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1.
J Toxicol Environ Health B Crit Rev ; 27(7): 233-263, 2024 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-38994870

RESUMEN

The microbiome-gut-brain axis is altered by environmental stressors such as heat, diet, and pollutants as well as microbes in the air, water, and soil. These stressors might alter the host's microbiome and symbiotic relationship by modifying the microbial composition or location. Compartmentalized mutualistic microbes promote the beneficial interactions in the host leading to circulating metabolites and hormones such as insulin and leptin that affect inter-organ functions. Inflammation and oxidative stress induced by environmental stressors may alter the composition, distribution, and activities of the microbes in the microbiomes such that the resultant metabolite and hormone changes are no longer beneficial. The microbiome-gut-brain axis and immune adverse changes that may accompany environmental stressors are reviewed for effects on innate and adaptive immune cells, which may make host immunity less responsive to pathogens and more reactive to self-antigens. Cardiovascular and fluid exchanges to organs might adversely alter organ functionality. Organs, especially the brain, need a consistent supply of nutrients and clearance of debris; disruption of these exchanges by stressors, and involvement of gut microbiome are discussed regarding neural dysfunctions with Alzheimer's disease, autistic spectrum disorders, viral infections, and autoimmune diseases. The focus of this review includes the manner in which environmental stressors may disrupt gut microbiota leading to adverse immune and hormonal influences on development of neuropathology related to hyperhomocysteinemia, inflammation, and oxidative stress, and how certain therapeutics may be beneficial. Strategies are explored to lessen detrimental effects of environmental stressors on central and peripheral health navigated toward (1) understanding neurological disorders and (2) promoting environmental and public health and well-being.


Asunto(s)
Eje Cerebro-Intestino , Microbioma Gastrointestinal , Enfermedades del Sistema Nervioso , Humanos , Microbioma Gastrointestinal/inmunología , Eje Cerebro-Intestino/fisiología , Eje Cerebro-Intestino/inmunología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/microbiología , Animales , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/toxicidad , Encéfalo/inmunología
2.
Viruses ; 16(6)2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38932242

RESUMEN

Multisystem Inflammatory Syndrome in Children (MIS-C) is a potentially life-threatening complication of COVID-19. The pathophysiological mechanisms leading to severe disease are poorly understood. This study leveraged clinical samples from a well-characterized cohort of children hospitalized with COVID-19 or MIS-C to compare immune-mediated biomarkers. Our objective was to identify selected immune molecules that could explain, in part, why certain SARS-CoV-2-infected children developed MIS-C. We hypothesized that type-2 helper T cell-mediated inflammation can elicit autoantibodies, which may account for some of the differences observed between the moderate-severe COVID-19 (COVID+) and MIS-C cohort. We enumerated blood leukocytes and measured levels of selected serum cytokines, chemokines, antibodies to COVID-19 antigens, and autoantibodies in children presenting to an academic medical center in Connecticut, United States. The neutrophil/lymphocyte and eosinophil/lymphocyte ratios were significantly higher in those in the MIS-C versus COVID+ cohort. IgM and IgA, but not IgG antibodies to SARS-CoV-2 receptor binding domain were significantly higher in the MIS-C cohort than the COVID+ cohort. The serum levels of certain type-2 cytokines (interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10, IL-13, and IL-33) were significantly higher in children with MIS-C compared to the COVID+ and SARS-CoV-2-negative cohorts. IgG autoantibodies to brain antigens and pentraxin were higher in children with MIS-C compared to SARS-CoV-19-negative controls, and children with MIS-C had higher levels of IgG anti-contactin-associated protein-like 2 (caspr2) compared to the COVID+ and SARS-CoV-19-negative controls. We speculate that autoimmune responses in certain COVID-19 patients may induce pathophysiological changes that lead to MIS-C. The triggers of autoimmunity and factors accounting for type-2 inflammation require further investigation.


