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PAS-15-055: High Priority Immunology Grants (R01)

NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: High Priority Immunology Grants (R01) PAS-15-055. NIAID
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Specific Areas of research interest

Basic immunology and basic immune mechanisms involved in host defense and immune-mediated diseases are of high programmatic interest in this FOA. Research that addresses innate and adaptive immunity at the molecular, cellular, organism, and systems level are encouraged, particularly the use of innovative animal models and studies of the human immune system.

Examples of topics of interest include, but are not limited to:

Molecular mechanisms responsible for long-term, antigen-specific tolerance in T and B cells.Molecular mechanisms responsible for short-term effector functions and long-term memory in T and B cells.Discovery and characterization of novel innate immune receptors, signaling pathways and functions.Ontogeny of the immune system.Structural immunology.Epigenetic modifications in immune responses and immunoregulation.Immunological mechanisms of vaccine efficacy.Genetic, molecular, and cellular immune mechanisms underlying allograft or xenograft rejection or acceptance.Development and preclinical evaluation of novel immunomodulatory approaches to prevent or treat allergies, immune-mediated diseases, and allograft rejection.Genetic, molecular, and cellular immune mechanisms underlying maintenance or loss of transplant tolerance.Non-HLA antigens in transplantation, including autoimmune and heterologous immune responses.Mucosal immunology.Immunological mechanisms of autoimmune disease pathogenesis, remission and relapse.Biomarkers of response to immunomodulatory therapies for autoimmune disease.Influence of gender, microbiome, and environmental factors on self-tolerance and autoimmunity.Immunological basis of effective allergen immunotherapy.Regulatory mechanisms in healthy vs asthmatic airways.Effects of microbial and other environmental exposures on early immune development.Mechanisms of maintenance or loss of tolerance in food allergy.Development and characterization of novel products for allergen immunotherapy.- See more at: http://grants.nih.gov/grants/guide/pa-files/PAS-15-055.html#sthash.DnaJlOuE.dpufSpecific

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This topic is focusing mainly on fundamental systemic immunology.

 

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PPARγ is critical for Mycobacterium tuberculosis induction of Mcl-1 and limitation of human macrophage apoptosis

PPARγ is critical for Mycobacterium tuberculosis induction of Mcl-1 and limitation of human macrophage apoptosis | Immunology | Scoop.it
Author summary The bacterium Mycobacterium tuberculosis is the causative agent of the disease tuberculosis (TB), which is a global health problem and a leading cause of death world-wide. There is a clear need for better therapies for this disease, the design of which is predicated on better...
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Exhausted T cells (Tex)

Exhausted T cells (Tex) | Immunology | Scoop.it
Chronic diseases, such as HIV and cancer, are typically associated with an “exhausted” class of T cells characterized by poor function in disease control. Based on the hypothesis that a better understanding of the phenotypic variation among exhausted T cells may more effectively guide immunotherapy approaches, Bengsch et al. set out t
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References:

Bengsch B., Ohtani T., Khan O., Setty M., Manne S., O'Brien S., Gherardini P.F., Herati R.S., Huang A.C., Chang K.M., Newell E.W., Bovenschen N., Pe'er D., Albelda S.M.,Wherry E.J. Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity. 2018 May 15.

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Immune-centric network of cytokines and cells in disease context identified by computational mining of PubMed

Immune-centric network of cytokines and cells in disease context identified by computational mining of PubMed | Immunology | Scoop.it
Interactions between hundreds of immune cells and cytokines in disease are mined from PubMed.
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ALAI/SMI Highlight:  Have you heard of IL-40? | Immunopaedia

ALAI/SMI Highlight:  Have you heard of IL-40? | Immunopaedia | Immunology | Scoop.it
The closing plenary lecture at the Latin America Congress was presented by Albert Zlotnik from the University of California, Irvine. One of the highlights of
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Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis

Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis | Immunology | Scoop.it
![Figure][1]



To understand the developmental trajectories in early lymphocyte differentiation, we identified differentially expressed surface markers on lineage-negative lymphoid progenitors (LPs). Single-cell polymerase chain reaction experiments allowed us to link surface marker expression to that of lineage-associated transcription factors (TFs) and identify GFRA2 and BST1 as markers of early B cells. Functional analyses in vitro and in vivo as well as single-cell gene expression analyses supported that surface expression of these proteins defined distinct subpopulations that include cells from both the classical common LPs (CLPs) and Fraction A compartments. The formation of the GFRA2-expressing stages of development depended on the TF EBF1, critical both for the activation of stage-specific target genes and modulation of the epigenetic landscape. Our data show that consecutive expression of Ly6D, GFRA2, and BST1 defines a developmental trajectory linking the CLP to the CD19+ progenitor compartment.

