Regulation of dsDNA binding B-cells.
Item
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Title
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Regulation of dsDNA binding B-cells.
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Identifier
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AAI3103179
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identifier
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3103179
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Creator
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Taylor, Devon Keith.
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Contributor
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Adviser: Linda Spatz
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Date
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2003
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry | Health Sciences, Immunology
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Abstract
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Anti-double stranded DNA (dsDNA) autoantibodies are the hallmark of SLE. The presence of these autoantibodies correlates with disease activity such as glomerulonephritis. The absence of high affinity autoantibodies in nonautoimmune individuals suggest that B-cell regulatory mechanisms play a role in averting autoimmunity. We have used a mouse model in which mice are transgenic for the IgM heavy chain of an anti-dsDNA antibody designated R4A to study the regulation of dsDNA binding B-cells.;We demonstrated that these IgM transgenic (R4A-Cp) mice do not spontaneously secrete transgenic autoantibody and maintain tolerance in part by anergy. These anergic B-cells preferentially utilize a Vkappa1 light chain and display a functionally inactive or anergic phenotype. The dsDNA binding B-cells in these mice are unresponsive to B-cell receptor (BCR) crosslinking. However, they can be activated to secrete antibody in response to LPS or T-cell derived factors such as CD40 ligand and IL4. We therefore propose that tolerance is maintained in these dsDNA binding B-cells by blocking early events specific to BCR signaling while not affecting more downstream events common to signaling pathways induced by LPS and costimulatory T-cell derived factors.;In this study we also compared the regulation of R4A-IgM dsDNA binding B-cells to that of R4A-IgG2b dsDNA binding B-cells. We observed that heavy chain isotype plays a role in tolerance induction and that IgG B-cells are more stringently regulated than IgM B-cells.;In an attempt to understand how varying signaling thresholds can affect tolerance induction, we bred R4A-Cmu transgenic mice to transgenic mice overexpressing hCD19 a molecule involved in lowering the threshold for B-cell activation. We demonstrated that CD19 overexpression can abrogate tolerance in transgenic IgM anti-dsDNA B-cells and lead to the spontaneous secretion of anti-dsDNA antibody. We observed that this does not require T-cell help. We also observed that transgenic anti-dsDNA B-cells are derived from the conventional B-2 cell compartment and not the B-1 subset. They reside in the marginal zone of the spleen which has recently been shown to be the residence for some autoantibody secreting cells. Finally, we have demonstrated that transgenic dsDNA binding B-cells in mice that overexpress CD19, are still unresponsive to BCR crosslinking but are hyperresponsive to BCR independent innate immune mechanisms.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
