Journal articles on the topic 'WASp, pDCs, Type-I-IFN, autoimmunity'
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1
Prete, Francesca, Marco Catucci, Mayrel Labrada, Stefania Gobessi, Maria Carmina Castiello, Elisa Bonomi, Alessandro Aiuti, et al. "Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells." Journal of Experimental Medicine 210, no. 2 (January 21, 2013): 355–74. http://dx.doi.org/10.1084/jem.20120363.
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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.
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Schmitt, Heike, Sabrina Sell, Julia Koch, Martina Seefried, Sophia Sonnewald, Christoph Daniel, Thomas H. Winkler, and Lars Nitschke. "Siglec-H protects from virus-triggered severe systemic autoimmunity." Journal of Experimental Medicine 213, no. 8 (July 4, 2016): 1627–44. http://dx.doi.org/10.1084/jem.20160189.
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It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs). The secretion of type I IFN of pDCs is modulated by Siglec-H, a DAP12-associated receptor on pDCs. In this study, we show that Siglec-H–deficient pDCs produce more of the type I IFN, IFN-α, in vitro and that Siglec-H knockout (KO) mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo. This did not impact control of viral replication. Remarkably, several weeks after a single mCMV infection, Siglec-H KO mice developed a severe form of systemic lupus–like autoimmune disease with strong kidney nephritis. In contrast, uninfected aging Siglec-H KO mice developed a mild form of systemic autoimmunity. The induction of systemic autoimmune disease after virus infection in Siglec-H KO mice was accompanied by a type I IFN signature and fully dependent on type I IFN signaling. These results show that Siglec-H normally serves as a modulator of type I IFN responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.
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Karnell, Jodi L., Yanping Wu, Nanette Mittereder, Michael A. Smith, Michele Gunsior, Li Yan, Kerry A. Casey, et al. "Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus." Science Translational Medicine 13, no. 595 (May 26, 2021): eabf8442. http://dx.doi.org/10.1126/scitranslmed.abf8442.
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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.
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Cao, Wei, Jeremy Di Domizio, Stephanie Dorta-Estramera, Mihai Gagea, Ping Li, Liqi Bi, and Michel Gilliet. "Nucleic acid-containing amyloid fibrils potently induce Type I interferon and stimulate systemic autoimmunity (P4075)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 127.9. http://dx.doi.org/10.4049/jimmunol.190.supp.127.9.
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Abstract The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms. In systemic lupus erythematosus, type I IFN (IFNI) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Amyloid precursor proteins can form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of selfantigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.
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Barrat, Franck J., and Lishan Su. "A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection." Journal of Experimental Medicine 216, no. 9 (August 16, 2019): 1974–85. http://dx.doi.org/10.1084/jem.20181359.
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Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here.
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Lorant, Alina K., and Adam Lacy-Hulbert. "Integrin αvβ3 limits TLR signaling in plasmacytoid dendritic cells to prevent autoimmunity." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 60.09. http://dx.doi.org/10.4049/jimmunol.206.supp.60.09.
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Abstract SLE is a chronic, systemic autoimmune disease affecting millions of people worldwide. SLE is caused by a breakdown of tolerance to self-derived nucleic acids (NA) and characterized by the presence of autoantibodies to DNA/RNA. Plasmacytoid dendritic cells (pDCs) are highly tuned to respond to NA and express a range of receptors for RNA and DNA, including TLRs 7 and 9. Following TLR engagement, pDCs produce high levels of type I interferon (IFN-I), which promotes loss of tolerance, implicating pDCs in development of autoimmunity. However, relatively little is known about how innate immune signaling is regulated in pDCs, and particularly how they distinguish self-derived from foreign NA. TLRs 7 and 9 are both localized in endosomal compartments, and their NA ligands must be internalized and processed before they can bind. One source of these NA is dying cells and loss of their receptors is associated with SLE. We studied the role of an apoptotic cell receptor, Integrin αvβ3, in TLR signaling of pDCs and found that αvβ3 limits IFN-I production. αvβ3-knockout pDCs show increased TLR signaling and produce more IFN-I and inflammatory cytokines when stimulated in culture. In mice without αvβ3, there is a systemic increase in circulating ISGs and IFN-I after TLR7 stimulation. This corresponds with an increase in pDC activation and a decrease in marginal zone B cells, indicating elevated IFN-I production. These data indicate αvβ3 has a pDC-intrinsic role in limiting TLR signaling, which we propose is through activation of non-canonical autophagy. Based on these data, we hypothesize that co-receptors involved in capture and internalization of nucleic acids provide contextual ‘cues’ to regulate TLR signaling and prevent autoimmunity.
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Bencze, Dóra, Tünde Fekete, and Kitti Pázmándi. "Type I Interferon Production of Plasmacytoid Dendritic Cells under Control." International Journal of Molecular Sciences 22, no. 8 (April 18, 2021): 4190. http://dx.doi.org/10.3390/ijms22084190.
