Browsing by Author "Cook-Mills, Joan"

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    Associations of alpha and gamma-tocopherol during early life with lung function in childhood
    (Elsevier, 2020) Kumar, Rajesh; Ferrie, Ryan; Balmert, Lauren; Kienzi, Matthew; Rifas-Shiman, Sheryl L.; Gold, Diane R.; Sordillo, Joanne E.; Kleinman, Ken; Camargo, Carlos A., Jr.; Litonjua, Augusto A.; Oken, Emily; Cook-Mills, Joan; Pediatrics, School of Medicine
    Background: Tocopherol isoforms may regulate child lung growth and spirometric measures. Objective: Our aim was to determine the extent to which plasma a-tocopherol (a-T) or g-tocopherol (g-T) isoform levels in early childhood or in utero are associated with childhood lung function. Methods: We included 622 participants in the Project Viva cohort who had lung function at a mid-childhood visit (age 6-10 years). Maternal and child tocopherol isoform levels were measured by HPLC at the second trimester and 3 years of age, respectively. Multivariable linear regression models (adjusted for mid-childhood body mass index z scores, maternal education, smoking in pregnancy, and prenatal particulate matter with diameter of <2.5 micrometers (PM2.5) particulate exposure) stratified by tertiles of child g-T level were used to assess the association of a-T levels with FEV1 and forced vital capacity (FVC) percent predicted. Similarly, models stratified by child a-T tertile evaluated associations of g-T levels with lung function. We performed similar analyses with maternal second trimester tocopherol isoform levels. Results: The median maternal second trimester a-T level was 63 mM (interquartile range 5 47-82). The median early-childhood level was 25 mM (interquartile range 5 20-33 mM). In the lowest tertile of early-childhood g-T, children with a higher a-T level (per 10 mM) had a higher mid-childhood FEV1 percent predicted (b 5 3.09; 95% CI 5 0.58-5.59 and a higher FVC percent predicted (b 5 2.77; 95% CI 5 0.47-5.06). This protective association of a-T was lost at higher g-T levels. We did not see any consistent associations of second trimester levels of either a-T or g-T with mid-childhood FEV1 or FVC. Conclusion: When g-T levels were in the lowest tertile, a higher early-childhood a-T level was associated with better lung function at mid-childhood. Second trimester maternal plasma a-T concentration was 3-fold higher than in the adult nonpregnant female population.
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    Cell-Type Specific Function of STAT4 in an Animal Model of Multiple Sclerosis
    (2023-12) Alakhras, Nada S.; Kaplan, Mark H.; Cook-Mills, Joan; Dong, X. Charlie; Quilliam, Lawrence A.
    Signal transducer and activator of transcription 4 (STAT4) is a critical regulator of inflammation. STAT4 promotes protective immunity and autoimmunity downstream of pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), germ-line deletion of STAT4 in mice results in resistance to the development of inflammation and paralysis. In parallel, genome-wide association studies (GWAS) have identified polymorphisms in the STAT4 gene associated with susceptibility to several autoimmune diseases including MS demonstrating a potential role for STAT4 in human autoimmunity. Here, we examined cell-type requirements for STAT4 in EAE. Using conditional Stat4 mutant mice, we found that mice lacking Stat4 in T cells and CD11c+-expressing cells are resistant to EAE, while mice lacking Stat4 in Lyz2+-expressing cells are susceptible to EAE. STAT4 is expressed and activated in CD11c+ dendritic cells (DCs) in the CNS during peak disease severity. Stat4fl/flCD11cCre mice exhibit significantly decreased classical dendritic cell (cDC) expansion in the CNS and this correlates with diminished numbers of infiltrated T cells in the CNS and decreased inflammatory cytokine production. Adoptive transfer of wild type but not Stat4-/- or Il23r-/- DCs into Stat4fl/flCD11cCre rescues the development of EAE. Transferred Il23r-/- DCs were retained in the lymph nodes suggesting that IL-23-STAT4 signaling promotes their migration to and expansion in the CNS. Single-cell RNA-seq analyses of CNS DCs from WT and Stat4fl/flCD11cCre mice identified cDC populations with STAT4-dependent gene expression and migratory phenotypes. Collectively, our results demonstrate that STAT4 in cDCs is required for expansion in the CNS, the development of encephalitogenic T cells, and the clinical symptoms of EAE. Thus, our study reveals previously unrecognized functions of STAT4 in cDCs that provide mechanistic insight into CNS autoimmunity and provide a foundation for identifying new therapeutic targets for the disease.
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    HUNK as an Immune Regulator of Triple Negative Breast Cancer
    (2024-05) Ramos Solis, Nicole; Yeh, Elizabeth; Arrizabalaga, Gustavo; Fehrenbacher, Jill; Cook-Mills, Joan; Jerde, Travis J.
    Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Unlike other breast cancer types, TNBC tumors do not respond to endocrine therapy, and standardized treatment protocols for TNBC are currently unavailable. TNBC is recognized as a more metastatic, aggressive, and immunogenic subtype of breast cancer, rendering it to be more receptive to immunotherapy. Among the immune cell populations abundant in TNBC tumors, tumor-associated macrophages (TAMs) are particularly more prevalent and are particularly known to play a role in cancer metastasis. This work focuses on and investigates the involvement of the protein kinase HUNK in tumor immunity. With the use of gene expression analysis, such as NanoString's nCounter PanCancer Immune Profiling panel, we found that targeting HUNK is associated with alterations in the IL-4/IL-4R cytokine signaling pathway. Experimental analysis and work demonstrated that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. Furthermore, in vivo, analysis shows that HUNK-dependent control of IL-4 secretion from tumor cells leads to the polarization of macrophages into an M2-like phenotype, and consequently, IL-4 induction promotes cancer metastasis and prompts macrophage's metastatic capacities. These findings underscore HUNK as a potential therapeutic target for mitigating TNBC metastasis by modulating the TAM population.
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    Immunological and Social Determinants of Asthma: From Cytokine Signaling to Air Pollution Disparities
    (2024-10) Cheung, Cherry Cheuk Lam; Kaplan, Mark H.; Cook, Nathan; Cook-Mills, Joan; Yang, Kai
    Asthma is a chronic respiratory disease characterized by airway inflammation and hyperresponsiveness, impacting 262 million individuals globally. This heterogeneous condition results from a complex interplay of genetic, environmental, and social factors. The pathophysiology involves dysregulated immune responses, particularly through cytokine signaling, and is exacerbated by environmental pollutants and social determinants of health (SDOH). This thesis aims to (1) elucidate novel cytokine signaling pathways involved in asthma, specifically a potential type II IL-9 receptor complex, and (2) evaluate the impact of California's Assembly Bill 617 (AB 617) on reducing air pollution and asthma disparities in disadvantaged communities. The research employs molecular biology techniques, including flow cytometry, proximity ligation assay, and RNA sequencing, to investigate IL-9 signaling in airway epithelial cells. It also involves a policy analysis of AB 617's initial effectiveness in reducing fine particulate matter (PM2.5) levels and asthmaassociated emergency room (ER) visits through environmental monitoring and hospital records. The study identifies a novel type II IL-9 receptor complex composed of IL-9Rα and IL-13Rα1, suggesting new therapeutic targets for asthma management. Policy analysis reveals limited initial success of AB 617 in reducing air pollution and asthma incidence, highlighting the need for enhanced regulatory measures and community engagement. Understanding the molecular mechanisms of IL-9 signaling and addressing environmental and social determinants are crucial for comprehensive asthma management. Integrating scientific research with policy interventions can improve health outcomes and reduce disparities in asthma prevalence and severity.
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    The Role of IL-9 in Inflammatory Diseases: Allergic Asthma, Lung Cancer, and Urinary Tract Infections
    (2023-06) Pajulas, Abigail Lacanlale; Kaplan, Mark H.; Cook-Mills, Joan; Dent, Alexander; Zhou, Baohua
    Among the cytokines regulating immunity, interleukin 9 (IL-9) has gained considerable attention for its role in inflammation, immune tolerance, and tumor immunity. IL-9 has a broad array of functions and acts on multiple cell types to regulate immune responses. IL-9 receptor is expressed on both non-hematopoietic cells and hematopoietic cells in the innate and adaptive immune system. IL-9 demonstrates a remarkable degree of tissue-specific functionality that varies by tissue site and the context of the inflammatory milieu. In this dissertation, we investigate the biological activities of IL-9 and identify distinct IL-9-responsive cell type in the immune pathogenesis of disease models including allergic airway disease, lung cancer, and urinary tract infection. When examining airway hyperreactivity, we found IL-9-dependent mast cell function was critical. Using adoptive transfer models and newly generated mice with an inactivation of the Il9 gene restricted to T cells generated by CD4-cre/LoxP-mediated targeting, we demonstrate that T cell secreted IL-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration during allergic airway inflammation. In IL-9-mediated pro-tumor responses, interstitial macrophages, but not mast cells, respond to T cell IL-9 to enhance B16 metastatic tumor growth. In the context of urinary tract infection, IL-9 contributes to protection against E. coli bladder infection potentially by enhancing CCL20 production in epithelial cells to recruit macrophages and neutrophils. Altogether, IL-9 can exert cell type-specific effects that identify its roles in immunity and disease. This perspective will be important in defining the diseases where targeting IL-9 as a therapeutic strategy would be beneficial, and where it has the potential to complicate clinical outcomes.
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    T follicular regulatory cells and IL-10 promote food antigen–specific IgE
    (American Society for Clinical Investigation, 2020-07-01) Xie, Markus M.; Chen, Qiang; Liu, Hong; Yang, Kai; Koh, Byunghee; Wu, Hao; Maleki, Soheila J.; Hurlburt, Barry K.; Cook-Mills, Joan; Kaplan, Mark H.; Dent, Alexander L.; Microbiology and Immunology, School of Medicine
    Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell–deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development.