Asunto(s)
Autoanticuerpos , COVID-19 , Citocinas , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , COVID-19/inmunología , COVID-19/sangre , COVID-19/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Niño , Femenino , Masculino , Estudios Prospectivos , SARS-CoV-2/inmunología , Preescolar , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Citocinas/sangre , Adolescente , Lactante , Biomarcadores/sangre , Anticuerpos Antivirales/sangre , Inflamación/inmunología , Inflamación/sangre
3.
Vaccines (Basel) ; 12(4)2024 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-38675771

RESUMEN

Immune responses to influenza (flu) antigens reflect memory of prior infections or vaccinations, which might influence immunity to new flu antigens. Memory of past antigens has been termed "original antigenic sin" or, more recently, "immune imprinting" and "seniority". We have researched a comparison between the immune response to live flu infections and inactivated flu vaccinations. A brief history of antibody generation theories is presented, culminating in new findings about the immune-network theory and suggesting that a network of clones exists between anti-idiotypic antibodies and T cell receptors. Findings regarding the 2009 pandemic flu strain and immune responses to it are presented, including memory B cells and conserved regions within the hemagglutinin protein. The importance of CD4+ memory T cells and cytotoxic CD8+ T cells responding to both infections and vaccinations are discussed and compared. Innate immune cells, like natural killer (NK) cells and macrophages, are discussed regarding their roles in adaptive immune responses. Antigen presentation via macroautophagy processes is described. New vaccines in development are mentioned along with the results of some clinical trials. The manuscript concludes with how repeated vaccinations are impacting the immune system and a sketch of what might be behind the imprinting phenomenon, including future research directions.

4.
PLoS One ; 18(11): e0293652, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37992059

RESUMEN

Studies suggest perinatal infection with SARS-CoV-2 can induce adverse birth outcomes, but studies published to date have substantial limitations. We therefore conducted an observational study of 211 births occurring between January 2020-September 2021 in three urban cohorts participating in the Environmental Influences on Child Health Outcomes Program. Serology was assessed for IgG, IgM and IgA antibodies to nucleocapsid, S1 spike, S2 spike, and receptor-binding domain. There were no differences in gestational age (GA), birth weight, preterm birth (PTB) or low birth weight (LBW) among seropositive mothers. However, the few (n = 9) IgM seropositive mothers had children with lower BW (434g, 95% CI: 116-752), BW Z score-for-GA (0.73 SD, 95% CI 0.10-1.36) and were more likely to deliver preterm (OR 8.75, 95% CI 1.22-62.4). Though there are limits to interpretation, the data support efforts to prevent SARS-CoV-2 infections in pregnancy.


Asunto(s)
COVID-19 , Nacimiento Prematuro , Embarazo , Femenino , Recién Nacido , Humanos , Niño , SARS-CoV-2 , Nacimiento Prematuro/epidemiología , Cohorte de Nacimiento , COVID-19/epidemiología , Inmunoglobulina M , Evaluación de Resultado en la Atención de Salud
5.
J Toxicol Environ Health A ; 86(17): 597-613, 2023 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-37335069

RESUMEN

Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and dichlorodiphenyltrichloroethane (p,p'-DDT) were reported to influence immunological activity. As endocrine-disrupting chemicals (EDC), these pollutants may disrupt normal thyroid function and act as catalysts for development of autoimmune thyroid disease by directly and indirectly affecting levels of thyroid peroxidase antibodies (TPOAbs). Native American communities are disproportionately exposed to harmful toxicants and are at an increased risk of developing an autoimmune disease. The aim of this study was to determine the association between POPs and TPOAbs in serum obtained from Native American women. This assessment was used to measure whether increased risk of autoimmune thyroid disease occurred as a result of exposure to POPs. Data were collected from 183 Akwesasne Mohawk women, 21-38 years of age, between 2009 and 2013. Multivariate analyses were conducted to determine the association between toxicant exposure and levels of TPOAbs. In multiple logistic regression analyses, exposure to PCB congener 33 was related to elevated risk of individuals possessing above normal levels of TPOAbs. Further, HCB was associated with more than 2-fold higher risk of possessing above normal levels of TPOAbs compared to women with normal levels of TPOAbs. p,p'-DDE was not associated with TPOAb levels within this study. Exposure to PCB congener 33 and HCB was correlated with above normal levels of TPOAbs, a marker of autoimmune thyroid disease. Additional investigations are needed to establish the causes and factors surrounding autoimmune thyroid disease which are multiple and complex.


