T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study.

BACKGROUND: Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. METHODS: This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. FINDINGS: Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. INTERPRETATION: Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines. FUNDING: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.

Gut bacteria at 6 months of age are associated with immune cell status in 1-year-old children.

Age-related gut bacterial changes during infancy have been widely studied, but it remains still unknown how these changes are associated with immune cell composition. This study's aim was to explore if the temporal development of gut bacteria during infancy prospectively affects immune cell composition. Faecal bacteria and short-chain fatty acids were analysed from 67 PreventADALL study participants at four timepoints (birth to 12 months) using reduced metagenome sequencing and gas chromatography. Immune cell frequencies were assessed using mass cytometry in whole blood samples at 12 months. The infants clustered into four groups based on immune cell composition: clusters 1 and 2 showed a high relative abundance of naïve cells, cluster 3 exhibited increased abundance of classical- and non-classical monocytes and clusters 3 and 4 had elevated neutrophil levels. At all age groups, we did observe significant associations between the gut microbiota and immune cell clusters; however, these were generally from low abundant species. Only at 6 months of age we observed significant associations between abundant (>8%) species and immune cell clusters. Bifidobacterium adolescentis and Porphyromonadaceae are associated with cluster 1, while Bacteroides fragilis and Bifidobacterium longum are associated with clusters 3 and 4 respectively. These species have been linked to T-cell polarization and maturation. No significant correlations were found between short-chain fatty acids and immune cell composition. Our findings suggest that abundant gut bacteria at 6 months may influence immune cell frequencies at 12 months, highlighting the potential role of gut microbiota in shaping later immune cell composition.

Immune cell profiles associated with human exposure to perfluorinated compounds (PFAS) suggest changes in natural killer, T helper, and T cytotoxic cell subpopulations.

Per- and polyfluoroalkyl substances (PFAS) constitutes a group of highly persistent man-made substances. Recent evidence indicates that PFAS negatively impact the immune system. However, it remains unclear how different PFAS are associated with alterations in circulating leukocyte subpopulations. More detailed knowledge of such potential associations can provide better understanding into mechanisms of PFAS immunotoxicity in humans. In this exploratory study, associations of serum levels of common PFAS (perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS)) and immune cell profiles of peripheral blood mononuclear cells, both with and without immunostimulation, were investigated. High-dimensional single cell analysis by mass cytometry was done on blood leukocytes from fifty participants in the Norwegian human biomonitoring EuroMix study. Different PFAS were associated with changes in various subpopulations of natural killer (NK), T helper (Th), and cytotoxic T (Tc) cells. Broadly, PFAS concentrations were related to increased frequencies of NK cells and activated subpopulations of NK cells. Additionally, increased levels of activated T helper memory cell subpopulations point to Th2/Th17 and Treg-like skewed profiles. Finally, PFAS concentrations were associated with decreased frequencies of T cytotoxic cell subpopulations with CXCR3+ effector memory (EM) phenotypes. Several of these observations point to biologically plausible mechanisms that may contribute to explaining the epidemiological reports of immunosuppression by PFAS. Our results suggest that PFAS exposures even at relatively low levels are associated with changes in immune cell subpopulations, a finding which should be explored more thoroughly in a larger cohort. Additionally, causal relationships should be confirmed in experimental studies. Overall, this study demonstrates the strength of profiling by mass cytometry in revealing detailed changes in immune cells at a single cell level.

Data management and protection in occupational and environmental exposome research - A case study from the EU-funded EXIMIOUS project.

Within collaborative projects, such as the EU-funded Horizon 2020 EXIMIOUS project (Mapping Exposure-Induced Immune Effects: Connecting the Exposome and the Immunome), collection and analysis of large volumes of data pose challenges in the domain of data management, with regards to both ethical and legal aspects. However, researchers often lack the right tools and/or accurate understanding of the ethical/legal framework to independently address such challenges. With the guidance and support within and between the partner institutes (the researchers and the ethical and legal teams) in the EXIMIOUS project, we have been able to understand and solve most challenges during the first two project years. This has fed into the development of a Data Management Plan and the establishment of data management platforms in accordance with the ethical and legal framework laid down by the EU and the different national regulations of the partners involved. Through this elaborate exercise, we have acquired tools which allow us to make our research data FAIR (Findable, Accessible, Interoperable, and Reusable), while at the same time ensuring data privacy and security (GDPR compliant). Herein we share our experience of creating and managing the data workflow through an open research communication, with the aim of helping other researchers build their data management framework in their own projects. Based on the measures adopted in EXIMIOUS to ensure FAIR data management, we also put together a checklist "DMP CHECK" containing a series of recommendations based on our experience.

