Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus

2021 ◽  
Vol 13 (595) ◽  
pp. eabf8442
Author(s):  
Jodi L. Karnell ◽  
Yanping Wu ◽  
Nanette Mittereder ◽  
Michael A. Smith ◽  
Michele Gunsior ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Local Type ◽  
Biomarker Analysis ◽  
Cutaneous Lupus

Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced effector function, mediated rapid and potent depletion of pDCs through antibody-dependent cellular cytotoxicity. In cynomolgus monkeys, treatment with VIB7734 reduced pDCs in blood below the lower limit of normal by day 1 after the first dose. In two phase 1 studies in patients with autoimmune diseases, VIB7734 demonstrated an acceptable safety profile, comparable to that of placebo. In individuals with cutaneous lupus, VIB7734 profoundly reduced both circulating and tissue-resident pDCs, with a 97.6% median reduction in skin pDCs at study day 85 in VIB7734-treated participants. Reductions in pDCs in the skin correlated with a decrease in local type I IFN activity as well as improvements in clinical disease activity. Biomarker analysis suggests that responsiveness to pDC depletion therapy may be greater among individuals with high baseline type I IFN activity, supporting a central role for pDCs in type I IFN production in autoimmunity and further development of VIB7734 in IFN-associated diseases.

scholarly journals Type I Interferon Inhibition and Dendritic Cell Activation during Gammaherpesvirus Respiratory Infection

2007 ◽  
Vol 81 (18) ◽  
pp. 9778-9789 ◽  
Author(s):  
Janet L. Weslow-Schmidt ◽  
Nancy A. Jewell ◽  
Sara E. Mertz ◽  
J. Pedro Simas ◽  
Joan E. Durbin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Cell Activation ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
The Body ◽  
Type I ◽  
Type I Ifn ◽  
Dendritic Cell Activation ◽  
Murine Gammaherpesvirus

ABSTRACT The respiratory tract is a major mucosal site for microorganism entry into the body, and type I interferon (IFN) and dendritic cells constitute a first line of defense against viral infections. We have analyzed the interaction between a model DNA virus, plasmacytoid dendritic cells, and type I IFN during lung infection of mice. Our data show that murine gammaherpesvirus 68 (γHV68) inhibits type I IFN secretion by dendritic cells and that plasmacytoid dendritic cells are necessary for conventional dendritic cell maturation in response to γHV68. Following γHV68 intranasal inoculation, the local and systemic IFN-α/β response is below detectable levels, and plasmacytoid dendritic cells are activated and recruited into the lung with a tissue distribution that differs from that of conventional dendritic cells. Our results suggest that plasmacytoid dendritic cells and type I IFN have important but independent roles during the early response to a respiratory γHV68 infection. γHV68 infection inhibits type I IFN production by dendritic cells and is a poor inducer of IFN-α/β in vivo, which may serve as an immune evasion strategy.

scholarly journals Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

2013 ◽  
Vol 210 (2) ◽  
pp. 355-374 ◽  
Author(s):  
Francesca Prete ◽  
Marco Catucci ◽  
Mayrel Labrada ◽  
Stefania Gobessi ◽  
Maria Carmina Castiello ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Actin Polymerization ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
Actin Dynamics ◽  
Type I ◽  
Type I Ifn ◽  
Wiskott Aldrich Syndrome ◽  
Elevated Type ◽  
Chronic Activation

Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pDCs numbers, and hyperresponsiveness to TLR9. Importantly, ablating IFN-I signaling in WASp null mice rescued chronic activation of conventional DCs, splenomegaly, and colitis. Using WASp-deficient mice, we demonstrated that WASp null pDCs are intrinsically more responsive to multimeric agonist of TLR9 and constitutively secrete type-I IFN but become progressively tolerant to further stimulation. By acute silencing of WASp and actin inhibitors, we show that WASp-mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in pDCs restraining exaggerated activation of the TLR9–IFN-α pathway. Together, these data highlight the role of actin dynamics in pDC innate functions and imply the pDC–IFN-α axis as a player in the onset of autoimmune phenomena in WAS disease.

scholarly journals Multiple Viral microRNAs Regulate Interferon Release and Signaling Early during Infection with Epstein-Barr Virus

