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Browsing by Author "Cook-Mills, Joan M."
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Item Asthma, Allergy and Vitamin E: Current and Future Perspectives(Elsevier, 2022) Cook-Mills, Joan M.; Averill, Samantha H.; Lajiness, Jacquelyn D.; Pediatrics, School of MedicineAsthma and allergic disease result from interactions of environmental exposures and genetics. Vitamin E is one environmental factor that can modify development of allergy early in life and modify responses to allergen after allergen sensitization. Seemingly varied outcomes from vitamin E are consistent with the differential functions of the isoforms of vitamin E. Mechanistic studies demonstrate that the vitamin E isoforms α-tocopherol and γ-tocopherol have opposite functions in regulation of allergic inflammation and development of allergic disease, with α-tocopherol having anti-inflammatory functions and γ-tocopherol having pro-inflammatory functions in allergy and asthma. Moreover, global differences in prevalence of asthma by country may be a result, at least in part, of differences in consumption of these two isoforms of tocopherols. It is critical in clinical and animal studies that measurements of the isoforms of tocopherols be determined in vehicles for the treatments, and in the plasma and/or tissues before and after intervention. As allergic inflammation is modifiable by tocopherol isoforms, differential regulation by tocopherol isoforms provide a foundation for development of interventions to improve lung function in disease and raise the possibility of early life dietary interventions to limit the development of lung disease.Item b-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells(American Association of Immunologists, 2022-11-15) Lajiness, Jacquelyn D.; Amarsaikhan, Nansalmaa; Tat, Kiet; Tsoggerel, Angar; Cook-Mills, Joan M.; Microbiology and Immunology, School of MedicineIn humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. The elevated βGlcCers increase numbers of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers increased development of GM-CSF-stimulated mouse bone marrow-derived DCs (BMDCs) in vitro without altering expression of costimulatory molecules. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCers increased PKCα and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Antigen processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. Pups of allergic mothers had an increased proportion of CD11b+CD11c+ subsets of DCs, contributing to enhanced stimulation of T cell proliferation ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for the prevention or intervention in asthma and allergic disease.Item Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma(Elsevier, 2021) James, Briana N.; Oyeniran, Clement; Sturgill, Jamie L.; Newton, Jason; Martin, Rebecca; Bieberich, Erhard; Weigel, Cynthia; Maczis, Melissa A.; Palladino, Elisa N. D.; Lownik, Joseph C.; Trudeau, John B.; Cook-Mills, Joan M.; Wenzel, Sally; Milstein, Sheldon; Spiegel, Sarah; Pediatrics, School of MedicineBackground Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity. Objective We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma. Methods Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry. Results Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma. Conclusion Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease.Item Cord blood sphingolipids are associated with atopic dermatitis and wheeze in the first year of life(Elsevier, 2022) Hoji, Aki; Kumar, Rajesh; Gern, James E.; Bendixsen, Casper G.; Seroogy, Christine M.; Cook-Mills, Joan M.; Pediatrics, School of MedicineBackground: Allergen-sensitized pregnant mice have increased plasma levels of the lipids β-glucosylceramides (βGlcCers) that are transplacentally transferred to the fetus, increased subsets of proinflammatory dendritic cells in the fetal liver and pup lung, and increased allergen-induced offspring lung inflammation. Objective: Our aim was to determine whether these preclinical observations extend to a human association of βGlcCers with wheeze and allergic disease in the prospective Wisconsin Infant Study Cohort. Methods: We measured 74 lipids in cord blood plasma by using mass spectrometry detection of sphingolipids, eicosanoids, and docosinoids, as well as an ELISA for 13-hydroxyoctadecadienoic acid. Lipid profiles were determined by unbiased Uniform Manifold Approximation and Projection dimensional reduction machine learning. Lipid profiles and a proinflammatory lipid index were analyzed for association with maternal allergy and childhood outcomes of wheeze, atopic dermatitis, cord blood leukocytes, and total IgE level at age 1 year. Results: Uniform Manifold Approximation and Projection analysis of lipids defined 8 cluster-specific plasma lipid profiles. Cluster 6 had significantly lower levels of plasma βGlcCers and a higher frequency of cord blood plasmacytoid dendritic cells that mediate anti-inflammatory responses, which is consistent with an anti-inflammatory profile. For clusters and for each infant, a proinflammatory lipid index was calculated to reflect the sum of the proinflammatory lipids minus the anti-inflammatory lipids that were significantly different than in cluster 6. The cluster proinflammatory lipid index was associated