Toxic effects of mineral oil saturated hydrocarbons (MOSH) and relation to accumulation in rat liver.

Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported (Barp et al. 2017a, 2017b). Rats were exposed to feed containing 0-4000 mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular masses < C25 (S-C25), ii) dewaxed, mainly molecular masses > C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanes > C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were related to accumulated n-alkanes (wax) above C25, presumably not relevant for humans, but also to MOSH from S-C25, mainly consisting of iso-alkanes and substituted cycloalkanes below C25 with a small proportion of n-alkanes. Induction of liver granuloma appeared to be related to n-alkanes > C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. Iso-alkanes and substituted cycloalkanes accumulating in rat liver and spleen were similar to those accumulating in humans.

Suspected gut barrier disruptors and development of food allergy: Adjuvant effects and early immune responses.

Food allergy is an increasing public health challenge worldwide. It has recently been hypothesized that the increase in exposure to intestinal epithelial barrier-damaging biological and chemical agents contribute to this development. In animal models, exposure to adjuvants with a food allergen has been shown to promote sensitization and development of food allergy, and barrier disrupting capacities have been suggested to be one mechanism of adjuvant action. Here, we investigated how gut barrier disrupting compounds affected food allergy development in a mouse model of peanut allergy. Sensitization and clinical peanut allergy in C3H/HEOuJ mice were assessed after repeated oral exposure to peanut extract together with cholera toxin (CT; positive control), the mycotoxin deoxynivalenol (DON), house dust mite (HDM) or the pesticide glyphosate (GLY). In addition, we investigated early effects 4 to 48 h after a single exposure to the compounds by assessing markers of intestinal barrier permeability, alarmin production, intestinal epithelial responses, and local immune responses. CT and DON exerted adjuvant effects on peanut allergy development assessed as clinical anaphylaxis in mice. Early markers were affected only by DON, observed as increased IL-33 (interleukin 33) and thymic stromal lymphopoietin (TSLP) alarmin production in intestines and IL-33 receptor ST2 in serum. DON also induced an inflammatory immune response in lymph node cells stimulated with lipopolysaccharide (LPS). HDM and GLY did not clearly promote clinical food allergy and affected few of the early markers at the doses tested. In conclusion, oral exposure to CT and DON promoted development of clinical anaphylaxis in the peanut allergy mouse model. DON, but not CT, affected the early markers measured in this study, indicating that DON and CT have different modes of action at the early stages of peanut sensitization.

Exposure to persistent organic pollutants alters the serum metabolome in non-obese diabetic mice.

INTRODUCTION: Autoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized. OBJECTIVES: Here we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfluoroalkyl substances (PFAS). METHODS: Analysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS. RESULTS: Experimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins. CONCLUSION: Taken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunity.

Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults.

The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.

Dibutyl phthalate exposure alters T-cell subsets in blood from allergen-sensitized volunteers.

Phthalates are ubiquitous environmental contaminants associated with allergic disease in epidemiological and animal studies. This investigation aims to support these associations by interrogating systemic immune effects in allergen-sensitized volunteers after controlled indoor air exposure to a known concentration of dibutyl phthalate (DBP). The phthalate-allergen immune response (PAIR) study enrolled 16 allergen-sensitized participants to a double-blinded, randomized, crossover exposure to two conditions (DBP or control air for 3 hr), each followed immediately by inhaled allergen challenge. Peripheral blood immune cell composition and activation along with inflammatory mediators were measured before and after exposure. DBP exposure prior to the inhaled allergen challenge increased the percentage of CD4+ T helper cells and decreased the percentage of regulatory T cells (3 hr and 20 hr post-exposure), while only modest overall effects were observed for inflammatory mediators. The cells and mediators affected by the phthalate exposure were generally not overlapping with the endpoints affected by allergen inhalation alone. Thus, in distinction to our previously published effects on lung function, DBP appears to alter endpoints in peripheral blood that are not necessarily enhanced by allergen alone. Further studies are needed to clarify the role of phthalate-induced systemic effects in disease pathogenesis.