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One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.
8
Lorant, Alina K., and Adam Lacy-Hulbert. "Integrin αv limits TLR signaling in plasmacytoid dendritic cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 226.3. http://dx.doi.org/10.4049/jimmunol.204.supp.226.3.
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Abstract SLE is a chronic, systemic autoimmune disease affecting millions of people worldwide. SLE is caused by a breakdown of tolerance to self-derived nucleic acids (NA) and characterized by the presence of autoantibodies to DNA/RNA. Plasmacytoid dendritic cells (pDCs) are highly tuned to respond to NA and express a range of receptors for RNA and DNA, including TLRs 7 and 9. Following TLR engagement, pDCs produce high levels of type I interferon (IFN-I), which promotes loss of tolerance, implicating pDCs in development of autoimmunity. However, relatively little is known about how innate immune signaling is regulated in pDCs, and particularly how they distinguish self-derived from foreign NA. TLRs 7 and 9 are both localized in endosomal compartments, and their NA ligands must be internalized and processed before they can bind. One source of these NA is dying cells and loss of their receptors is associated with SLE. We studied the role of an apoptotic cell receptor, Integrin αv, in TLR signaling of pDCs and found that αv limits IFN-I production. In mice without αv, there is a systemic increase in IFN-I and inflammatory cytokines after TLR7 stimulation. This corresponds with an increase in pDC activation and the number of IFN-I-producing pDCs in the spleen. αv-knockout pDCs show increased TLR signaling and produce more IFN-I and inflammatory cytokines when stimulated in culture. These data indicate αv has a pDC-intrinsic role in limiting TLR signaling, which we propose is through activation of non-canonical autophagy. Based on these data, we hypothesize that co-receptors involved in capture and internalization of nucleic acids provide contextual ‘cues’ to regulate TLR signaling and prevent autoimmunity.
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Lande, Roberto, Anna Mennella, Raffaella Palazzo, Immacolata Pietraforte, Katia Stefanantoni, Nicoletta Iannace, Alessia Butera, et al. "Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature." International Journal of Molecular Sciences 21, no. 14 (July 19, 2020): 5102. http://dx.doi.org/10.3390/ijms21145102.
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Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.
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Babcock, Rachel Lauren, Haiyan S. Li, Yifan Zhou, Taylor T. Chrisikos, and Stephanie S. Watowich. "Regulation of Id2 gene expression in plasmacytoid dendritic cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 229.3. http://dx.doi.org/10.4049/jimmunol.204.supp.229.3.
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Abstract Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that mediate anti-viral responses, anti-tumor immunity, and autoimmunity. When exposed to Toll-like receptor 7 (TLR7)- and TLR9-ligands, pDCs mature and produce IFN-Is; pDCs also acquire conventional DC (cDC)-like morphology and features, including the cell surface expression of antigen presentation and co-stimulatory molecules, secretion of additional cytokines, and ability to activate adaptive T cell responses. Yet, the transcriptional pathways regulating TLR-induced pDC maturation are poorly characterized. We found the mRNA and protein expression of the inhibitor of DNA binding protein 2 (Id2) was induced in TLR7/9-stimulated pDCs, and Id2 expression correlated with greater cDC-like features. Id2 normally blocks pDC development by antagonizing the pDC-master regulator, E2-2, while E2-2 suppresses Id2 transcription. Thus, we hypothesize TLR-activated signaling pathways in pDCs control the abundance of transcriptional regulators (e.g., E2-2) at the Id2 promoter as well as the promoter chromatin state, leading to induction of Id2 transcription during pDC maturation. Using genetic knockout mouse models, we found Id2 induction was independent of interferon alpha receptor and nuclear factor kappa beta signaling pathways. Chromatin-immunoprecipitation assays suggested E2-2 abundance at the Id2 promoter decreased following TLR stimulation, while activating histone modifications increased. These data are consistent with transcriptional induction of Id2 upon TLR stimulation. Future work will investigate the effect of additional regulators and TLR-regulated pathways on Id2 induction in TLR7/9-stimulated pDCs.
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Greene, Trever T., and Elina I. Zuniga. "Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings." Viruses 13, no. 9 (September 15, 2021): 1839. http://dx.doi.org/10.3390/v13091839.
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Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as “pDC exhaustion”, favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.
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Qiu, Connie Claire, and Stefania Gallucci. "Bacterial amyloids from biofilms induce type I interferon response in plasmacytoid dendritic cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 162.6. http://dx.doi.org/10.4049/jimmunol.200.supp.162.6.