with cord blood basophil frequency and with wheeze and atopic dermatitis in the first year of life. The infant inflammatory lipid index was associated with increased risk of wheeze in the first year of life. Conclusion: The cord blood proinflammatory lipid index is associated with early-life atopic dermatitis and wheezing.Item Dysbiotic lung microbial communities of neonates from allergic mothers confer neonate responsiveness to suboptimal allergen(Frontiers Media, 2023-03-10) Bloodworth, Jeffery C.; Hoji, Aki; Wolff, Garen; Mandal, Rabindra K.; Schmidt, Nathan W.; Deshane, Jessy S.; Morrow, Casey D.; Kloepfer, Kirsten M.; Cook-Mills, Joan M.; Pediatrics, School of MedicineIn humans and animals, offspring of allergic mothers have increased responsiveness to allergens. This is blocked in mice by maternal supplementation with α-tocopherol (αT). Also, adults and children with allergic asthma have airway microbiome dysbiosis with increased Proteobacteria and may have decreased Bacteroidota. It is not known whether αT alters neonate development of lung microbiome dysbiosis or whether neonate lung dysbiosis modifies development of allergy. To address this, the bronchoalveolar lavage was analyzed by 16S rRNA gene analysis (bacterial microbiome) from pups of allergic and non-allergic mothers with a basal diet or αT-supplemented diet. Before and after allergen challenge, pups of allergic mothers had dysbiosis in lung microbial composition with increased Proteobacteria and decreased Bacteroidota and this was blocked by αT supplementation. We determined whether intratracheal transfer of pup lung dysbiotic microbial communities modifies the development of allergy in recipient pups early in life. Interestingly, transfer of dysbiotic lung microbial communities from neonates of allergic mothers to neonates of non-allergic mothers was sufficient to confer responsiveness to allergen in the recipient pups. In contrast, neonates of allergic mothers were not protected from development of allergy by transfer of donor lung microbial communities from either neonates of non-allergic mothers or neonates of αT-supplemented allergic mothers. These data suggest that the dysbiotic lung microbiota is dominant and sufficient for enhanced neonate responsiveness to allergen. Importantly, infants within the INHANCE cohort with an anti-inflammatory profile of tocopherol isoforms had an altered microbiome composition compared to infants with a pro-inflammatory profile of tocopherol isoforms. These data may inform design of future studies for approaches in the prevention or intervention in asthma and allergic disease early in life.Item Epithelial barrier regulation, antigen sampling, and food allergy(Elsevier, 2022-09) Cook-Mills, Joan M.; Emmerson, Lauren N.; Microbiology and Immunology, School of MedicineFood allergy is often associated with development of atopic dermatitis. Atopic dermatitis is a chronic inflammatory skin condition with a strong association with skin barrier gene mutations. Loss-of-function mutations in skin barrier genes increase transepidermal water loss. Also, reduction of the skin barrier can be mediated by environmental exposures. In preclinical studies of mice with skin barrier disruption, exposure to allergens on the skin induces food allergy. Exposure to food allergens on the skin with coexposure of the skin to other environmental factors induces signals in the skin for activation of food allergy, allergen-specific IgE, and oral food–induced anaphylaxis. In contrast, oral food allergen consumption before skin exposure to food allergen induces tolerance to the food allergen. However, this induction of tolerance may be blocked if skin is exposed to environmental allergens at the time of initial oral food allergen consumption. Further studies are needed to address the mechanisms of induction of food allergy by coexposure of the skin to food allergens, aeroallergens, and other environmental factors. Furthermore, clinical studies are needed to determine the effects of food allergen on skin before skin development of atopic dermatitis.Item Exposure: Staphylococcus aureus skin colonization predisposes to food allergy in the Learning Early about Allergy to Peanut (LEAP) and LEAP-On studies(Elsevier, 2019-08) Cook-Mills, Joan M.; Kaplan, Mark H.; Turner, Matthew J.; Kloepfer, Kirsten M.; Kumar, Rajesh; Pediatrics, School of MedicineItem Mechanism for Initiation of Food Allergy: Dependence on skin barrier mutations and environmental allergen co-stimulation(Elsevier, 2018) Walker, Matthew; Green, Jeremy; Ferrie, Ryan; Queener, Ashley; Kaplan, Mark H.; Cook-Mills, Joan M.; Pediatrics, School of MedicineBackground Mechanisms for the development of food allergy in neonates are unknown but are clearly linked in patient populations to a genetic predisposition towards skin barrier defects. Whether skin barrier defects functionally contribute to development of food allergy is unknown. Objective The purpose of the study was to determine whether skin barrier mutations, that are primarily heterozygous in patient populations, contribute to the development of food allergy. Methods Mice heterozygous for the Flgft and Tmem79ma mutations were skin sensitized with environmental allergens and food allergens. After sensitization, mice received oral challenge with food allergen and then inflammation, inflammatory