The EXIMIOUS project-Mapping exposure-induced immune effects: connecting the exposome and the immunome.

Immune-mediated, noncommunicable diseases-such as autoimmune and inflammatory diseases-are chronic disorders, in which the interaction between environmental exposures and the immune system plays an important role. The prevalence and societal costs of these diseases are rising in the European Union. The EXIMIOUS consortium-gathering experts in immunology, toxicology, occupational health, clinical medicine, exposure science, epidemiology, bioinformatics, and sensor development-will study eleven European study populations, covering the entire lifespan, including prenatal life. Innovative ways of characterizing and quantifying the exposome will be combined with high-dimensional immunophenotyping and -profiling platforms to map the immune effects (immunome) induced by the exposome. We will use two main approaches that "meet in the middle"-one starting from the exposome, the other starting from health effects. Novel bioinformatics tools, based on systems immunology and machine learning, will be used to integrate and analyze these large datasets to identify immune fingerprints that reflect a person's lifetime exposome or that are early predictors of disease. This will allow researchers, policymakers, and clinicians to grasp the impact of the exposome on the immune system at the level of individuals and populations.

Lipidomic Analyses Reveal Modulation of Lipid Metabolism by the PFAS Perfluoroundecanoic Acid (PFUnDA) in Non-Obese Diabetic Mice.

Exposure to Per- and polyfluoroalkyl substances (PFAS) has been linked to multiple undesirable health outcomes across a full lifespan, both in animal models as well as in human epidemiological studies. Immunosuppressive effects of PFAS have been reported, including increased risk of infections and suppressed vaccination responses in early childhood, as well as association with immunotoxicity and diabetes. On a mechanistic level, PFAS exposure has been linked with metabolic disturbances, particularly in lipid metabolism, but the underlying mechanisms are poorly characterized. Herein we explore lipidomic signatures of prenatal and early-life exposure to perfluoroundecanoic acid (PFUnDA) in non-obese diabetic (NOD) mice; an experimental model of autoimmune diabetes. Female NOD mice were exposed to four levels of PFUnDA in drinking water at mating, during gestation and lactation, and during the first weeks of life of female offspring. At offspring age of 11-12 weeks, insulitis and immunological endpoints were assessed, and serum samples were collected for comprehensive lipidomic analyses. We investigated the associations between exposure, lipidomic profile, insulitis grade, number of macrophages and apoptotic, active-caspase-3-positive cells in pancreatic islets. Dose-dependent changes in lipidomic profiles in mice exposed to PFUnDA were observed, with most profound changes seen at the highest exposure levels. Overall, PFUnDA exposure caused downregulation of phospholipids and triacylglycerols containing polyunsaturated fatty acids. Our results show that PFUnDA exposure in NOD mice alters lipid metabolism and is associated with pancreatic insulitis grade. Moreover, the results are in line with those reported in human studies, thus suggesting NOD mice as a suitable model to study the impacts of environmental chemicals on T1D.

Maternal gestational mercury exposure in relation to cord blood T cell alterations and placental gene expression signatures.

The immunotoxic impacts of mercury during early life is poorly understood. We investigated the associations between gestational mercury exposure and frequency of cord blood T cells as well as placental gene expression. Frequency of natural Treg cells was positively associated with prenatal and postpartum mercury toenail concentrations. Frequency of NKT and activated naïve Th cells was positively associated with prenatal toenail mercury concentrations and number of maternal silver-mercury dental amalgams, respectively. Placental gene expression analyses revealed distinct gene signatures associated with mercury exposure. Decreased placental expression of a histone demethylase, KDM4DL, was associated with both higher prenatal and postpartum maternal toenail mercury levels among male infants and remained statistically significant after adjustment for fish and seafood consumption. The results suggest that gestational exposure to mercury concentrations contribute to alterations in both T cells and gene expression in placenta at birth. These alterations may inform mechanisms of mercury immunotoxicity.

