Interferon-mediated NK cell activation is associated with limited neutralization breadth during SARS-CoV-2 infection.

Best known for their ability to kill infected or malignant cells, natural killer (NK) cells are also underappreciated regulators of the antibody response to viral infection. In mice, NK cells can kill T follicular helper (Tfh) cells, decreasing somatic hypermutation and vaccine responses. Although human NK cell activation correlates with poor vaccine response, the mechanisms of human NK cell regulation of adaptive immunity are poorly understood. We found that in human ancestral SARS-CoV-2 infection, broad neutralizers, who were capable of neutralizing Alpha, Beta, and Delta, had fewer NK cells that expressed inhibitory and immaturity markers whereas NK cells from narrow neutralizers were highly activated and expressed interferon-stimulated genes (ISGs). ISG-mediated activation in NK cells from healthy donors increased cytotoxicity and functional responses to induced Tfh-like cells. This work reveals that NK cell activation and dysregulated inflammation may play a role in poor antibody response to SARS-CoV-2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens.

The epithelial barrier theory and its associated diseases.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.

Epithelial barrier dysfunction and associated diseases in companion animals: Differences and similarities between humans and animals and research needs.

Since the 1960s, more than 350,000 new chemicals have been introduced into the lives of humans and domestic animals. Many of them have become part of modern life and some are affecting nature as pollutants. Yet, our comprehension of their potential health risks for both humans and animals remains partial. The "epithelial barrier theory" suggests that genetic predisposition and exposure to diverse factors damaging the epithelial barriers contribute to the emergence of allergic and autoimmune conditions. Impaired epithelial barriers, microbial dysbiosis, and tissue inflammation have been observed in a high number of mucosal inflammatory, autoimmune and neuropsychiatric diseases, many of which showed increased prevalence in the last decades. Pets, especially cats and dogs, share living spaces with humans and are exposed to household cleaners, personal care products, air pollutants, and microplastics. The utilisation of cosmetic products and food additives for pets is on the rise, unfortunately, accompanied by less rigorous safety regulations than those governing human products. In this review, we explore the implications of disruptions in epithelial barriers on the well-being of companion animals, drawing comparisons with humans, and endeavour to elucidate the spectrum of diseases that afflict them. In addition, future research areas with the interconnectedness of human, animal, and environmental well-being are highlighted in line with the "One Health" concept.

Environmental exposures influence multigenerational epigenetic transmission.

Epigenetic modifications control gene expression and are essential for turning genes on and off to regulate and maintain differentiated cell types. Epigenetics are also modified by a multitude of environmental exposures, including diet and pollutants, allowing an individual's environment to influence gene expression and resultant phenotypes and clinical outcomes. These epigenetic modifications due to gene-environment interactions can also be transmitted across generations, raising the possibility that environmental influences that occurred in one generation may be transmitted beyond the second generation, exerting a long-lasting effect. In this review, we cover the known mechanisms of epigenetic modification acquisition, reprogramming and persistence, animal models and human studies used to understand multigenerational epigenetic transmission, and examples of environmentally induced epigenetic change and its transmission across generations. We highlight the importance of environmental health not only on the current population but also on future generations that will experience health outcomes transmitted through epigenetic inheritance.

Role of allergen immunotherapy and biologics in allergic diseases.

The rise in the prevalence of allergic diseases has become a global health burden. Allergic diseases are a group of immune-mediated disorders characterized by IgE-mediated conditions resulting from a type 2 helper T cell (Th2)-skewed immune response. This review aims to comprehensively summarize recent research on the roles of allergen immunotherapy (AIT) and biologics in allergic diseases. Specifically, we review the mechanisms of AIT and biologics in modulating innate and adaptive immunity involved in allergic disease pathogenesis, as well as their safety and efficacy in the treatment of allergic diseases. We also discuss current new AIT strategies such as recombinant allergen-based vaccines and allergen extract nanoencapsulation. Further research is needed to understand immune tolerance mechanisms beyond the Th2 pathway and to characterize immunological changes in responders and nonresponders to AIT or biologics. This additional research may uncover new targets for monitoring treatment responses and developing personalized treatment strategies for allergic diseases.

Early-life risk factors for both infant colic and excessive crying without colic.