mediators, and anaphylaxis were measured. Results We define development of inflammation, inflammatory mediators, and food allergen-induced anaphylaxis in neonatal mice with skin barrier mutations following brief concurrent cutaneous exposure to food and environmental allergens. Moreover, neonates of allergic mothers have elevated responses to suboptimal sensitization with food allergens. Importantly, the responses to food allergens by these neonatal mice were dependent on genetic defects in skin barrier function and on exposure to environmental allergens. Blockade of ST2 during skin sensitization inhibited development of anaphylaxis, antigen-specific IgE and inflammatory mediators. The neonatal anaphylactic responses and antigen-specific IgE were also inhibited by oral pre-exposure to food allergen but, interestingly, this was blunted by concurrent pre-exposure of the skin to environmental allergen. Conclusion These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early life exposures and genetics in clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen.Item Mechanisms for Alternaria alternata Function in the Skin During Induction of Peanut Allergy in Neonatal Mice With Skin Barrier Mutations(Frontiers, 2021-09) Buelow, Lauren M.; Hoji, Akihiko; Tat, Kiet; Schroeder-Carter, Lindsay M.; Carroll, Daniela J.; Cook-Mills, Joan M.; Pediatrics, School of MedicineNeonatal mice with heterozygous mutations in genes encoding the skin barrier proteins filaggrin and mattrin (flaky tail mice [FT+/−]) exhibit oral peanut-induced anaphylaxis after skin sensitization. As we have previously reported, sensitization in this model is achieved via skin co- exposure to the environmental allergen Alternaria alternata (Alt), peanut extract (PNE), and detergent. However, the function of Alt in initiation of peanut allergy in this model is little understood. The purpose of this study was to investigate candidate cytokines induced by Alt in the skin and determine the role of these cytokines in the development of food allergy, namely oncostatin M (Osm), amphiregulin (Areg), and IL-33. RT-qPCR analyses demonstrated that skin of FT+/− neonates expressed Il33 and Osm following Alt or Alt/PNE but not PNE exposure. By contrast, expression of Areg was induced by either Alt, PNE, or Alt/PNE sensitization in FT+/− neonates. In scRNAseq analyses, Osm, Areg, and Il33 were expressed by several cell types, including a keratinocyte cluster that was expanded in the skin of Alt/PNE-exposed FT+/− pups as compared to Alt/PNE-exposed WT pups. Areg and OSM were required for oral PNE-induced anaphylaxis since anaphylaxis was inhibited by administration of neutralizing anti-Areg or anti-OSM antibodies prior to each skin sensitization with Alt/PNE. It was then determined if intradermal injection of recombinant IL33 (rIL33), rAreg, or rOSM in the skin could substitute for Alt during skin sensitization to PNE. PNE skin sensitization with intradermal rIL33 was sufficient for oral PNE-induced anaphylaxis, whereas skin sensitization with intradermal rAreg or rOSM during skin exposure to PNE was not sufficient for anaphylaxis to oral PNE challenge. Based on these studies a pathway for IL33, Areg and OSM in Alt/PNE sensitized FT+/− skin was defined for IgE induction and anaphylaxis. Alt stimulated two pathways, an IL33 pathway and a pathway involving OSM and Areg. These two pathways acted in concert with PNE to induce food allergy in pups with skin barrier mutations.Item TL1A Priming Induces a Multi-Cytokine Th9 Cell Phenotype That Promotes Robust Allergic Inflammation in Murine Models of Asthma(2024-03) Niese, Michelle Liu; Kaplan, Mark H.; Cook-Mills, Joan M.; Brutkiewicz, Randy R.; Tepper, Robert S.The TNF superfamily member TL1A is a costimulatory molecule that signals through its receptor DR3 on T lymphocytes. The Th9 subset of T lymphocytes secretes the pleiotropic cytokine IL-9 which has functions in allergic airway disease, helminth infections, and tumor immunity. TL1A increases IL-9 production from Th9 cells. However, its role in regulating other functions of Th9 cells is unknown. Here we demonstrate that TL1A increases expression of IL-9 and IL-13 as well as the frequency of IL-9 and IL-13 co-expressing cells in murine Th9 cell cultures, inducing a robust multi-cytokine phenotype. Mechanistically, this is linked to histone modifications allowing for increased accessibility at the Il9 and Il13 loci. We further show that TL1A alters the transcription factor network underlying expression of IL-9 and IL-13 in Th9 cells and increases binding of these transcription factors to Il9 and Il13 loci. IL-9 and IL- 13 expression have been well studied in the context of allergic airway disease (AAD) and both have been shown to exacerbate AAD. We demonstrate that TL1A-priming enhances pathogenicity of Th9 cells in murine models of AAD and that this is largely mediated through the increased expression of IL-9 and IL-13. We lastly show in both chronic and memory recall models of AAD that blockade of TL1A signaling decreases the multicytokine Th9 cell population and attenuates the allergic phenotype. Taken together, these data demonstrate that TL1A promotes development of multi-cytokine Th9 cells that drive allergic airway diseases and that targeting TL1A could be an effective approach for modifying disease.