Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2322-2332 ◽  
Author(s):  
Nadine Prinz ◽  
Natascha Clemens ◽  
Dennis Strand ◽  
Inge Pütz ◽  
Mareike Lorenz ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antiphospholipid Antibodies ◽  
Ex Vivo ◽  
Fetal Loss ◽  
Signal Transduction Pathway ◽  
Plasmacytoid Dendritic Cells ◽  
Systemic Autoimmunity ◽  
Subsequent Activation ◽  
Inappropriate Expression ◽  
Increase Mrna Expression

Abstract The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity.

Antithymocyte Globulin Induces Ex Vivo and In Vivo Depletion of Myeloid and Plasmacytoid Dendritic Cells

2005 ◽  
Vol 79 (3) ◽  
pp. 369-371 ◽  
Author(s):  
Lubin Fang ◽  
Boris Fehse ◽  
Melanie Engel ◽  
Axel Zander ◽  
Nicolaus Kr??ger
Keyword(s):  
Dendritic Cells ◽  
Antithymocyte Globulin ◽  
Ex Vivo ◽  
Plasmacytoid Dendritic Cells

scholarly journals Molecular Mechanisms of “Antiphospholipid Antibodies” and Their Paradoxical Role in the Pathogenesis of “Seronegative APS”

2020 ◽  
Vol 21 (21) ◽  
pp. 8411
Author(s):  
Roberta Misasi ◽  
Agostina Longo ◽  
Serena Recalchi ◽  
Daniela Caissutti ◽  
Gloria Riitano ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Molecular Mechanisms ◽  
Strong Association ◽  
Fetal Loss ◽  
Signal Transduction Pathway ◽  
Therapeutic Strategies ◽  
Transduction Pathway ◽  
Laboratory Methods ◽  
Pregnancy Morbidity ◽  
Glycoprotein I

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with circulating antiphospholipid antibodies (aPL). In some cases, patients with a clinical profile indicative of APS (thrombosis, recurrent miscarriages or fetal loss), who are persistently negative for conventional laboratory diagnostic criteria, are classified as “seronegative” APS patients (SN-APS). Several findings suggest that aPL, which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), may contribute to thrombotic diathesis by interfering with hemostasis. Despite the strong association between aPL and thrombosis, the exact pathogenic mechanisms underlying thrombotic events and pregnancy morbidity in APS have not yet been fully elucidated and multiple mechanisms may be involved. Furthermore, in many SN-APS patients, it is possible to demonstrate the presence of unconventional aPL (“non-criteria” aPL) or to detect aPL with alternative laboratory methods. These findings allowed the scientists to study the pathogenic mechanism of SN-APS. This review is focused on the evidence showing that these antibodies may play a functional role in the signal transduction pathway(s) leading to thrombosis and pregnancy morbidity in SN-APS. A better comprehension of the molecular mechanisms triggered by aPL may drive development of potential therapeutic strategies in APS patients.

scholarly journals Functional characterization of ex vivo blood myeloid and plasmacytoid dendritic cells after infection with dengue virus

Virology ◽  
2009 ◽  
Vol 383 (2) ◽  
pp. 207-215 ◽  
Author(s):  
Peifang Sun ◽  
Stefan Fernandez ◽  
Mary A. Marovich ◽  
Dupeh R. Palmer ◽  
Christina M. Celluzzi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dengue Virus ◽  
Ex Vivo ◽  
Functional Characterization ◽  
Plasmacytoid Dendritic Cells

Dynamic accumulation of plasmacytoid dendritic cells in lymph nodes is regulated by interferon-β

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2623-2631 ◽  
Author(s):  
Yunfei Gao ◽  
Beata Majchrzak-Kita ◽  
Eleanor N. Fish ◽  
Jennifer L. Gommerman
Keyword(s):  
Dendritic Cells ◽  
Virus Infection ◽  
Lymph Nodes ◽  
Viral Infection ◽  
Ex Vivo ◽  
Plasmacytoid Dendritic Cells ◽  
Lymphoid Organs ◽  
Type I ◽  
Secondary Lymphoid Organs

