Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy

AbstractThe use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.

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Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

Toxicologic Pathology ◽

10.1177/0192623319886304 ◽

2019 ◽

Vol 48 (2) ◽

pp. 302-316 ◽

Cited By ~ 4

Author(s):

Michelle Curran ◽

Maelle Mairesse ◽

Alba Matas-Céspedes ◽

Bethany Bareham ◽

Giovanni Pellegrini ◽

...

Keyword(s):

Immune System ◽

New Technologies ◽

Immune Cell ◽

Human Immune System ◽

Immunodeficient Mice ◽

Graft Versus Host ◽

Human Immune ◽

And Function ◽

Human Cytokines

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

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Cellular and metabolic mechanisms of nutrient actions in immune function

Nutrition and Diabetes ◽

10.1038/s41387-021-00162-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Philip Newsholme

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Vitamin D ◽

Immune System ◽

Cell Function ◽

Immune Cell ◽

Cell Structure ◽

Nutritional Intervention ◽

Immune Cell Function ◽

And Function

AbstractVarious nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency.

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Human immune system variation during one year

10.1101/2020.01.22.915025 ◽

2020 ◽

Cited By ~ 1

Author(s):

Tadepally Lakshmikanth ◽

Sayyed Auwn Muhammad ◽

Axel Olin ◽

Yang Chen ◽

Jaromir Mikes ◽

...

Keyword(s):

Immune System ◽

Individual Variation ◽

Immune Cell ◽

Metabolic Health ◽

Individual Feature ◽

Human Immune System ◽

Principal Curve ◽

Human Immune ◽

One Year ◽

Over Time

SUMMARYThe human immune system varies extensively between individuals, but variation within individuals over time has not been well characterized. Systems-level analyses allow for simultaneous quantification of many interacting immune system components, and the inference of global regulatory principles. Here we present a longitudinal, systems-level analysis in 99 healthy adults, 50 to 65 years of age and sampled every 3rd month during one year. We describe the structure of inter-individual variation and characterize extreme phenotypes along a principal curve. From coordinated measurement fluctuations, we infer relationships between 115 immune cell populations and 750 plasma proteins constituting the blood immune system. While most individuals have stable immune systems, the degree of longitudinal variability is an individual feature. The most variable individuals, in the absence of overt infections, exhibited markers of poor metabolic health suggestive of a functional link between metabolic and immunologic homeostatic regulation.HIGHLIGHTSLongitudinal variation in immune cell composition during one yearInter-individual variation can be described along a principal curveImmune cell and protein relationships are inferredVariability over time is an individual feature correlating with markers of poor metabolic health

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EZH2 function in immune cell development

Biological Chemistry ◽

10.1515/hsz-2019-0436 ◽

2020 ◽

Vol 401 (8) ◽

pp. 933-943 ◽

Cited By ~ 5

Author(s):

Stephen L. Nutt ◽

Christine Keenan ◽

Michaël Chopin ◽

Rhys S. Allan

Keyword(s):

Immune System ◽

Cell Function ◽

Immune Cell ◽

Proliferating Cells ◽

Hematopoietic Stem ◽

Polycomb Repressive Complex 2 ◽

Current State ◽

Core Components ◽

And Function ◽

Cell Cycle Inhibitors

AbstractThe polycomb repressive complex 2 (PRC2) consists of three core components EZH2, SUZ12 and EED. EZH2 catalyzes the methylation of lysine 27 of histone H3, a modification associated with gene silencing. Through gene duplication higher vertebrate genomes also encode a second partially redundant methyltransferase, EZH1. Within the mammalian immune system most research has concentrated on EZH2 which is expressed predominantly in proliferating cells. EZH2 and other PRC2 components are required for hematopoietic stem cell function and lymphocyte development, at least in part by repressing cell cycle inhibitors. At later stages of immune cell differentiation, EZH2 plays essential roles in humoral and cell-mediated adaptive immunity, as well as the maintenance of immune homeostasis. EZH2 is often overactive in cancers, through both gain-of-function mutations and over-expression, an observation that has led to the development and clinical testing of specific EZH2 inhibitors. Such inhibitors may also be of use in inflammatory and autoimmune settings, as EZH2 inhibition dampens the immune response. Here, we will review the current state of understanding of the roles for EZH2, and PRC2 more generally, in the development and function of the immune system.