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Mickaël Bouvet ◽  
Stefanie Voigt ◽  
Takanobu Tagawa ◽  
Manuel Albanese ◽  
Yen-Fu Adam Chen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Viral Dna ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV), a human herpesvirus, encodes 44 microRNAs (miRNAs), which regulate many genes with various functions in EBV-infected cells. Multiple target genes of the EBV miRNAs have been identified, some of which play important roles in adaptive antiviral immune responses. Using EBV mutant derivatives, we identified additional roles of viral miRNAs in governing versatile type I interferon (IFN) responses upon infection of human primary mature B cells. We also found that Epstein-Barr virus-encoded small RNAs (EBERs) and LF2, viral genes with previously reported functions in inducing or regulating IFN-I pathways, had negligible or even contrary effects on secreted IFN-α in our model. Data mining and Ago PAR-CLIP experiments uncovered more than a dozen previously uncharacterized, direct cellular targets of EBV miRNA associated with type I IFN pathways. We also identified indirect targets of EBV miRNAs in B cells, such as TRL7 and TLR9, in the prelatent phase of infection. The presence of epigenetically naive, non-CpG methylated viral DNA was essential to induce IFN-α secretion during EBV infection in a TLR9-dependent manner. In a newly established fusion assay, we verified that EBV virions enter a subset of plasmacytoid dendritic cells (pDCs) and determined that these infected pDCs are the primary producers of IFN-α in EBV-infected peripheral blood mononuclear cells. Our findings document that many EBV-encoded miRNAs regulate type I IFN response in newly EBV infected primary human B cells in the prelatent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV. IMPORTANCE Acute antiviral functions of all nucleated cells rely on type I interferon (IFN-I) pathways triggered upon viral infection. Host responses encompass the sensing of incoming viruses, the activation of specific transcription factors that induce the transcription of IFN-I genes, the secretion of different IFN-I types and their recognition by the heterodimeric IFN-α/β receptor, the subsequent activation of JAK/STAT signaling pathways, and, finally, the transcription of many IFN-stimulated genes (ISGs). In sum, these cellular functions establish a so-called antiviral state in infected and neighboring cells. To counteract these cellular defense mechanisms, viruses have evolved diverse strategies and encode gene products that target antiviral responses. Among such immune-evasive factors are viral microRNAs (miRNAs) that can interfere with host gene expression. We discovered that multiple miRNAs of Epstein-Barr virus (EBV) control over a dozen cellular genes that contribute to the antiviral states of immune cells, specifically B cells and plasmacytoid dendritic cells (pDCs). We identified the viral DNA genome as the activator of IFN-α and question the role of abundant EBV EBERs, that, contrary to previous reports, do not have an apparent inducing function in the IFN-I pathway early after infection.

scholarly journals Human plasmacytoid dendritic cells at the crossroad of type I interferon-regulated B cell differentiation and antiviral response to tick-borne encephalitis virus

2021 ◽  
Vol 17 (4) ◽  
pp. e1009505
Author(s):  
Marilena P. Etna ◽  
Aurora Signorazzi ◽  
Daniela Ricci ◽  
Martina Severa ◽  
Fabiana Rizzo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
B Cell ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
B Cell Differentiation ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

The Tick-borne encephalitis virus (TBEV) causes different disease symptoms varying from asymptomatic infection to severe encephalitis and meningitis suggesting a crucial role of the human host immune system in determining the fate of the infection. There is a need to understand the mechanisms underpinning TBEV-host interactions leading to protective immunity. To this aim, we studied the response of human peripheral blood mononuclear cells (PBMC) to the whole formaldehyde inactivated TBEV (I-TBEV), the drug substance of Encepur, one of the five commercially available vaccine. Immunophenotyping, transcriptome and cytokine profiling of PBMC revealed that I-TBEV generates differentiation of a sub-population of plasmacytoid dendritic cells (pDC) that is specialized in type I interferon (IFN) production. In contrast, likely due to the presence of aluminum hydroxide, Encepur vaccine was a poor pDC stimulus. We demonstrated I-TBEV-induced type I IFN together with Interleukin 6 and BAFF to be critical for B cell differentiation to plasmablasts as measured by immunophenotyping and immunoglobulin production. Robust type I IFN secretion was induced by pDC with the concerted action of both viral E glycoprotein and RNA mirroring previous data on dual stimulation of pDC by both S. aureus and influenza virus protein and nucleic acid that leads to a type I IFN-mediated sustained immune response. E glycoprotein neutralization or high temperature denaturation and inhibition of Toll-like receptor 7 signalling confirmed the importance of preserving the functional integrity of these key viral molecules during the inactivation procedure and manufacturing process to produce a vaccine able to stimulate strong immune responses.