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Abstract An increased expression of type I interferon (IFN) regulated genes is a hallmark of systemic lupus erythematosus, a complex autoimmune inflammatory disease. Although the exact etiology of lupus is unknown, infections can be an important environmental trigger for flares, and are a major cause of morbidity and mortality. Medically, bacterial biofilms are important for the establishment of chronic, persistent infections. Bacteria within these aggregates are embedded into their biofilms, allowing them to dramatically increase their ability to withstand physical insults and tolerate host defenses. To strengthen the extracellular matrix of their biofilms, bacteria produce amyloids, complex proteins with a conserved beta sheet structure. We have reported that Salmonella and E. coli biofilms contain the functional amyloid protein curli, which complexes with eukaryotic and bacterial DNA. Systemic administration of curli-DNA complexes accelerated autoimmunity in lupus-prone mice. Infections with curli-expressing Salmonella or E. coli gave the same results, implicating curli as a pathogenic factor in how biofilm-producing infections may contribute to lupus pathogenesis. We present here for the first time that bacterial amyloid curli activates plasmacytoid dendritic cells (pDCs), the primary producer of type I IFNs, in vitro. Additionally, we show that curli induces a robust production of IFNα and expression of interferon-stimulated genes, including CXCL10. Furthermore, curli induces in vivo activation of DCs in lupus-prone and wild-type mice. Our results identify bacterial amyloid curli as a novel activator of pDCs, and suggest that curli may accelerate lupus by directly activating pDCs and their powerful type I IFN activity.
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Qiu, Connie Claire, Michael Hweemoon Lee, and Stefania Gallucci. "Modulation of the energy metabolism inhibits plasmacytoid dendritic cell activation and delays onset of autoantibody production in murine models of systemic lupus erythematosus." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 80.12. http://dx.doi.org/10.4049/jimmunol.198.supp.80.12.
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Abstract Despite the heterogeneity of systemic lupus erythematosus (SLE) clinical manifestations, an increased expression of type I interferon (IFN) regulated genes, termed the interferon signature, has been reported in most SLE patients. Long recognized to facilitate the progression of SLE, Type I IFNs can be produced in small amounts by most cell types, but the plasmacytoid dendritic cells (pDCs) are the primary producers. Since murine models of SLE have shown that depletion of pDCs stop the onset and progression of autoimmunity, we speculated that it is important to suppress pDC activities that go beyond the production of type I IFNs. We have confirmed that changes in fatty acid metabolism are essential for pDC activation. Using inhibitors of fatty acid oxidation, oxidative phosphorylation, and glycolysis, we have found that metabolic modulation prevents pDC activation upon stimulation with TLR ligands CpG and R848. This metabolic inhibition did not affect pDC viability. Moreover, in vivo treatment of mice with metabolic inhibitors delayed the onset of autoantibody production in murine models of SLE. Indeed, the inhibition of energy metabolism strongly reduced the production of anti-dsDNA and antichromatin autoanti-bodies in i) a model of lupus induced by Graft versus Host Disease (GvHD) and ii) in lupus-prone mice accelerated by TLR stimulation. Therefore, our findings suggest that the in vivo suppression of the major producers of type I IFN through inhibition of energy metabolism may therapeutically downregulate the production of autoantibodies in murine lupus. Our data raises the possibility of manipulating cellular metabolic pathways to regulate the detrimental type I IFN effects in SLE.
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Burlock, Brianna, Gabrielle Richardson, Sonia García-Rodríguez, Salvador Guerrero, Mercedes Zubiaur, and Jaime Sancho. "The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus." International Journal of Molecular Sciences 19, no. 10 (September 25, 2018): 2906. http://dx.doi.org/10.3390/ijms19102906.
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Previous work from our group has shown that Cd38−/− mice develop a milder pristane-induced lupus disease than WT or Art2−/− counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19+CD1dhiCD5+ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38−/− splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished. The low proportion of pDCs correlated with lower amounts of IFN-α in the peritoneal lavage fluids of the Cd38−/− mice than of WT and Art2−/− mice. Functional ex vivo assays showed increased frequencies of IL-10-producing B cells in Cd38−/− splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb. Overall these results strongly suggest that Cd38−/− mice are better suited than WT mice to generate and expand regulatory B10 cells following the appropriate stimulation.
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Di Domizio, Jeremy, Ran Zhang, Ming Zhuo, Loren Stagg, John Ladbury, Michel Gilliet, and Wei Cao. "A novel class of host-derived etiological agent for autoimmunity: oligomers of endogenous proteins bind to self-nucleic acids and trigger type I IFN production by plasmacytoid dendritic cells (44.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 44.2. http://dx.doi.org/10.4049/jimmunol.186.supp.44.2.
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Abstract Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.
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Liu, Yi, Reginald Gray, Gareth Hardy, John Kuchtey, Derek Abbott, Steven Emancipator, and Clifford Harding. "CpG-B oligodeoxynucleotides inhibit Toll-like receptor-dependent and -independent induction of type I IFN in dendritic cells (136.10)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 136.10. http://dx.doi.org/10.4049/jimmunol.184.supp.136.10.