BACKGROUND: Infantile colic may represent gastrointestinal distress, yet most definitions emphasize excessive crying. Each may have distinct etiologies. DESIGN/METHODS: In a pre-birth cohort, we used maternal reports of infant crying and apparent abdominal discomfort at 6mos to categorize infants as (1) unaffected (no excessive crying or colic), (2) excessive crying only, and (3) colic (abdominal discomfort +/- excessive crying). We examined associations of potential risk factors in separate models with excessive crying and colic (each vs. unaffected) using unadjusted multinomial logistic regression, and associations between count of risk factors and colic using logistic regression. RESULTS: Of 1403 infants, 140 (10%) had excessive crying, and 346 (25%) colic. Infants that were non-Hispanic white, low birthweight, firstborn, or had a maternal history of atopy, high postpartum depressive symptoms, or persistent prenatal nausea, had a 40-80% higher relative risk of colic. Preterm birth was associated with double the risk. Being firstborn, low birthweight, and preterm birth predicted excessive crying. Infants with ≥four (vs. 0-1) of the seven identified risk factors had 3.9 times (95% CI: 2.6, 6.1) higher odds of colic. CONCLUSIONS: Colic characterized by apparent abdominal discomfort can be phenotypically distinguished from excessive crying only. Multiple risk factors may further increase colic risk. IMPACT: Infant colic characterized by apparent gastrointestinal distress may be phenotypically distinct from excessive crying only. Literature that defines colic only based on crying behaviors may miss important predictors. Mother-reported colic and excessive crying appear to have overlapping risk factors, with additional risk factors identified for colic. The presence of multiple risk factors increases the risk of colic, supporting a multifactorial etiology.

HLA-DR+ regulatory T cells and IL-10 are associated with success or failure of desensitization outcomes.

BACKGROUND: Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT. METHODS: Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data. RESULTS: Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines. CONCLUSIONS: We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

Single cell multi-omic analysis identifies key genes differentially expressed in innate lymphoid cells from COVID-19 patients.

Introduction: Innate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing. Methods: To gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection, we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression, transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls. Results: We found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover, all ILC subsets displayed a significantly higher frequency of CD69-expressing cells, indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation, activation and homeostasis. In addition, differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC. Discussion: Overall, this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection.

Association of Short-Term Increases in Ambient Fine Particulate Matter With Hospitalization for Asthma or COPD During Wildfire Season and Other Time Periods.

BACKGROUND: Short-term increases in air pollution are associated with poor asthma and COPD outcomes. Short-term elevations in fine particulate matter (PM2.5) due to wildfire smoke are becoming more common. RESEARCH QUESTION: Are short-term increases in PM2.5 and ozone in wildfire season and in winter inversion season associated with a composite of emergency or inpatient hospitalization for asthma and COPD? STUDY DESIGN AND METHODS: Case-crossover analyses evaluated 63,976 and 18,514 patients hospitalized for primary discharge diagnoses of asthma and COPD, respectively, between January 1999 and March 2022. Patients resided on Utah's Wasatch Front where PM2.5 and ozone were measured by Environmental Protection Agency-based monitors. ORs were calculated using Poisson regression adjusted for weather variables. RESULTS: Asthma risk increased on the same day that PM2.5 increased during wildfire season (OR, 1.057 per + 10 µg/m3; 95% CI, 1.019-1.097; P = .003) and winter inversions (OR, 1.023 per +10 µg/m3; 95% CI, 1.010-1.037; P = .0004). Risk decreased after 1 week, but during wildfire season risk rebounded at a 4-week lag (OR, 1.098 per +10 µg/m3; 95% CI, 1.033-1.167). Asthma risk for adults during wildfire season was highest in the first 3 days after PM2.5 increases, but for children, the highest risk was delayed by 3 to 4 weeks. PM2.5 exposure was weakly associated with COPD hospitalization. Ozone exposure was not associated with elevated risks. INTERPRETATION: In a large urban population, short-term increases in PM2.5 during wildfire season were associated with asthma hospitalization, and the effect sizes were greater than for PM2.5 during inversion season.

Concepts for the Development of Person-Centered, Digitally Enabled, Artificial Intelligence-Assisted ARIA Care Pathways (ARIA 2024).