Asunto(s)
Contaminantes Ambientales , Bifenilos Policlorados , Enfermedades de la Tiroides , Humanos , Femenino , Bifenilos Policlorados/análisis , Hexaclorobenceno/análisis , Yoduro Peroxidasa , Peroxidasa , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/análisis , Autoanticuerpos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/epidemiología
6.
Front Bioeng Biotechnol ; 11: 1066391, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37064248

RESUMEN

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that can develop 4-6 weeks after a school age child becomes infected by SARS-CoV-2. To date, in the United States more than 8,862 cases of MIS-C have been identified and 72 deaths have occurred. This syndrome typically affects children between the ages of 5-13; 57% are Hispanic/Latino/Black/non-Hispanic, 61% of patients are males and 100% have either tested positive for SARS-CoV-2 or had direct contact with someone with COVID-19. Unfortunately, diagnosis of MIS-C is difficult, and delayed diagnosis can lead to cardiogenic shock, intensive care admission, and prolonged hospitalization. There is no validated biomarker for the rapid diagnosis of MIS-C. In this study, we used Grating-coupled Fluorescence Plasmonic (GCFP) microarray technology to develop biomarker signatures in pediatric salvia and serum samples from patients with MIS-C in the United States and Colombia. GCFP measures antibody-antigen interactions at individual regions of interest (ROIs) on a gold-coated diffraction grating sensor chip in a sandwich immunoassay to generate a fluorescent signal based on analyte presence within a sample. Using a microarray printer, we designed a first-generation biosensor chip with the capability of capturing 33 different analytes from 80  µ L of sample (saliva or serum). Here, we show potential biomarker signatures in both saliva and serum samples in six patient cohorts. In saliva samples, we noted occasional analyte outliers on the chip within individual samples and were able to compare those samples to 16S RNA microbiome data. These comparisons indicate differences in relative abundance of oral pathogens within those patients. Microsphere Immunoassay (MIA) of immunoglobulin isotypes was also performed on serum samples and revealed MIS-C patients had several COVID antigen-specific immunoglobulins that were significantly higher than other cohorts, thus identifying potential new targets for the second-generation biosensor chip. MIA also identified additional biomarkers for our second-generation chip, verified biomarker signatures generated on the first-generation chip, and aided in second-generation chip optimization. Interestingly, MIS-C samples from the United States had a more diverse and robust signature than the Colombian samples, which was also illustrated in the MIA cytokine data. These observations identify new MIS-C biomarkers and biomarker signatures for each of the cohorts. Ultimately, these tools may represent a potential diagnostic tool for use in the rapid identification of MIS-C.

7.
Cell Stress Chaperones ; 28(2): 201-217, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36795226

RESUMEN

Oxidative stress including decreased antioxidant enzyme activities, elevated lipid peroxidation, and accumulation of advanced glycation end products in the blood from children with autism spectrum disorders (ASD) has been reported. The mechanisms affecting the development of ASD remain unclear; however, toxic environmental exposures leading to oxidative stress have been proposed to play a significant role. The BTBRT+Itpr3tf/J (BTBR) strain provides a model to investigate the markers of oxidation in a mouse strain exhibiting ASD-like behavioral phenotypes. In the present study, we investigated the level of oxidative stress and its effects on immune cell populations, specifically oxidative stress affecting surface thiols (R-SH), intracellular glutathione (iGSH), and expression of brain biomarkers that may contribute to the development of the ASD-like phenotypes that have been observed and reported in BTBR mice. Lower levels of cell surface R-SH were detected on multiple immune cell subpopulations from blood, spleens, and lymph nodes and for sera R-SH levels of BTBR mice compared to C57BL/6 J (B6) mice. The iGSH levels of immune cell populations were also lower in the BTBR mice. Elevated protein expression of GATA3, TGM2, AhR, EPHX2, TSLP, PTEN, IRE1α, GDF15, and metallothionein in BTBR mice is supportive of an increased level of oxidative stress in BTBR mice and may underpin the pro-inflammatory immune state that has been reported in the BTBR strain. Results of a decreased antioxidant system suggest an important oxidative stress role in the development of the BTBR ASD-like phenotype.


