Browsing by Author "Qayum, Amina Abdul"

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    A conserved enhancer regulates Il9 expression in multiple lineages
    (Nature Research, 2018-11-15) Koh, Byunghee; Qayum, Amina Abdul; Srivastava, Rajneesh; Fu, Yongyao; Ulrich, Benjamin J.; Janga, Sarath Chandra; Kaplan, Mark H.; Pediatrics, School of Medicine
    Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production.
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    Covalent Heterobivalent Inhibitor Design for Inhibition of IgE-Dependent Penicillin Allergy in a Murine Model
    (Science Publications, 2019-05-17) Deak, Peter E.; Kim, Baksun; Koh, Byunghee; Qayum, Amina Abdul; Kiziltepe, Tanyel; Kaplan, Mark H.; Bilgicer, Basar; Pediatrics, School of Medicine
    Drug allergies occur when hapten-like drug metabolites conjugated to serum proteins, through their interactions with specific immunoglobulin E (IgE), trigger allergic reactions that can be life-threatening. A molecule termed covalent heterobivalent inhibitor (cHBI) was designed to specifically target drug-hapten specific IgE to prevent it from binding drug-haptenated serum proteins. cHBI binds the two independent sites on a drug-hapten specific antibody and covalently conjugates only to the specific IgE, permanently inhibiting it. The cHBI design was evaluated via ELISA to measure cHBI-IgE binding, degranulation assays of rat basophil leukemia (RBL) cells for in vitro efficacy, and mouse models of ear swelling and systemic anaphylaxis responses for in vivo efficacy. The cHBI design was evaluated using two seperate models: one specific to inhibit penicillin G reactive IgE, and another to inhibit IgE specific to a model compound, dansyl. We show that cHBI conjugated specifically to its target antibody and inhibited degranulation in cellular degranulation assays using RBL cells. Furthermore, cHBIs demonstrated in vivo inhibition of allergic responses in both murine models. We establish the cHBI design to be a versatile platform for inhibiting hapten/IgE interactions, which can potentially be applied to inhibit IgE mediated allergic reactions to any drug/small molecule allergy.
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    Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen
    (National Academy of Sciences, 2019-04-30) Deak, Peter E.; Kim, Baksun; Qayum, Amina Abdul; Shin, Jaeho; Vitalpur, Girish; Kloepfer, Kirsten M.; Turner, Matthew J.; Smith, Neal; Shreffler, Wayne G.; Kiziltepe, Tanyel; Kaplan, Mark H.; Bilgicer, Basar; Pediatrics, School of Medicine
    Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.
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    HIPK2 directs cell type-specific regulation of STAT3 transcriptional activity in Th17 cell differentiation
    (National Academy of Science, 2022) Cheung, Ka Lung; Jaganathan, Anbalagan; Hu, Yuan; Xu, Feihong; Lejeune, Alannah; Sharma, Rajal; Caescu, Cristina I.; Meslamani, Jamel; Vincek, Adam; Zhang, Fan; Lee, Kyung; Zaware, Nilesh; Qayum, Amina Abdul; Ren, Chunyan; Kaplan, Mark H.; He, John Cijiang; Xiong, Huabao; Zhou, Ming-Ming; Microbiology and Immunology, School of Medicine
    SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.
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    The Il9 CNS-25 Regulatory Element Controls Mast Cell and Basophil IL-9 Production
    (American Association of Immunologists, 2019-09-01) Qayum, Amina Abdul; Koh, Byunghee; Martin, Rebecca K.; Kenworthy, Blake T.; Kharwadkar, Rakshin; Fu, Yongyao; Wu, Wenting; Conrad, Daniel H.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Interleukin 9 (IL-9) is an important mediator of allergic disease that is critical for mast cell driven diseases. IL-9 is produced by many cell types including T cells, basophils, and mast cells. Yet, how IL-9 is regulated in mast cells or basophils is not well characterized. In this report we tested the effects of deficiency of a mouse Il9 gene regulatory element (Il9 CNS-25) in these cells in vivo and in vitro. In mast cells stimulated with IL-3 and IL-33, the Il9 CNS-25 enhancer is a potent regulator of mast cell Il9 gene transcription and epigenetic modification at the Il9 locus. Our data show preferential binding of STAT5 and GATA1 to CNS-25 over the Il9 promoter in mast cells, and that T cells and mast cells have differing requirements for the induction of IL-9 production. Il9 CNS-25 is required for IL-9 production from T cells, basophils, and mast cells in a food allergy model, and deficiency in IL-9 expression results in decreased mast cell expansion. In a Nippostrongylus brasiliensis infection model we observed a similar decrease in mast cell accumulation. Although decreased mast cells correlated with higher parasite egg burden and delayed clearance in vivo, T cell-deficiency in IL-9 also likely contributes to the phenotype. Thus, our data demonstrate IL-9 production in mast cells and basophils in vivo requires Il9 CNS-25, and that Il9 CNS-25-dependent IL-9 production is required for mast cell expansion during allergic intestinal inflammation.