Immune Regulation News Volume 11.44 | Nov 22 2019

TOP STORY

NLRP3 Inflammasome Activation Drives Tau Pathology

Researchers showed that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. [Nature] Abstract | Press Release

(Ranked by impact factor of the journal)

Identification of a Novel Arthritis-Associated Osteoclast Precursor Macrophage Regulated by FoxM1

Scientists showed that osteoclasts in pannus originated exclusively from circulating bone marrow-derived cells and not from locally resident macrophages. Tamoxifen-inducible Foxm1 deletion suppressed the capacity of arthritis-associated osteoclastogenic macrophages to differentiate into osteoclasts in vitro and in vivo. [Nat Immunol] Abstract

Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung

In murine models of allergen exposure, the dopamine-DRD4 pathway augmented T helper 2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. [Immunity] Full Article | Graphical Abstract

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4⁺ T Cell Pathogenicity and Suppresses Autoimmunity

Treatment of T cells with TEPP-46, an allosteric activator that induced pyruvate kinase M2 tetramerization and blocked its nuclear translocation, strongly reduced their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. [Cell Metab] Full Article | Press Release | Graphical Abstract

Impaired ATM Activation in B Cells Is Associated with Bone Resorption in Rheumatoid Arthritis

Using a humanized mouse model, investigators showed that ataxia telangiectasia-mutated (ATM) inhibition in vivo induced altered Igκ repertoire and receptor activator of nuclear factor κB ligand production by immature B cells in the bone marrow, leading to decreased bone density. [Sci Transl Med] Abstract

Anti-CD20 Therapy Depletes Activated Myelin-Specific CD8⁺ T Cells in Multiple Sclerosis

Peptide:MHC I tetramers were used to identify and validate five myelin CD8⁺ T cell epitopes, including two newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8⁺ T cells in the peripheral blood of untreated multiple sclerosis patients and HLA allele-matched healthy controls. [Proc Natl Acad Sci USA] Full Article

Cancer-Derived Sialylated IgG Promotes Tumor Immune Escape by Binding to Siglecs on Effector T Cells

Cancer-derived IgG, which carried an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4⁺ and CD8⁺ T-cell infiltration into tumor tissues. [Cell Mol Immunol] Abstract

BRF1 Accelerates Prostate Tumorigenesis and Perturbs Immune Infiltration

In a BRF1 overexpression Pten-deficient mouse, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which could be explained by decreased levels of complement factor D and C7 components of the complement cascade, an innate immune pathway that influenced the adaptive immune response. [Oncogene] Full Article

HCMV miR-US22 Down-Regulation of EGR-1 Regulates CD34⁺ Hematopoietic Progenitor Cell Proliferation and Viral Reactivation

Scientists demonstrated that the transcription factor early growth response gene 1 (EGR-1) was directly targeted for down-regulation by Human Cytomegalovirus (HCMV) miR-US22 that resulted in decreased proliferation of CD34⁺ hematopoietic progenitor cells and a decrease in total hematopoietic colony formation. [PLoS Pathog] Full Article

Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell-Mediated Autoimmunity

Researchers evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient mice and the Ags driving disease manifestations. Data indicated that B cell activation and IgG1/IgE production was triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. [J Immunol] Full Article

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TSLP: From Allergy to Cancer

The authors highlight major recent advances in TSLP biology, along with results from emerging clinical trials of anti-TSLP agents used for the treatment of a variety of inflammatory conditions. [Nat Immunol] Abstract

Controlling Immunity and Inflammation through Integrin-Dependent Regulation of TGF-β

Scientists review the spatiotemporal control of transforming growth factor (TGF)-β activation by integrins, and its effects on immune cell signaling and function. They discuss the underlying molecular and cell-biological mechanisms, the implications for human health and disease, and possibilities for future therapeutic exploitation. [Trends Cell Biol] Abstract

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Sangamo Announces UK Authorization of a Phase I/II Clinical Trial Evaluating the CAR-Treg Cell Therapy TX200 for Kidney Transplantation

Sangamo Therapeutics, Inc. announced that the UK Medicines Healthcare Products Regulatory Agency has granted authorization of the first-in-human clinical trial to evaluate a Chimeric Antigen Receptor Regulatory T Cell (CAR-Treg) therapy. TX200 is being studied for the prevention of immune-mediated rejection following HLA-A2 mismatched kidney transplantation for end-stage renal disease. [Sangamo Therapeutics, Inc.] Press Release

Novartis Receives Positive CHMP Opinion for Mayzent^® (Siponimod) for the Treatment of Adult Patients with Active Secondary Progressive Multiple Sclerosis (SPMS)

Novartis announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion for siponimod for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging features of inflammatory activity. [Novartis AG] Press Release

Science Funders Gamble on Grant Lotteries

The Health Research Council of New Zealand is one of a growing number of funders that award grants partly through random selection. Earlier this year, for example, David Ackerley, a biologist at Victoria University of Wellington, received NZ$150,000 (US$96,000) to develop new ways to eliminate cells – after his number came up in the council’s annual lottery. [Nature News] Editorial

The Science Institutions Hiring Integrity Inspectors to Vet Their Papers

Some researchers have their manuscripts screened for errors before they go to journals. [Nature News] Editorial

NEW Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies
January 9-12, 2020
San Diego, California, United States

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NEW Postdoctoral Fellowship – Genetic Mechanisms of Lupus (Oklahoma Medical Research Foundation)

Research Associate – Immunology (STEMCELL Technologies Inc.)

Scientist – Human Immunology (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Cancer Immunology/Bioengineering (West Virginia University)

Doctoral Student Position – Human Immune Development (Karolinska Institutet)

Postdoctoral Position – Pro-Inflammatory B Cells (Institut Necker Enfants Malades)

Postdoctoral Researcher – CAR T-Cell Immunology (Washington University School of Medicine)

Postdoctoral Research Fellow – Neuro-Immune Control of Metabolism (Fred Hutchinson Cancer Research Center)

Postdoctoral Position – Translational Immuno-Oncology (Georg-Speyer-Haus – Institute for Tumor Biology and Experimental Therapy)

Postdoctoral Fellow – Immunology and Vaccines (University of Maryland)

Postdoctoral Research Associate – Innate Immune Signaling Pathways and Mechanisms (University of Utah)

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