The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own lives based on their lived experiences. Improving healthcare safety, quality, and coordination, as well as quality of life, is an important aim in the care of patients with chronic conditions. Person-centered care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (1) digital care pathways for rhinitis and asthma multimorbidity and (2) digitally enabled, person-centered care.1 It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally enabled, patient-centered care. The paper includes (1) Allergic Rhinitis and its Impact on Asthma (ARIA), a 2-decade journey, (2) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (3) mHealth impact on airway diseases, (4) From guidelines to digital care pathways, (5) Embedding Planetary Health, (6) Novel classification of rhinitis and asthma, (7) Embedding real-life data with population-based studies, (8) The ARIA-EAACI (European Academy of Allergy and Clinical Immunology) strategy for the management of airway diseases using digital biomarkers, (9) Artificial intelligence, (10) The development of digitally enabled, ARIA person-centered care, and (11) The political agenda. The ultimate goal is to propose ARIA 2024 guidelines centered around the patient to make them more applicable and sustainable.

Novel Reference Equations for Pulmonary Artery Size and Pulsatility Using Echocardiography and Their Diagnostic Value in Pulmonary Hypertension.

BACKGROUND: According to the most recent pulmonary hypertension (PH) guidelines, a main pulmonary artery (MPA) diameter > 25 mm on transthoracic echocardiography supports the diagnosis of PH. However, the size of the pulmonary artery (PA) may vary according to body size, age, and cardiac phases. RESEARCH QUESTION: (1) What are the reference limits for PA size on transthoracic echocardiography, considering differences in body size, sex, and age? (2) What is the diagnostic value of the PA size for classifying PH? (3) How does the selection of different reference groups (healthy volunteers vs patients referred for right heart catheterization [RHC]) influence the diagnostic OR (DOR)? STUDY DESIGN AND METHODS: The study included a reference cohort of 248 healthy individuals as control patients, 693 patients with PH proven by RHC, and 156 patients without PH proven by RHC. In the PH cohort, 300 had group 1 PH, 207 had group 2 PH, and 186 had group 3 PH. MPA and right PA diameters and areas were measured in the upper sternal short-axis and suprasternal notch views. Reference limits (5th-95th percentile) were based on absolute values and height-indexed measures. Quantile regression analysis was used to derive median and 95th quantile reference equations for the PA measures. DORs and probability diagnostic plots for PH were then determined using healthy control and non-PH cohorts. RESULTS: The 95th percentile for indexed MPA diameter was 15 mm/m in diastole and 19 mm/m in systole in both sexes. Quantile regression analysis revealed a weak age effect (pseudo-R2 of 0.08-0.10 for MPA diameters). Among measures, the MPA size in diastole had the highest DOR (156.2; 95% CI, 68.3-357.5) for detection of group 1 PH. Similarly, the DORs were also high for groups 2 and 3 PH when compared with the control cohort but significantly lower compared with the non-PH cohort. INTERPRETATION: This study presents novel reference limits for MPA based on height indexing and quantile regression.

Pyroptosis, gasdermins and allergic diseases.

Pyroptosis is an inflammatory form of programmed cell death that is distinct from necrosis and apoptosis. Pyroptosis is primarily mediated by the gasdermin family of proteins (GSDMA-E and PVJK), which, when activated by proteolytic cleavage, form pores in the plasma membrane, leading to cell death. While much of the past research on pyroptosis has focused on its role in cancer, metabolic disorders, and infectious diseases, recent experimental and observational studies have begun to implicate pyroptosis in allergic diseases. These studies suggest that gasdermin-mediated pyroptosis contributes to the development of allergic conditions and could offer novel targets for therapy. Here, we review our current understanding of pyroptosis with an emphasis on the role of gasdermins as executioners of pyroptosis and potential mediators to allergic disease. We highlight new discoveries that establish a mechanistic link between the biochemical actions of gasdermins and the onset of allergic diseases. Additionally, we discuss how pyroptosis and gasdermins might contribute to the dysfunction of epithelial barrier, a key factor believed to initiate the progression of various allergic diseases.

Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

BACKGROUND: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. METHODS: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. RESULTS: Vaccine-mediated complement activation correlated with anti-polyethelyne glycol (PEG) IgG (but not IgM) levels while anti-PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine-mediated basophil activation. Single-cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll-like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL-13 and IL-1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. CONCLUSION: These findings provide insights into the mechanisms underlying allergic reactions to COVID-19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy.