Improved diet quality is associated with decreased concentrations of inflammatory markers in adults with uncontrolled asthma.

BACKGROUND: Asthma has become one of the major public health challenges, and recent studies show promising clinical benefits of dietary interventions, such as the Dietary Approaches to Stop Hypertension (DASH) diet. OBJECTIVE: The objective of this study was to examine whether changes in diet quality are associated with changes in inflammatory markers important in asthma pathophysiology. METHODS: In this exploratory study in patients with poorly controlled asthma participating in a randomized controlled trial of a DASH intervention study, changes in concentrations of a broad panel of serum proteins (51-plex Luminex assay, Affymetrix) were determined, and their relation to diet quality (DASH score) assessed by combining data of both intervention and usual-care control groups. Second, the relation between the serum proteins, other biomarkers of inflammation and nutrition, and Asthma Control Questionnaire (ACQ) was assessed. RESULTS: During the first 3 mo, diet quality (DASH scores) were inversely associated (P < 0.05, false discovery rate P < 0.09) with serum concentrations of a large number serum proteins, reflecting not only general proinflammatory markers such as IL-1ß, transforming growth factor α (TGF-α), and IL-6 (r = -0.31 to -0.39) but also a number of proteins associated with asthmatic conditions, specifically several T-helper (Th) 2 (Th2; r = -0.29 to -0.34) and Th17 (r = -0.4) associated cytokines and growth factors. Monokine induced by gamma/chemokine (C-X-C motif) ligand 9 (CXCL9) (MIG/CXCL9), a T-cell attractant induced by IFN-γ previously linked to asthma exacerbations, appeared to be the marker most consistently associated with DASH diet quality for the entire 6-mo study period (r = -0.40 and -0.30 for 0-3 and 3-6 mo, respectively, and standardized coefficient loadings -0.13 in the partial least squares analyses). Decreases in 19 serum protein concentrations were also correlated with improved asthma control during the 6-mo study period. CONCLUSIONS: Our data in adult patients with poorly controlled asthma suggest that dietary changes, like the introduction of DASH, may have beneficial effects on reducing inflammatory status. This trial was registered at http://www.clinicaltrials.gov as NCT01725945.

Aging and CMV discordance are associated with increased immune diversity between monozygotic twins.

BACKGROUND: Broadly, much of variance in immune system phenotype has been linked to the influence of non-heritable factors rather than genetics. In particular, two non-heritable factors: aging and human cytolomegavirus (CMV) infection, have been known to account for significant inter-individual immune variance. However, many specific relationships between them and immune composition remain unclear, especially between individuals over narrower age ranges. Further exploration of these relationships may be useful for informing personalized intervention development. RESULTS: To address this need, we evaluated 41 different cell type frequencies by mass cytometry and identified their relationships with aging and CMV seropositivity. Analyses were done using 60 healthy individuals, including 23 monozygotic twin pairs, categorized into young (12-31 years) and middle-aged (42-59 years). Aging and CMV discordance were associated with increased immune diversity between monozygotic twins overall, and particularly strongly in various T cell populations. Notably, we identified 17 and 11 cell subset frequencies as relatively influenced and uninfluenced by non-heritable factors, respectively, with results that largely matched those from studies on older-aged cohorts. Next, CD4+ T cell frequency was shown to diverge with age in twins, but with lower slope than in demographically similar non-twins, suggesting that much inter-individual variance in this cell type can be attributed to interactions between genetic and environmental factors. Several cell frequencies previously associated with memory inflation, such as CD27- CD8+ T cells and CD161+ CD4+ T cells, were positively correlated with CMV seropositivity, supporting findings that CMV infection may incur rapid aging of the immune system. CONCLUSIONS: Our study confirms previous findings that aging, even within a relatively small age range and by mid-adulthood, and CMV seropositivity, both contribute significantly to inter-individual immune diversity. Notably, we identify several key immune cell subsets that vary considerably with aging, as well as others associated with memory inflation which correlate with CMV seropositivity.