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Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

Frontiers in Immunology ◽

10.3389/fimmu.2021.657293 ◽

2021 ◽

Vol 12 ◽

Author(s):

Javier Traba ◽

Michael N. Sack ◽

Thomas A. Waldmann ◽

Olga M. Anton

Keyword(s):

Immune System ◽

Immune Cells ◽

Immune Cell ◽

Cell Metabolism ◽

Immune Surveillance ◽

Antitumor Effects ◽

Cancer Management ◽

Immunosuppressive Tumor Microenvironment ◽

And Function ◽

Main Effects

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

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Immunological Consequences of In Utero Exposure to Foreign Antigens

Frontiers in Immunology ◽

10.3389/fimmu.2021.638435 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jeng-Chang Chen

Keyword(s):

Immune System ◽

Immune Surveillance ◽

In Utero ◽

Fetal Exposure ◽

Hematopoietic Stem ◽

Unique Approach ◽

Hematopoietic Chimerism ◽

Potential Basis ◽

Donor Specific Tolerance ◽

Fetal Immune System

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen’s observation of blood cell sharing in twin calves. Owen’s conceptual framework subsequently constituted the backbone of Medawar’s “actively acquired tolerance” as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as “self” so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of “actively acquired tolerance” might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.

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Comprehensive multi-omics single-cell data integration reveals greater heterogeneity in the human immune system

10.1101/2021.07.25.453651 ◽

2021 ◽

Author(s):

Congmin Xu ◽

Junkai Yang ◽

Astrid Kosters ◽

Benjamin R Babcock ◽

Peng Qiu ◽

...

Keyword(s):

Immune System ◽

Single Cell ◽

Immune Cell ◽

Cell Types ◽

Cell Receptor ◽

Surface Proteins ◽

Cell Type ◽

Human Immune System ◽

Receptor Repertoire ◽

Human Immune

Single-cell transcriptomics enables the definition of diverse human immune cell types across multiple tissue and disease contexts. Still, deeper biological understanding requires comprehensive integration of multiple single-cell omics (transcriptomic, proteomic, and cell receptor repertoire). To improve the identification of diverse cell types and the accuracy of cell-type classification in our multi-omics single-cell datasets, we developed SuPERR-seq, a novel analysis workflow to increase the resolution and accuracy of clustering and allow for the discovery and characterization of previously hidden cell subsets. We show that by incorporating information from cell-surface proteins and immunoglobulin transcript counts, we accurately remove cell doublets and prevent widespread cell-type misclassification. This approach uniquely improves the identification of heterogeneous cell types in the human immune system, including a novel subset of antibody-secreting cells in the bone marrow.

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Sexual-dimorphism in human immune system aging

10.1101/755702 ◽

2019 ◽

Author(s):

Eladio J. Márquez ◽

Cheng-han Chung ◽

Radu Marches ◽

Robert J. Rossi ◽

Djamel Nehar-Belaid ◽

...

Keyword(s):

Immune System ◽

Mononuclear Cells ◽

Immune Cell ◽

Rna Seq ◽

Human Immune System ◽

Peripheral Blood Mononuclear ◽

Cell Functions ◽

Age Related ◽

Male Specific

AbstractDifferences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow-cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte/cytotoxic cell functions. These changes were greater in magnitude in men and accompanied by a male-specific genomic decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune cell genomes can be visualized at https://immune-aging.jax.org to provide insights into future studies.

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Immunostimulatory Potential of Natural Compounds and Extracts: A Review

Current Nutrition & Food Science ◽

10.2174/1573401315666190301154200 ◽

2020 ◽

Vol 16 (4) ◽

pp. 444-454

Author(s):

Andreea C. Stroe ◽

Simona Oancea

Keyword(s):

Immune System ◽

Plant Species ◽

Biological Effects ◽

Scientific Evidence ◽

Natural Compounds ◽

Food Supplements ◽

Human Immune System ◽

Species Type ◽

Human Immune ◽

Immunomodulatory Properties

The proper functioning of human immune system is essential for organism survival against infectious, toxic and oncogenic agents. The present study aimed to describe the scientific evidence regarding the immunomodulatory properties of the main micronutrients and specific phytochemicals. Plants of food interest have the ability to dynamically affect the immune system through particular molecules. Plant species, type of compounds and biological effects were herein reviewed mainly focusing on plants which are not commonly used in food supplements. Several efficient phytoproducts showed significant advantages compared to synthetic immunomodulators, being good candidates for the development of immunotherapeutic drugs.

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