Abstract Plasmacytoid dendritic cells (pDCs) represent a major cellular component of our front-line defense against viruses because of their capacity to rapidly secrete type I interferon (IFN)–α and -β after infection. Constant immunosurveillance of the host requires that lymphocytes traffic through lymph nodes (LNs) to sample antigen, yet little is known about the dynamics of pDC accumulation within the secondary lymphoid organs. Here we show that pDCs readily accumulate within the secondary lymphoid organs of mice after virus infection. Interestingly, retention of pDC within LNs is enhanced in the presence of the sphingoshine-1-phosphate receptor agonist FTY720 in a manner similar to that observed for B and T lymphocytes. Ex vivo comparison of mouse pDCs with lymphocytes revealed that pDCs express sphingoshine-1-phosphate 4 and also constitutively express CD69, which is further up-regulated upon virus infection. In IFN-β−/− mice, accumulation of pDC and lymphocytes within LNs is reduced both during viral infection and under steady state conditions, and these defects can be reversed by adding recombinant IFN-β in vivo. These data suggest that pDC and lymphocytes use similar mechanisms for retention within LNs and that these processes are influenced by IFN-β even in the absence of viral infection.

scholarly journals Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma

2021 ◽  
pp. annrheumdis-2020-218439
Author(s):  
Rebecca L Ross ◽  
Clarissa Corinaldesi ◽  
Gemma Migneco ◽  
Ian M Carr ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Severe Combined Immunodeficiency ◽  
Indirect Evidence ◽  
Plasmacytoid Dendritic Cells ◽  
Induced Response ◽  
Type I ◽  
Therapeutic Application ◽  
Gene And Protein Expression

ObjectivesPlasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of autoimmune diseases, such as scleroderma (SSc). However, this has been derived from indirect evidence using ex vivo human samples or mouse pDC in vivo. We have developed human-specific pDC models to directly identify their role in inflammation and fibrosis, as well as attenuation of pDC function with BDCA2-targeting to determine its therapeutic application.MethodsRNAseq of human pDC with TLR9 agonist ODN2216 and humanised monoclonal BDCA2 antibody, CBS004. Organotypic skin rafts consisting of fibroblasts and keratinocytes were stimulated with supernatant from TLR9-stimulated pDC and with CBS004. Human pDC were xenotransplanted into Nonobese diabetic/severe combined immunodeficiency (NOD SCID) mice treated with Aldara (inflammatory model), or bleomycin (fibrotic model) with CBS004 or human IgG control. Skin punch biopsies were used to assess gene and protein expression.ResultsRNAseq shows TLR9-induced activation of human pDC goes beyond type I interferon (IFN) secretion, which is functionally inactivated by BDCA2-targeting. Consistent with these findings, we show that BDCA2-targeting of pDC can completely suppress in vitro skin IFN-induced response. Most importantly, xenotransplantation of human pDC significantly increased in vivo skin IFN-induced response to TLR agonist and strongly enhanced fibrotic and immune response to bleomycin compared with controls. In these contexts, BDCA2-targeting suppressed human pDC-specific pathological responses.ConclusionsOur data indicate that human pDC play a key role in inflammation and immune-driven skin fibrosis, which can be effectively blocked by BDCA2-targeting, providing direct evidence supporting the development of attenuation of pDC function as a therapeutic application for SSc.

scholarly journals Predominant Role of Plasmacytoid Dendritic Cells in Stimulating Systemic Autoimmunity

2015 ◽  
Vol 6 ◽  
Author(s):  
Xinfang Huang ◽  
Stephanie Dorta-Estremera ◽  
Yihong Yao ◽  
Nan Shen ◽  
Wei Cao
Keyword(s):  
Dendritic Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Predominant Role ◽  
Systemic Autoimmunity

scholarly journals Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anders Laustsen ◽  
Renée M van der Sluis ◽  
Albert Gris-Oliver ◽  
Sabina Sánchez Hernández ◽  
Ena Cemalovic ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Dendritic Cells ◽  
Whole Blood ◽  
Immune Cell ◽  
Ex Vivo ◽  
Plasmacytoid Dendritic Cells ◽  
Rare Type ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function

Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole blood HSPCs, and these cells display a pDC phenotype and function. Using GMP compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood, and lay the foundation for investigating HSPC-pDCs for cell-based immunotherapy.

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