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Abstract CpG oligodeoxynucleotides (ODNs) signal through TLR9 to induce type-I IFN (IFNαβ) in dendritic cells. CpG-A ODNs are more efficacious than CpG-B ODNs for induction of IFNαβ. Because IFNαβ may contribute to autoimmunity, it is important to identify mechanisms to inhibit induction of IFNαβ. In our studies, CpG-B ODN inhibited induction of IFNαβ by CpG-A ODN, while induction of TNFα and IL-12p40 by CpG-A ODN was not affected. CpG-B inhibition of IFNαβ was observed in Flt3L-induced murine DCs, purified murine mDCs and pDCs, and human PBMCs. CpG-B ODN inhibited induction of IFNαβ by agonists of multiple receptors, including MyD88-dependent TLRs and MyD88-independent receptors. CpG-B ODN did not inhibit the IFNαβ positive feedback loop “second wave” IFNαβ, since IFNαβ-induced expression of IFNαβ mRNA was unaffected, and CpG-B inhibition of IFNαβ was manifested in IFNαβR-/- DCs, which lack the positive feedback mechanism. Rather, CpG-B ODN inhibited early “first-wave” IFNα4 and IFNβ. Chromatin immunoprecipitation revealed that association of IRF1 with the IFNα4 and IFNβ promoters was induced by CpG-A ODN but not CpG-B ODN. Moreover, CpG-A-induced association of IRF1 with these promoters was inhibited by CpG-B ODN. Our studies demonstrate a novel mechanism of transcriptional regulation of first-wave IFNαβ that selectively inhibits induction of IFNαβ downstream of multiple receptors and may provide targets for future therapeutic inhibition of IFNαβ expression in vivo.
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Chaudhary, Vidyanath, Marie Dominique Ah Kioon, Sung-Min Hwang, Bikash Mishra, Kimberly Lakin, Kyriakos A. Kirou, Jeffrey Zhang-Sun, et al. "Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses." Journal of Experimental Medicine 219, no. 11 (September 2, 2022). http://dx.doi.org/10.1084/jem.20221085.
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Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I–stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1–controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1–PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
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Szumilas, Nadine, Odilia B. J. Corneth, Christian H. K. Lehmann, Heike Schmitt, Svenia Cunz, Jolie G. Cullen, Talyn Chu, et al. "Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections." Frontiers in Immunology 12 (August 23, 2021). http://dx.doi.org/10.3389/fimmu.2021.698420.
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Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.
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Minaga, Kosuke, Tomohiro Watanabe, Akane Hara, Tomoe Yoshikawa, Ken Kamata, and Masatoshi Kudo. "Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease." Frontiers in Immunology 12 (July 23, 2021). http://dx.doi.org/10.3389/fimmu.2021.713779.
Full textAbstract:
Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.
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Ghanem, Mustafa H., Andrew J. Shih, Houman Khalili, Emily G. Werth, Jayanta K. Chakrabarty, Lewis M. Brown, Kim R. Simpfendorfer, and Peter K. Gregersen. "Proteomic and Single-Cell Transcriptomic Dissection of Human Plasmacytoid Dendritic Cell Response to Influenza Virus." Frontiers in Immunology 13 (March 23, 2022). http://dx.doi.org/10.3389/fimmu.2022.814627.
Full textAbstract:
Plasmacytoid dendritic cells [pDCs] represent a rare innate immune subset uniquely endowed with the capacity to produce substantial amounts of type-I interferons. This function of pDCs is critical for effective antiviral defenses and has been implicated in autoimmunity. While IFN-I and select cytokines have been recognized as pDC secreted products, a comprehensive agnostic profiling of the pDC secretome in response to a physiologic stimulus has not been reported. We applied LC-MS/MS to catalogue the repertoire of proteins secreted by pDCs in the unperturbed condition and in response to challenge with influenza H1N1. We report the identification of a baseline pDC secretome, and the repertoire of virus-induced proteins including most type-I interferons, various cytokines, chemokines and granzyme B. Additionally, using single-cell RNA-seq [scRNA-seq], we perform multidimensional analyses of pDC transcriptional diversity immediately ex vivo and following stimulation. Our data evidence preexisting pDC heterogeneity, with subsequent highly specialized roles within the pDC population upon stimulation ranging from dedicated cytokine super-producers to cells with APC-like traits. Dynamic expression of transcription factors and surface markers characterize subclusters within activated pDCs. Integrating the proteomic and transcriptomic datasets confirms the pDC-subcluster origin of the proteins identified in the secretome. Our findings represent the most comprehensive molecular characterization of primary human pDCs at baseline, and in response to influenza virus, reported to date.