Immune cell profiles associated with measured exposure to phthalates in the Norwegian EuroMix biomonitoring study - A mass cytometry approach in toxicology.

BACKGROUND: Phthalate exposure has been associated with immune-related diseases such as asthma and allergies, but there is limited knowledge on mechanisms, effect biomarkers and thus biological support of causality. OBJECTIVES: To investigate associations between exposure to the phthalates DEHP (di(2-ethylhexyl) phthalate) and DiNP (diisononyl phthalate) and functional immune cell profiles. METHODS: Peripheral blood mononuclear cells (PBMCs) from 32 healthy adult Norwegian participants in the EuroMix biomonitoring study were selected based on high or low (n = 16) levels of urine metabolites of DEHP and DiNP. High-dimensional immune cell profiling including phenotyping and functional markers was performed by mass cytometry (CyTOF) using two broad antibody panels after PMA/ionomycin-stimulation. The CITRUS algorithm with unsupervised clustering was used to identify group differences in cell subsets and expression of functional markers, verified by manual gating. RESULTS: The group of participants with high phthalate exposure had a higher proportion of some particular innate immune cells, including CD11c positive NK-cell and intermediate monocyte subpopulations. The percentage of IFNγ TNFα double positive NK cells and CD11b expression in other NK cell subsets were higher in the high exposure group. Among adaptive immune cells, however, the percentage of IL-6 and TNFα expressing naïve B cell subpopulations and the percentage of particular naïve cytotoxic T cell populations were lower in the high exposure group. DISCUSSION: Cell subset percentages and expression of functional markers suggest that DEHP and DiNP phthalate exposure may stimulate subsets of innate immune cells and suppress adaptive immune cell subsets. By revealing significant immunological differences even in small groups, this study illustrates the promise of the broad and deep information obtained by high-dimensional single cell analyses of human samples to answer toxicological questions regarding health effects of environmental exposures.

Reduced polyfunctional T cells and increased cellular activation markers in adult allergy patients reporting adverse reactions to food.

BACKGROUND: The underlying cellular mechanisms causing adverse reactions to food are complex and still not fully understood. Therefore, in this study we aimed to identify functional and/or phenotypical immune cell signatures characteristic for adult patients reporting adverse reactions to food. By mass cytometry, we performed high-dimensional profiling of peripheral blood mononuclear cells (PBMC) from adult patients reporting adverse reactions to food and healthy controls. The patients were grouped according to sIgE-positive or sIgE-negative serology to common food and inhalant allergens. Two broad antibody panels were used, allowing determination of major immune cell populations in PBMC, as well as activation status, proliferation status, and cytokine expression patterns after PMA/ionomycin-stimulation on a single cell level. RESULTS: By use of data-driven algorithms, several cell populations were identified showing significantly different marker expression between the groups. Most striking was an impaired frequency and function of polyfunctional CD4+ and CD8+ T cells in patients reporting adverse reactions to food compared to the controls. Further, subpopulations of monocytes, T cells, and B cells had increased expression of functional markers such as CD371, CD69, CD25, CD28, and/or HLA-DR as well as decreased expression of CD23 in the patients. Most of the differing cell subpopulations were similarly altered in the two subgroups of patients. CONCLUSION: Our results suggest common immune cell features for both patient subgroups reporting adverse reactions to food, and provide a basis for further studies on mechanistic and diagnostic biomarker studies in food allergy.

Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes.

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.

Predicting Skin Barrier Dysfunction and Atopic Dermatitis in Early Infancy.