Asunto(s)
Trastorno Autístico , Ratones , Animales , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Endorribonucleasas/metabolismo , Antioxidantes/metabolismo , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/metabolismo , Estrés Oxidativo , Modelos Animales de Enfermedad
8.
Am J Reprod Immunol ; 89(4): e13688, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36788284

RESUMEN

PROBLEM: Previous studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS). METHOD OF STUDY: The Upstate KIDS Study (2008-2010) is a prospective cohort of mother-child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1 , IgG2 , IgG3 , IgG4 , and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status. RESULTS: IgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively. CONCLUSIONS: MOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD. Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted.


Asunto(s)
Cesárea , Parto , Embarazo , Femenino , Recién Nacido , Lactante , Humanos , Estudios Prospectivos , Inmunoglobulina A , Inmunoglobulina G
9.
Artículo en Inglés | MEDLINE | ID: mdl-38248493

RESUMEN

This review delves into the complex relationship between environmental factors, their mechanistic cellular and molecular effects, and their significant impact on human health. Climate change is fueled by industrialization and the emission of greenhouse gases and leads to a range of effects, such as the redistribution of disease vectors, higher risks of disease transmission, and shifts in disease patterns. Rising temperatures pose risks to both food supplies and respiratory health. The hypothesis addressed is that environmental stressors including a spectrum of chemical and pathogen exposures as well as physical and psychological influences collectively impact genetics, metabolism, and cellular functions affecting physical and mental health. The objective is to report the mechanistic associations linking environment and health. As environmental stressors intensify, a surge in health conditions, spanning from allergies to neurodegenerative diseases, becomes evident; however, linkage to genetic-altered proteomics is more hidden. Investigations positing that environmental stressors cause mitochondrial dysfunction, metabolic syndrome, and oxidative stress, which affect missense variants and neuro- and immuno-disorders, are reported. These disruptions to homeostasis with dyslipidemia and misfolded and aggregated proteins increase susceptibility to cancers, infections, and autoimmune diseases. Proposed interventions, such as vitamin B supplements and antioxidants, target oxidative stress and may aid mitochondrial respiration and immune balance. The mechanistic interconnections of environmental stressors and disruptions in health need to be unraveled to develop strategies to protect public health.


Asunto(s)
Antioxidantes , Enfermedades Autoinmunes , Humanos , Animales , Cambio Climático , Suplementos Dietéticos , Vectores de Enfermedades
10.
Brain Behav Immun Health ; 26: 100563, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36439055

RESUMEN

Autism spectrum disorder (ASD) is a complicated neurodevelopmental disorder, which is categorized by deficiency of social contact and communication, and stereotyped forms of performance. Meningeal immunity conditions the immune reflection and immune defense in the meningeal area involving meningeal lymphatic organization, glymphatic structure, immune cells, and cytokines. The development of meningeal immunity dysfunction might be the leading cause for many neural diseases including ASD. The inbred mouse strain BTBRT + Itpr3tf/J (BTBR) shows multiple ASD-like behavioral phenotypes, thus making this strain a widely used animal model for ASD. In our previous study, we reported an altered peripheral immune profile in BTBR mice. Herein, we are investigating immunological and neural interactions associated with the aberrant behavior of BTBR mice. BTBR mice have an increased level of immune cell deposition in the meninges along with a higher level of CD4+ T cells expressing CD25 and of B and myeloid cells expressing more MHCII than C57BL/6 (B6) mice, which have normal behaviors. BTBR mice also have higher levels of autoantibodies to dsDNA, Aquaporin-4, NMDAR1, Pentraxin/SAP and Caspr2 than B6 mice, which may affect neural functions. Interestingly, the T regulatory (Treg) cell population and their function was significantly reduced in the meninges and brain draining lymph nodes, which may explain the increased level of activated B and T cells in the meninges of BTBR mice. A low level of Treg cells, less IL-10 production by Treg, and activated T and B cells in meninges together with higher autoantibody levels might contribute to the development of autism-like behavior through neuroinflammation, which is known to be increased in BTBR mice.

