Regulation of Human Monocyte Function by Cross-Linking of Immunoglobulin E

dc.contributor.advisorFarrar, J. Daviden
dc.contributor.committeeMemberGill, Michelle A.en
dc.contributor.committeeMemberGruchalla, Rebecca S.en
dc.contributor.committeeMemberYarovinsky, Felixen
dc.contributor.committeeMemberKahn, Jeffreyen
dc.creatorPyle, David Michael, 1984-en 2015
dc.description.abstractCross-linking of IgE by allergen triggers many cellular processes that drive allergic disease. While the role of IgE in mediating allergic responses is best described on basophils and mast cells, expression of the high-affinity IgE receptor on other innate immune cells, including monocytes, suggests that it may impact the function of these cells in allergic environments. Exacerbations of allergic disease have been associated with allergen exposure as well as viral and bacterial infection, but the mechanisms of these phenomena are not well understood. Monocytes are recruited to sites of inflammation in both allergic disease and infection, serving a number of important functions, including cytokine secretion, phagocytosis, and stimulation of adaptive immune responses. However, the impact of IgE cross-linking on monocyte functions is poorly understood. To determine how IgE cross-linking affects monocyte phenotype and function I isolated primary human monocytes from blood samples and stimulated them in the presence or absence of a cross-linking anti-IgE antibody. My studies reveal that IgE cross-linking induces up regulation of CD14, an important component of inflammatory responses. IgE cross-linking on monocytes also induces secretion of inflammatory cytokines - including tumor necrosis factor α, and interleukin-1, -6, and -23 - as well as autoregulatory interleukin-10. These inflammatory responses to IgE cross-linking are enhanced in monocytes from individuals with elevated serum IgE concentration, compared to monocytes from individuals with normal IgE concentration. In contrast, IgE cross-linking suppresses expression of an important mediator of phagocytosis, CD64. Indeed, IgE cross-linking specifically impairs monocyte phagocytic function without disrupting the capacity of monocytes to kill intracellular bacteria. IgE cross-linking also reduces expression of several surface molecules associated with antigen presentation and inhibits virus-induced up regulation of these molecules. Furthermore, IgE cross-linking during virus exposure suppresses monocyte-driven differentiation of type 1 helper T cells. My findings suggest that IgE cross-linking on monocytes may contribute to allergic disease as well as pathogen-associated exacerbations of disease by three mechanisms: 1) enhancing detrimental inflammatory responses in a serum IgE-dependent manner, 2) concomitantly crippling phagocytosis, a primary mechanism utilized by these cells to resolve inflammation, and 3) suppressing stimulation of appropriate T cell responses in response to infection.en
dc.subjectImmunoglobulin Een
dc.titleRegulation of Human Monocyte Function by Cross-Linking of Immunoglobulin Een
dc.type.materialtexten School of Biomedical Sciencesen Southwestern Medical Centeren of Philosophyen


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