Nitrogen dioxide exposure, health outcomes, and associated demographic disparities due to gas and propane combustion by U.S. stoves.

Gas and propane stoves emit nitrogen dioxide (NO2) pollution indoors, but the exposures of different U.S. demographic groups are unknown. We estimate NO2 exposure and health consequences using emissions and concentration measurements from >100 homes, a room-specific indoor air quality model, epidemiological risk parameters, and statistical sampling of housing characteristics and occupant behavior. Gas and propane stoves increase long-term NO2 exposure 4.0 parts per billion volume on average across the United States, 75% of the World Health Organization's exposure guideline. This increased exposure likely causes ~50,000 cases of current pediatric asthma from long-term NO2 exposure alone. Short-term NO2 exposure from typical gas stove use frequently exceeds both World Health Organization and U.S. Environmental Protection Agency benchmarks. People living in residences <800 ft2 in size incur four times more long-term NO2 exposure than people in residences >3000 ft2 in size; American Indian/Alaska Native and Black and Hispanic/Latino households incur 60 and 20% more NO2 exposure, respectively, than the national average.

Adopting electric school buses in the United States: Health and climate benefits.

Electric school buses have been proposed as an alternative to reduce the health and climate impacts of the current U.S. school bus fleet, of which a substantial share are highly polluting old diesel vehicles. However, the climate and health benefits of electric school buses are not well known. As they are substantially more costly than diesel buses, assessing their benefits is needed to inform policy decisions. We assess the health benefits of electric school buses in the United States from reduced adult mortality and childhood asthma onset risks due to exposure to ambient fine particulate matter (PM2.5). We also evaluate climate benefits from reduced greenhouse-gas emissions. We find that replacing the average diesel bus in the U.S. fleet in 2017 with an electric bus yields $84,200 in total benefits. Climate benefits amount to $40,400/bus, whereas health benefits amount to $43,800/bus due to 4.42*10-3 fewer PM2.5-attributable deaths ($40,000 of total) and 7.42*10-3 fewer PM2.5-attributable new childhood asthma cases ($3,700 of total). However, health benefits of electric buses vary substantially by driving location and model year (MY) of the diesel buses they replace. Replacing old, MY 2005 diesel buses in large cities yields $207,200/bus in health benefits and is likely cost-beneficial, although other policies that accelerate fleet turnover in these areas deserve consideration. Electric school buses driven in rural areas achieve small health benefits from reduced exposure to ambient PM2.5. Further research assessing benefits of reduced exposure to in-cabin air pollution among children riding buses would be valuable to inform policy decisions.

Effects of extreme weather on health in underserved communities.

Increased fossil fuel use has increased carbon dioxide concentrations leading to global warming and climate change with increased frequency and intensity of extreme weather events such as thunderstorms, wildfires, droughts, and heat waves. These changes increase the risk of adverse health effects for all human beings. However, these experiences do not affect everyone equally. Underserved communities, including people of color, the elderly, people living with chronic conditions, and socioeconomically disadvantaged groups, have greater vulnerability to the impacts of climate change. These vulnerabilities are a result of multiple factors such as disparities in health care, lower educational status, and systemic racism. These social inequities are exacerbated by extreme weather events, which act as threat multipliers increasing disparities in health outcomes. It is clear that without human action, these global temperatures will continue to increase to unbearable levels creating an existential crisis. There is now global consensus that climate change is caused by anthropogenic activity and that actions to mitigate and adapt to climate change are urgently needed. The 2015 Paris Accord was the first truly global commitment that set goals to limit further warming. It also aimed to implement equity in action, founded on the principle of common but differentiated responsibilities. Meeting these goals requires individual, community, organizational, national, and global cooperation. Health care professionals, often in the frontline with firsthand knowledge of the health impacts of climate change, can play a key role in advocating for just and equitable climate change adaptation and mitigation policies.

Leukotriene B4: A potential mediator and biomarker for cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in the development of CAV. METHODS: We used an established preclinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy nontransplant controls. RESULTS: We showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found nonsignificantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, nontransplant controls. CONCLUSIONS: This study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.