[1]: pending:yes
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mice

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Induction and transcriptional regulation of the co-inhibitory gene module in T cells

Induction and transcriptional regulation of the co-inhibitory gene module in T cells | Immunology | Scoop.it
A module of co-inhibitory T cell receptors, driven by the cytokine IL-27, is identified in mice that is regulated by the transcription factors PRDM1 and c-MAF.
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Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection | Immunology | Scoop.it
Resisters are individuals who show resistance to infection despite long-term, high exposure to Mycobacterium tuberculosis. In this Review, Simmons and colleagues discuss potential mechanisms underlying this resistance, such as those mediated by macrophages, T cells and B cells, and how an understanding of these mechanisms might aid in the development of therapies for tuberculosis.
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Single- Genomics: A Stepping Stone for Future Immunology Discoveries

Single- Genomics: A Stepping Stone for Future Immunology Discoveries | Immunology | Scoop.it
Recent and forthcoming technological and analytical advances in single-cell genomics
have the potential to shape the future of immunology research and immunotherapy.
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Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections

Innate Immunity to Staphylococcus aureus: Evolving Paradigms in Soft Tissue and Invasive Infections | Immunology | Scoop.it
Staphylococcus aureus causes a wide range of diseases that together embody a significant public health burden. Aided by metabolic flexibility and a large virulence repertoire, S. aureus has the remarkable ability to hematogenously disseminate and infect various tissues, including skin, lung, heart, and bone, among others. The hallmark lesions of invasive staphylococcal infections, abscesses, simultaneously denote the powerful innate immune responses to tissue invasion as well as the ability of staphylococci to persist within these lesions. In this article, we review the innate immune responses to S. aureus during infection of skin and bone, which serve as paradigms for soft tissue and bone disease, respectively.
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A Single-Cell Transcriptomic Atlas of Thymus Organogenesis Resolves Cell Types and Developmental Maturation

A Single-Cell Transcriptomic Atlas of Thymus Organogenesis Resolves Cell Types and Developmental Maturation | Immunology | Scoop.it
Studies of thymus development typically lack single-cell resolution, use indirect
readouts, or target narrow cell subsets. Using single-cell RNA sequencing during thymus
organogenesis, Kernfeld and Genga et al. reveal cellular heterogeneity, interrogate
developmental dynamics by direct observation, and pinpoint cell-specific expression
patterns in stromal and blood populations.
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Cells |  A Caspase-3 Reporter for Fluorescence Lifetime Imaging of Single-Cell Apoptosis

Cells |  A Caspase-3 Reporter for Fluorescence Lifetime Imaging of Single-Cell Apoptosis | Immunology | Scoop.it
Fluorescence lifetime imaging (FLIM) is a powerful imaging modality used to gather fluorescent reporter data independent of intracellular reporter intensity or imaging depth. We applied this technique to image real-time activation of a reporter for the proteolytic enzyme, caspase-3, in response to...
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Production of complement components by cells of the immune system - Lubbers - 2017 - Clinical & Experimental Immunology - Wiley Online Library

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The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. - PubMed - NCBI

The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. - PubMed - NCBI | Immunology | Scoop.it
Immunol Lett. 2017 Dec;192:72-78. doi: 10.1016/j.imlet.2017.10.012. Epub 2017 Oct 26.
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Frontiers | Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults | Immunology

Frontiers | Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults | Immunology | Immunology | Scoop.it
BACKGROUND:Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. OBJECTIVES: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. METHODS: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. RESULTS: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.4%) met diagnostic criteria for Common Variable Immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining 4 patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, wit
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Frontiers | “Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology | Immunology

Frontiers | “Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology | Immunology | Immunology | Scoop.it
Primary immunodeficiencies (PIDs) represent a group of mostly monogenic disorders caused by loss- or gain-of-function mutations in over 340 known genes that lead to abnormalities in the development and/or the function of the immune system. However, mutations in different genes can affect the same cell-signaling pathway and result in overlapping clinical phenotypes. In particular, mutations in the genes encoding for members of the PI3K/AKT/mTOR/S6K signaling cascade or for molecules interacting with this pathway have been associated with different PIDs that are often characterized by the coexistence of both immune deficiency and autoimmunity. The serine/threonine kinase mTOR (mechanistic/mammalian target of rapamycin), which acts downstream of PI3K and AKT, is emerging as a key regulator of immune responses. It integrates a variety of signals from the microenvironment to control cell growth, proliferation, and metabolism. mTOR plays therefore a central role in the regulation of immune cells’ differentiation and functions. Here, we review the different PIDs that share an impairment of the PI3K/AKT/mTOR/S6K pathway and we propose to name them “immune TOR-opathies” by analogy with a group of neurological disorders that has been originally defined by PB Crino and that are due to aberrant mTOR signaling (1). A better understanding of the role played by this complex intracellular cascade in the pathophysiology of “immune TOR-opathies” is crucial to develop targeted therapies.
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Developmental Origin Governs CD8+ T Fate Decisions during Infection