11.
Environ Pollut ; 308: 119656, 2022 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-35787426

RESUMEN

Infant exposure to per/polyfluoroalkyl compounds is associated with immune disruption. We examined associations between neonatal concentrations of perflurooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) and immunoglobulin (Ig) isotype profiles in a prospective cohort of infants. We measured Ig isotypes, including IgA, IgE, IgM and the IgG subclasses IgG1, IgG2, IgG3, and IgG4, and PFOA and PFOS in newborn dried bloodspots from N = 3175 infants in the Upstate KIDS Study (2008-2010). We examined the association between newborn Ig isotype levels and individual PFOS and PFOA concentrations using mixed effects regression models with a random intercept to account for twins among study participants. We assessed the joint effect PFOA and PFOS with quantile-based g-computation on all singletons and one randomly selected twin (N = 2901), with Ig categorized as above or below median value. Models were adjusted for infant sex, and maternal pre-pregnancy body mass index, race, parity, age and infertility treatment. In adjusted models, PFOA was inversely associated with IgE (coefficient = -0.12 per unit increase in PFOA, 95% CI: -0.065, -0.17), whereas IgG2, IgM, and IgA were positively associated with PFOA (coefficient for IgG2 = 0.22, 95% CI: 0.15, 0.27; coefficient for IgM = 0.11, 95% CI: 0.08, 0.15; and coefficient for IgA = 0.15, 95% CI: 0.07, 0.18). There was no relation between PFOS and Ig isotypes. Analysis of the joint effect of PFOA and PFOS showed an OR of 1.2 (95% CI: 1.04, 1.36) for IgA and OR of 1.12 (95% CI: 1.00, 1.24) for IgG2 levels above the median for every quartile increase. PFOA levels were significantly associated with elevated IgA, IgM, IgG2, and reduced levels of IgE in single-pollutant models. A small but significant joint effect of PFOA and PFOS was observed. Our results suggest that early exposure to PFOA and PFOS may disrupt neonatal immunoglobulin levels.


Asunto(s)
Ácidos Alcanesulfónicos , Fluorocarburos , Caprilatos , Femenino , Humanos , Inmunoglobulina A , Inmunoglobulina E , Inmunoglobulina G , Inmunoglobulina M , Lactante , Recién Nacido , Embarazo , Estudios Prospectivos
12.
J Neuroimmunol ; 368: 577893, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35617718

RESUMEN

Mitochondria-mediated metabolic impairment and dysfunction are highly related with autism. Herein, the mitochondria-mediated metabolism of BTBR T+Itpr3tf/J (BTBR) mice with autistic-like behaviors was investigated. A new BTBR-mtB6 strain generated by deriving BTBR mice with C57BL/6J (B6) mitochondria was used to determine the role of the mitochondrial genome. The BTBR-mtB6 mice had improved social behaviors, higher levels of glutamate and astrocytes in the brain and less neuroinflammation than the BTBR mice; however, many of the metabolic parameters of BTBR mice such as enhanced fatty acid ß-oxidation and lower glycolysis and glutaminolysis in immune cells compared to B6 mice were not or only partial improved in the BTBR-mtB6 strain. The BTBR and BTBR-mtB6 mice also had equivalent ETC (enhanced electron transport chain) activity of mitochondria, with an increase of reactive oxygen species (ROS) and decreased mitochondrial membrane potential compared to the B6 mice. The results suggest that the mitochondrial replacement with its metabolic alterations affect brain functions more than peripheral immune cell activities.


