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The usage of patient-reported measures inside epilepsy care: your Calgary Extensive Epilepsy System experience.
Taken together, these results indicate that pyrrole-imidazole polyamide targeting IL-23p19 could be a novel and feasible therapeutic strategy for patients with autoimmune diseases. Copyright © 2020 by The American Association of Immunologists, Inc.Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma. Copyright © 2020 by The American Association of Immunologists, Inc.Emerging evidence suggests comprehensive immune profiling represents a highly promising, yet insufficiently tapped approach to identify potentially prognostic signatures for periodontitis. In this report, we agnostically identified a periodontitis-associated inflammatory expression network with multiple biomarkers identified within gingival crevicular fluid samples from study participants by applying principal component analysis. We identified an IL-17-dominated trait that is associated with periodontal disease and is inversely modified by the level of IL-10. IL-10 mitigated chemokine CXCL5 and CXCL1 expressions in IL-17-stimulated peripheral blood monocytic cells and peripheral blood monocytic cell-derived macrophages. Il10-deficient mice presented more bone loss, which was associated with more Il17 and IL-17-mediated chemokine and cytokine expression at the transcriptional levels in comparison with control wild-type mice in both the Porphyromonas gingivalis-induced experimental murine periodontitis and ligature-induced alveolar bone-loss models. The dampening effect of IL-10 on the excessive signaling of IL-17 appeared to be mediated by innate immune cells populations rather than by gingival epithelial cells, which are the major cell target for IL-17 signaling. Additionally, elevated IL-17 response in Il10-deficient mice specifically elicited an M1-skewing macrophage phenotype in the gingiva that was associated with the advanced bone loss in the ligature model. In summary, IL-17 dominated an inflammatory network characteristic of periodontitis, and IL-10 dampens this excessive IL-17-mediated periodontitis trait. Copyright © 2020 by The American Association of Immunologists, Inc.Control of lymphocyte infiltration in kidney is a potential therapeutic strategy for lupus nephritis, considering that control of lymphocyte migration by sphingosine 1 phosphate has been implicated in inflammation-related pathology. The peptide inhibitor of the transendothelial migration (PEPITEM)/cadherin (CDH) 15 axis was recently reported to promote sphingosine 1 phosphate secretion. In this study, we investigated whether CDH15 is expressed in the kidney of MRL/lpr mice and whether lymphocyte infiltration is suppressed by exogenously administered PEPITEM. Mice (18 wk old) were randomized into 4-wk treatment groups that received PEPITEM or PBS encapsulated in dipalmitoylphosphatidylcholine liposomes. Enlargement of the kidney, spleen, and axillary lymph nodes was suppressed by PEPITEM treatment, which also blocked infiltration of double-negative T lymphocytes into the kidney and glomerular IgG/C3 deposition, reduced proteinuria, and increased podocyte density. Immunohistochemical analysis revealed that the PEPITEM receptor CDH15 was expressed on vascular endothelial cells of glomeruli and kidney arterioles, skin, and peritoneum in lupus mice at 22 wk of age but not in 4-wk-old mice. These results suggest that PEPITEM inhibits lymphocyte migration and infiltration into the kidney, thereby preserving the kidney structure and reducing proteinuria. Thus, PEPITEM administration may be considered as a potential therapeutic tool for systemic lupus erythematosus. Copyright © 2020 by The American Association of Immunologists, Inc.Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a "cytokine" are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8+ T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4+ T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response. Copyright © 2020 by The American Association of Immunologists, Inc.Plasmacytoid dendritic cells (pDCs) produce abundant type I IFNs (IFN-I) in response to viral nucleic acids. Generation of pDCs from bone marrow dendritic cell (DC) progenitors and their maintenance is driven by the transcription factor E2-2 and inhibited by its repressor Id2. In this study, we find that mouse pDCs selectively express the receptor for LIF that signals through STAT3. Stimulation of pDCs with LIF inhibited IFN-I, TNF, and IL-6 responses to CpG and induced expression of the STAT3 targets SOCS3 and Bcl3, which inhibit IFN-I and NF-κB signaling. Moreover, although STAT3 has been also reported to induce E2-2, LIF paradoxically induced its repressor Id2. A late-stage bone marrow DC progenitor expressed low amounts of LIFR and developed into pDCs less efficiently after being exposed to LIF, consistent with the induction of Id2. Conversely, pDC development and serum IFN-I responses to lymphocytic choriomeningitis virus infection were augmented in newly generated mice lacking LIFR in either CD11c+ or hematopoietic cells. Thus, an LIF-driven STAT3 pathway induces SOCS3, Bcl3, and Id2, which render pDCs and late DC progenitors refractory to physiological stimuli controlling pDC functions and development. This pathway can be potentially exploited to prevent inappropriate secretion of IFN-I in autoimmune diseases or promote IFN-I secretion during viral infections. Copyright © 2020 by The American Association of Immunologists, Inc.Immune reactions are controlled by the delicate spatiotemporal orchestration of multiple cells communicating by cytokines. Studies of cytokines that began with the discovery of IFN focused on positive regulatory mechanisms that induce secretion in response to harmful stimuli. However, there is a growing awareness that negative regulatory mechanisms that stop secretion of cytokines at specific times and spaces are also important for a successful immune reaction. Type I IFN is the primary cytokine in innate immunity. Although its induction is a prerequisite for the consequent adaptive immune reaction, its oversecretion can cause destructive tissue damage. IFN regulatory factor 7 (IRF7) is a master transcription factor of type I IFN, and multiple observations indicate the key role of IRF7 and the importance of its negative regulation. In this study, we found that the inducible heat shock protein 70 (HSP70) regulated the early type I IFN response by using mice knockout for HSP70. HSP70 dampened IRF7 activation; the inhibitory effect of HSP70 over IKKε-mediated IRF7 activation originated from simple competitive binding. This suggests the possibility of blocking the feed-forward loop between IRF7 and type I IFN in stress environments with increased expression of HSP70. Copyright © 2020 by The American Association of Immunologists, Inc.Nucleotide oligomerization domain-like receptors (NLRs) and RIG-I-like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus-infected NOD1-/- zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5-MAVS and TRAF3-MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(IC) and the formation of the MDA5a-MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1-MDA5 and NOD1-TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(IC) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form-mediated immune signaling in vertebrates. Copyright © 2020 by The American Association of Immunologists, Inc.Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help find a novel therapeutic target for treating Th17 cell-mediated diseases. In this study, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by posttranscriptionally regulating transcription factors Irf4 and Runx1 and receptor Il12rb1 expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation in C57BL/6J mice. Knockout of HuR altered the transcriptome of Th17 cells characterized by reducing the levels of RORγt, IRF4, RUNX1, and T-bet, thereby reducing the number of pathogenic IL-17+IFN-γ+CD4+ T cells in the spleen during experimental autoimmune encephalomyelitis. ML198 In keeping with the fact that HuR increased the abundance of adhesion molecule VLA-4 on Th17 cells, knockout of HuR impaired splenic Th17 cell migration to the CNS and abolished the disease.
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