scholarly journals A type I IFN–Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors

2013 ◽  
Vol 210 (12) ◽  
pp. 2515-2522 ◽  
Author(s):  
Yi-Ling Chen ◽  
Ting-Ting Chen ◽  
Li-Mei Pai ◽  
Joanna Wesoly ◽  
Hans A.R. Bluyssen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cell ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Flt3 Ligand ◽  
Lymphoid Progenitors

During infections and inflammation, plasmacytoid dendritic cells (pDCs) are the most potent type I interferon (IFN-I)–producing cells. However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. Here, we report a synergistic role for IFN-I and Flt3 ligand (FL) in pDC development from common lymphoid progenitors (CLPs). Both conventional DCs (cDCs) and pDCs were generated from CLPs in response to FL, whereas pDC generation required higher concentrations of FL and concurrent IFN-I signaling. An absence of IFN-I receptor, impairment of IFN-I signaling, or neutralization of IFN-I significantly impeded pDC development from CLPs. Furthermore, FL induced IFN-I expression in CLPs, which in turn induced Flt3 up-regulation that facilitated survival and proliferation of CLPs, as well as their differentiation into pDCs. Collectively, these results define a critical role for the FL/IFN-I/Flt3 axis in pDC differentiation from CLPs.

scholarly journals Plasmacytoid dendritic cells produce type I interferon and reduce viral replication in airway epithelial cells after SARS-CoV-2 infection

2021 ◽  
Author(s):  
Luisa Cervantes-Barragan ◽  
Abigail Vanderheiden ◽  
Charlotte J Royer ◽  
Meredith E Davis-Gardner ◽  
Philipp Ralfs ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Epithelial Cells ◽  
Viral Replication ◽  
Immune Cell ◽  
Type I Interferon ◽  
Airway Epithelial Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Airway Epithelial ◽  
Type I Ifn

Infection with SARS-CoV-2 has caused a pandemic of unprecedented dimensions. SARS-CoV-2 infects airway and lung cells causing viral pneumonia. The importance of type I interferon (IFN) production for the control of SARS-CoV-2 infection is highlighted by the increased severity of COVID-19 in patients with inborn errors of type I IFN response or auto-antibodies against IFN-α. Plasmacytoid dendritic cells (pDCs) are a unique immune cell population specialized in recognizing and controlling viral infections through the production of high concentrations of type I IFN. In this study, we isolated pDCs from healthy donors and showed that pDCs are able to recognize SARS-CoV-2 and rapidly produce large amounts of type I IFN. Sensing of SARS-CoV-2 by pDCs was independent of viral replication since pDCs were also able to recognize UV-inactivated SARS-CoV-2 and produce type I IFN. Transcriptional profiling of SARS-CoV-2 and UV-SARS-CoV-2 stimulated pDCs also showed a rapid type I and III IFN response as well as induction of several chemokines, and the induction of apoptosis in pDCs. Moreover, we modeled SARS-CoV-2 infection in the lung using primary human airway epithelial cells (pHAEs) and showed that co-culture of pDCs with SARS-CoV-2 infected pHAEs induces an antiviral response and upregulation of antigen presentation in pHAE cells. Importantly, the presence of pDCs in the co-culture results in control of SARS-CoV-2 replication in pHAEs. Our study identifies pDCs as one of the key cells that can recognize SARS-CoV-2 infection, produce type I and III IFN and control viral replication in infected cells.

scholarly journals Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit

2020 ◽  
Author(s):  
Jessica M. Salmon ◽  
Izabela Todorovski ◽  
Stephin J. Vervoort ◽  
Kym L. Stanley ◽  
Conor J. Kearney ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Transcriptional Activation ◽  
Type I Interferon ◽  
Combined Treatment ◽  
Leukemia Cell ◽  
Therapeutic Benefit ◽  
Plasmacytoid Dendritic Cells ◽  
Genetically Engineered ◽  
Type I ◽  
Type I Ifn

ABSTRACTPharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFNα improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

Sign in / Sign up

Export Citation Format

Share Document