Asunto(s)
Trastorno Autístico , Animales , Trastorno Autístico/genética , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Mitocondrias/metabolismo
13.
J Toxicol Environ Health A ; 85(17): 715-737, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-35611390

RESUMEN

Environmental contaminants perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are present in human serum at the highest concentration among all per- and polyfluoroalkyl substances (PFAS). Serum concentrations as high as 500 ng and 3000 ng PFOA/ml have been detected in individuals living near contamination sites and those occupationally exposed, respectively. Animal and human studies indicated that PFOA and PFOS at these serum concentrations perturb the immune system. The aim of this study was to examine the effects of in vitro exposure of human peripheral blood mononuclear cells (PBMC) to 1, 10, or 100 µM PFOA or PFOS in a medium with serum (RPMI-1640 + 5% human AB serum) on the measurement of proliferation, T cell activation, generation of memory T cells, and cytokine production/secretion. In addition, these immune system parameters were assessed for PBMC in a serum-free medium (OpSFM), which was stimulated with phytohemagglutinin (PHA) (2.5 µg/ml) or influenza vaccine antigen (0.625 µg/ml Flu Ag). PFOS decreased proliferation stimulated by PHA or Flu Ag. With Flu Ag stimulation, PFOA and PFOS inhibited the generation of memory T cells in a concentration-dependent manner. In OpSFM, PFOA and PFOS produced no marked change in proliferation and no inhibition of T cell activation. Cytokines measured in the media with Luminex methodology indicated decreased PBMC secretion of IFN-γ by PFOA and PFOS in medium with serum, but no alteration in OpSFM. The results indicated that changes in immune parameters due to PFOA or PFOS following Flu Ag stimulation are medium (±serum) dependent.


Asunto(s)
Ácidos Alcanesulfónicos , Fluorocarburos , Ácidos Alcanesulfónicos/toxicidad , Animales , Caprilatos/toxicidad , Fluorocarburos/toxicidad , Humanos , Leucocitos Mononucleares , Mitógenos/farmacología
14.
Front Pediatr ; 10: 859885, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35573953

RESUMEN

Obesity rates in women of childbearing age is now at 29%, according to recent CDC reports. It is known that obesity is associated with oxidative stress and inflammation, including disruptions in cellular function and cytokine levels. In pregnant women who are obese, associated placental dysfunction can lead to small for gestational age (SGA) infants. More frequently, however, maternal obesity is associated with large for gestational age (LGA) newborns, who also have higher incidence of metabolic disease and asthma due to elevated levels of inflammation. In addition, anthropogenic environmental exposures to "endocrine disrupting" and "forever" chemicals affect obesity, as well as maternal physiology, the placenta, and fetal development. Placental function is intimately associated with the control of inflammation during pregnancy. There is a large amount of literature examining the relationship of placental immunology, both cellular and humoral, with pregnancy and neonatal outcomes. Cells such as placental macrophages and NK cells have been implicated in spontaneous miscarriage, preeclampsia, preterm birth, perinatal neuroinflammation, and other post-natal conditions. Differing levels of placental cytokines and molecular inflammatory mediators also have known associations with preeclampsia and developmental outcomes. In this review, we will specifically examine the literature regarding maternal, placental, and fetal immunology and how it is altered by maternal obesity and environmental chemicals. We will additionally describe the relationship between placental immune function and clinical outcomes, including neonatal conditions, autoimmune disease, allergies, immunodeficiency, metabolic and endocrine conditions, neurodevelopment, and psychiatric disorders.

15.
J Cell Biol ; 221(6)2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35446348

RESUMEN

Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure. Here, we show that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1α, masquerading as unfolded proteins. IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings identify an unexpected cell-biological mechanism of antigen-driven IRE1α activation in DCs, revealing translational potential for cancer immunotherapy.


Asunto(s)
Reactividad Cruzada , Células Dendríticas , Estrés del Retículo Endoplásmico , Endorribonucleasas , Neoplasias , Proteínas Serina-Treonina Quinasas , Animales , Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Endorribonucleasas/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Ratones , Neoplasias/inmunología , Neoplasias/metabolismo , Péptidos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo
16.
Cell Biochem Funct ; 40(2): 150-162, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34978084

RESUMEN

Gene and protein expression of BTBR T+ Itpr3tf /J (BTBR) mice with autistic-like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf /J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8-oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA-3. Ogg1 inhibition and enhanced GATA-3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Linfocitos T/metabolismo
17.
Immunol Res ; 70(1): 114-128, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35023048