BACKGROUND: Dry skin is associated with increased transepidermal water loss (TEWL), which has been found to precede atopic dermatitis (AD) in childhood. OBJECTIVE: We aimed to identify parental, prenatal, and perinatal predictive factors of dry skin, high TEWL, and AD at 3 months of age, and to determine if dry skin or high TEWL at 3 months can predict AD at 6 months. METHODS: From the Preventing Atopic Dermatitis and Allergies in children prospective birth cohort study, we included 1150 mother-child pairs. Dry skin, TEWL, and eczema were assessed at 3- and 6-month investigations. Eczema, used as a proxy for AD, was defined as the presence of eczematous lesions, excluding differential diagnoses to AD. High TEWL was defined as TEWL >90th percentile, equaling 11.3 g/m2/h. Potential predictive factors were recorded from electronic questionnaires at 18- and 34-week pregnancy and obstetric charts. RESULTS: Significant predictive factors (P < .05) for dry skin at 3 months were delivery >38 gestational weeks and paternal age >37 years; for high TEWL, male sex, birth during winter season, and maternal allergic disease; and for eczema, elective caesarean section, multiparity, and maternal allergic diseases. Dry skin without eczema at 3 months was predictive for eczema at 6 months (adjusted odds ratio: 1.92, 95% confidence interval: 1.21-3.05; P = .005), whereas high TEWL at 3 months was not. CONCLUSION: In early infancy, distinct parental- and pregnancy-related factors were predictive for dry skin, high TEWL, and AD. Dry skin at 3 months of age was predictive for AD 3 months later.

Feasibility of desensitizing children highly allergic to peanut by high-dose oral immunotherapy.

BACKGROUND: There are limited data on the feasibility, efficacy and safety of high-dose oral immunotherapy (OIT) in children highly allergic to peanuts. OBJECTIVE: In children highly allergic to peanut, we primarily aimed to determine the feasibility of reaching the maximum maintenance dose (MMD) of 5000 mg peanut protein or, alternatively, a lower individual maintenance dose (IMD), by OIT up-dosing. Secondarily, we aimed to identify adverse events (AEs) and determine factors associated with reaching a maintenance dose. METHODS: The TAKE-AWAY peanut OIT trial enrolled 77 children 5-15 years old, with a positive oral peanut challenge. Fifty-seven were randomized to OIT with biweekly dose step-up until reaching MMD or IMD and 20 to observation only. Demographic and biological characteristics, AEs, medication and protocol deviations were explored for associations with reaching maintenance dose. RESULTS: All children had anaphylaxis defined by objective symptoms in minimum two organ systems during baseline challenge. The MMD was reached by 21.1%, while 54.4% reached an IMD of median (minimum, maximum) 2700 (250, 4000) mg peanut protein, whereas 24.5% discontinued OIT. During up-dosing, 19.4% experienced anaphylaxis. Not reaching the MMD was caused by distaste for peanuts (66.7%), unacceptable AEs (26.7%) and social reasons (6.7%). Increased peanut s-IgG4 /s-IgE ratio (OR [95% CI]: 1.02 [1.00, 1.04]) was associated with reaching MMD. CONCLUSION: Although 75.5% of children with peanut anaphylaxis reached a maintenance dose of 0.25-5 g, only 21.1% reached the MMD. Distaste for peanuts and AEs, including high risk of anaphylaxis, limited the feasibility of reaching MMD.

Toxic effects of mineral oil saturated hydrocarbons (MOSH) and relation to accumulation in rat liver.

Humans are daily exposed to mineral oil saturated hydrocarbons (MOSH) from the diet. We exposed female Fischer 344 rats to a broad mixture and sub-fractions of MOSH. Chemical characterization of the MOSH mixture used and material accumulated in rat tissues were previously reported. Rats were exposed to feed containing 0-4000 mg/kg broad MOSH mixture for 30, 60, 90 and 120 days; and for 120 days to feed containing different MOSH fractions: i) mainly molecular masses < C25 (S-C25), ii) dewaxed, mainly molecular masses > C25 (L-C25) and iii) the L-C25 fraction mixed with wax largely consisting of n-alkanes > C25 (L-C25W). Treatments related effects were increased liver and spleen weight, as well as vacuolization and granuloma formation with lymphoid cell clusters in the liver, but effects varied strongly between the MOSH fractions tested. We conclude that increased liver and spleen weights were mainly related to accumulated iso-alkanes and substituted cycloalkanes, but also wax n-alkanes. Induction of liver granuloma appeared to be related to n-alkanes > C25 and not to the accumulated amount of MOSH. Immune responses to an injected antigen were not affected. MOSH fractions associated with increased liver and spleen weights were similar to those accumulating in humans.