Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation.

T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17-producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4- and IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.

A Comparative Analysis of Eating Behavior of School-Aged Children with Eosinophilic Esophagitis and Their Caregivers' Quality of Life: Perspectives of Caregivers.

Eosinophilic esophagitis (EoE) can affect eating behavior in infants and children and this may lead to stressful interactions with their caregivers and potentially impact their caregivers' quality of life. Clinical evaluation of eating behaviors can be time consuming and burdensome. Caregivers can provide a comprehensive assessment of their child's eating behavior; however, this has not been well studied in children with EoE. In a case-control study, we used Child Eating Behavior Questionnaire (CEBQ) to compare caregivers' perception of eating behaviors in children (ages 11 ± 4 years; Mean ± SD) with EoE (cEoE; N = 42) to that of non-EoE controls (cControls; N = 38), and Feeding/Swallowing Impact on Children's Caregivers Questionnaire (FS-IS) to examine the impact of EoE-related eating problems on their caregivers' quality of life. There were no differences between the cEoE and cControls perceptions of eating behaviors as assessed by CEBQ. In FS-IS, the cEoE indicated that they were worried about the way their child would breathe or if the child would choke while feeding (2.28 ± 0.16 vs. 1.25 ± 0.13; p < 0.001), and also indicated that it was hard for them to feed their child as it took a long time to prepare liquids and foods the "right" way (2.1 ± 0.20 vs. 1.17 ± 0.09; p < 0.001) when compared to cControls. Our results suggest that caregivers' perception of the eating behavior of school-aged children with and without EoE do not differ significantly, yet the perception of feeding/swallowing issues in children with EoE can negatively impact their caregivers' quality of life. Further research is needed to discern the eating behavior in children with EoE and its relationship with their caregivers' quality of life.

Immediate Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have Recognized.

BACKGROUND: The most common immediate hypersensitivity to macrogols is associated with polyethylene glycol (PEG) 3350; however, the epidemiology, mechanisms, and cross-reactivity are poorly understood. Thousands of medications contain either PEGs or structurally similar polysorbates. OBJECTIVE: Our objective was to better understand the mechanism, cross-reactivity, and scope of PEG hypersensitivity. METHODS: Two cases with a past history of immediate hypersensitivity to PEG-containing medications were used to study potential mechanisms and cross-reactivity of immediate reactions to PEG 3350. Skin testing and oral challenges with PEG and polysorbate-containing agents were employed to determine clinical reactivity and cross-reactivity between the 2 allergens. Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay were used to detect anti-PEG specific IgG and IgE, respectively, using PEGylated protein or PEG alone as antigens in 2 cases and 6 PEG 3350 tolerant controls. We searched US Food and Drug Administration (FDA) adverse event reports for immediate reactions to PEG 3350 to determine the potential scope of this problem in the United States. RESULTS: Skin and provocation testing demonstrated symptomatic reactivity in both cases to PEG 3350 and polysorbate 80. Plasma samples were positive for anti-PEG specific IgE and IgG antibodies only in cases and binding increased directly proportional to the molecular weight of PEG tested. FDA adverse event reports revealed 53 additional cases of possible PEG 3350 anaphylaxis. CONCLUSIONS: Immediate hypersensitivity to PEG 3350 with cross-reactive polysorbate 80 hypersensitivity may be underrecognized in clinical practice and can be detected with clinical skin testing. Our studies raise the possibility of an IgE-mediated type I hypersensitivity mechanism in some cases.

The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy.

OBJECTIVE: Peanut allergy (PA) clearly has a heritable component. Specific genetic contributions are unknown, but human leukocyte antigen (HLA) loci are obvious candidates. This review focuses on emerging studies of HLA associations with PA. DATA SOURCES: PubMed was searched with no time limitations using key terms human leukocyte antigen, HLA, MHC, peanut, peanut hypersensitivity, and peanut allergy. STUDY SELECTIONS: Qualifying studies were English-language reports of genetic analyses examining PA and HLA associations. RESULTS: Seven relevant citations were identified, which were published from 1996 to 2015. Early studies using candidate gene approaches found associations between PA and HLA-DR and -DQ alleles (HLA-DRB1*08 and DQB1*06:03P) when comparing subjects with peanut allergy with nonallergic unrelated control groups. No significant associations were found between siblings with and without peanut allergy. However, a recent large genomewide association study of patients with peanut allergy and their family members found 2 PA-associated single-nucleotide polymorphisms (rs9275596 and rs7192) mapping to regions involving the HLA-DR and HLA-DQ genes. Associations with differential DNA methylation partly mediated the associations between PA and single-nucleotide polymorphisms. CONCLUSION: Early studies using candidate gene approaches identified HLA associations with PA compared with the general population, suggesting a link with atopy but failing to identify a PA-specific association. These studies had various limitations that included small samples. The most compelling evidence for a PA-specific HLA association comes from a genomewide association study, which examined the entire genome in large, well-defined, related cohorts. More research is needed to validate and replicate these findings, to perform fine genetic mapping of specific HLA loci, and to demonstrate underlying mechanisms of HLA contributions to PA.