RESUMEN

Blood was collected from the New York State Department of Health (NYSDOH) employees to assess variances in leukocyte numbers in January, May, and September throughout a year and over many years. Women and men of ages 20 to 80 volunteered to donate for this program. Most of the blood came from healthy individuals, and many remained healthy throughout the years of their blood donations. The major objective was to determine the extent that blood leukocyte numbers change so that transient vs more lingering changes may be helpful in assessing health status. Since some donors remained in the program for 14 years, age influences over time could be determined. Within a short period of 2-3 years, the flow cytometric immunophenotypic profile of blood lymphocyte is relatively stable with a CV% of < 20%. However, as humans age, the blood CD3+ T cell, CD8+ T cell, B cell, NKT cell, and CD4-/CD8- double-negative T cell (DN-T cell) subsets declined in cell numbers/µL, but the double-positive CD4+/CD8+ T cells (DP-T cells) increased in numbers. The extent and chronology of a variance, e.g., a subset exceeding its 75th or 90th percentile, might be indicative of a transient or chronic physiological or psychosocial stress affecting health or a developing pathology; however, because of the wide ranges of cell numbers/µL for each subset among individuals reported as healthy, everyone's immunity and health must be carefully evaluated. A CD4 to CD8 ratio (4/8R) of < 1 has been used to define an immunodeficiency such as HIV-induced AIDS, but a high 4/8R is less well associated with health status. A high 4/8R or granulocyte to lymphocyte ratio (GLR) might be an indicator of a stress, infection, or immune-related pathology. Sporadic and longitudinal increases of GLRs are reported. The results suggest that there are some age and sex differences in leukocyte numbers; stress influences on the blood profile of leukocytes likely exist. However, some values exceeding 2 standard deviations from means do not necessarily predict a health concern, whereas a longitudinal increase or decline might be indicative of a need for further evaluations.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Linfocitos T CD8-positivos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Citometría de Flujo , Humanos , Recuento de Leucocitos , Leucocitos , Recuento de Linfocitos , Subgrupos Linfocitarios , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T , Adulto Joven
18.
Nat Commun ; 12(1): 7310, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34911951

RESUMEN

Inositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs-degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.


Asunto(s)
Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Retículo Endoplásmico/genética , Endorribonucleasas/genética , Humanos , Proteínas Serina-Treonina Quinasas/genética , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Respuesta de Proteína Desplegada
19.
Sci Total Environ ; 780: 146399, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33770593

RESUMEN

Per- and polyfluoroalkyl substances (PFAS) make up a large group of persistent anthropogenic chemicals which are difficult to degrade and/or destroy. PFAS are an emerging class of contaminants, but little is known about the long-term health effects related to exposure. In addition, technologies to identify levels of contamination in the environment and to remediate contaminated sites are currently inadequate. In this opinion-type discussion paper, a team of researchers from the University of Connecticut and the University at Albany discuss the scientific challenges in their specific but intertwined PFAS research areas, including rapid and low-cost detection, energy-saving remediation, the role of T helper cells in immunotoxicity, and the biochemical and molecular effects of PFAS among community residents with measurable PFAS concentrations. Potential research directions that may be employed to address those challenges and improve the understanding of sensing, remediation, exposure to, and health effects of PFAS are then presented. We hope our account of emerging problems related to PFAS contamination will encourage a broad range of scientific experts to bring these research initiatives addressing PFAS into play on a national scale.

20.
Toxicol Appl Pharmacol ; 416: 115444, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33549591

RESUMEN

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD+/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.


Asunto(s)
Disparidades en el Estado de Salud , Mediadores de Inflamación/metabolismo , Líquido Intracelular/metabolismo , Estrés Oxidativo/fisiología , Determinantes Sociales de la Salud/tendencias , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/inmunología , Contaminantes Ambientales/metabolismo , Humanos , Mediadores de Inflamación/inmunología , Líquido Intracelular/inmunología , Investigación Biomédica Traslacional/métodos , Investigación Biomédica Traslacional/tendencias
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