (mDCs), to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of the aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMFin targeting DC functions, especially the IFN response of pDCs.MethodsWe isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.ResultsWe found that treatment with 1-10mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs(but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation in pDCsand IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.ConclusionsOur data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disordersby regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

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