Developmental Origin Governs CD8+ T  Fate Decisions during Infection | Immunology | Scoop.it
The discovery of multiple sub-populations of naive T cells, distinguished by their
developmental origin and molecular profiles prior to microbial challenge, explains
the heterogeneity observed in memory and effector pools.
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Treg cells protect babies from getting HIV infection from their mothers

Treg cells protect babies from getting HIV infection from their mothers | Immunology | Scoop.it
Scientists now report that Treg cells, a type of regulatory lymphocyte, may be protecting babies in the womb from getting infected with the HIV virus when the mother is infected.
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Frontiers | Immunometabolic Activation of Invariant Natural Killer T Cells | Immunology

Frontiers | Immunometabolic Activation of Invariant Natural Killer T Cells | Immunology | Immunology | Scoop.it
Invariant Natural Killer T (iNKT) cells are lipid- reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation to immunometabolic disease, metabolic programming of lipid antigen presentation and immunometabolic activation of iNKT cells. First, we outline the role of iNKT cells in immunometabolic disease. Second, we discuss the effects of cellular metabolism on lipid antigen processing and presentation to iNKT cells. The synthesis and processing of glycolipids and other potential endogenous lipid antigens depends on metabolic demand, and may steer iNKT cells towards adopting a Th1 or Th2 signature. Third, external signals such as Toll-like receptor ligands, adipokines and cytokines modulate antigen presentation and subsequent iNKT cell responses. Finally, we will discuss the relevance of metabolic programming of iNKT cells in human disease, focusing on their role in disorders such as obesity and atherosclerosis. The critical response to metabolic changes places iNKT cells at the helm of immunometabolic disease.
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Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis

Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis | Immunology | Scoop.it
The cytokine IL-2 is critical for promoting the development, homeostasis, and function of regulatory T (Treg) cells. The cellular sources of IL-2 that promote these processes remain unclear. T cells, B cells, and dendritic cells (DCs) are known to make IL-2 in peripheral tissues. We found that T cells and DCs in the thymus also make IL-2. To identify cellular sources of IL-2 in Treg cell development and homeostasis, we used Il2FL/FL mice to selectively delete Il2 in T cells, B cells, and DCs. Because IL-15 can partially substitute for IL-2 in Treg cell development, we carried out the majority of these studies on an Il15−/− background. Deletion of Il2 in B cells, DCs, or both these subsets had no effect on Treg cell development, either in wild-type (WT) or Il15−/− mice. Deletion of Il2 in T cells had minimal effects in WT mice but virtually eliminated developing Treg cells in Il15−/− mice. In the spleen and most peripheral lymphoid organs, deletion of Il2 in B cells, DCs, or both subsets had no effect on Treg cell homeostasis. In contrast, deletion of Il2 in T cells led to a significant decrease in Treg cells in either WT or Il15−/− mice. The one exception was the mesenteric lymph nodes where significantly fewer Treg cells were observed when Il2 was deleted in both T cells and DCs. Thus, T cells are the sole source of IL-2 needed for Treg cell development, but DCs can contribute to Treg cell homeostasis in select organs.
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New insights into the immunomodulatory properties of poxvirus cytokine decoy receptors at the cell surface - F1000Research

Poxviruses encode a set of secreted proteins that bind cytokines and chemokines as a strategy to modulate host defense mechanisms. These viral proteins mimic the activity of host cytokine decoy receptors but have unique properties that may enhance their activity.
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CD4+ T cell–mediated HLA class II cross-restriction in HIV controllers

CD4+ T cell–mediated HLA class II cross-restriction in HIV controllers | Immunology | Scoop.it
A small number of HIV-infected individuals (<1%) can spontaneously control HIV in the absence of antiretroviral therapy. Because CD4+ and CD8+ T cell responses are thought to contribute to protection, HIV-responsive T cell receptors (TCRs) from these individuals are of considerable interest. Galperin et al . have examined how three public class II–restricted TCRs—F24, F25, and F5—documented in spontaneous controllers are capable of binding a Gag peptide, Gag 293–312, in the context of multiple HLA-DR molecules. By solving the structures of multiple TCR–peptide–HLA-DR complexes, the authors report that the ability of these TCRs to recognize this Gag peptide in the context of multiple HLA-DR allomorphs is shaped by extensive contacts between these TCRs and the peptide itself.
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Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue

Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue | Immunology | Scoop.it
In HIV+ individuals receiving antiretroviral therapy, lymphoid tissues (LTs) that CD4+ T cells home to are a key site of HIV persistence. Studying the immune response to HIV in LTs has remained a challenge. By obtaining LTs from HIV+ individuals, Buggert et al. have carried out comprehensive transcriptional and epigenetic analyses on CD8+ T cells in these LTs. They report that CD8+ T cells in LTs of HIV+ individuals have a signature associated with resident memory T cells (TRMs) and that the frequency of these HIV-responsive LT-resident CD8+ T cells was considerably increased in elite controllers. The study brings to the fore the importance of HIV-specific LT-resident TRMs in restraining HIV replication in LTs.
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