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dc.contributor.advisorCambier, John C.
dc.contributor.authorAkerlund, Linda Jane
dc.contributor.committeememberHenson, Peter
dc.contributor.committeememberMarrack, Philippa
dc.contributor.committeememberTorres, Raul
dc.contributor.committeememberLeslie, Christina
dc.contributor.committeememberLenz, Laurel
dc.date.accessioned2015-08-27T03:56:04Z
dc.date.available2017-06-09T08:20:26Z
dc.date.submitted2015
dc.descriptionSpring
dc.descriptionIncludes bibliographical references.
dc.description.abstractAntigen receptor (BCR) signals direct fate, function and survival of B cells. These signals must be precisely regulated to generate a highly diverse BCR repertoire capable of mounting adaptive responses to pathogens, while simultaneously avoiding malignancy and autoimmunity. The inositol 5-phosphatase SHIP-1 has been established as a mediator of active inhibition of BCR signaling by co-aggregated FcɣRIIB. SHIP-1 converts PI(3,4,5)P₃ to PI(3,4)P₂, reducing recruitment of critical signaling intermediaries whose functions depend on plextrin homology domain-dependent association with plasma membrane inner leaflet PI(3,4,5)P₃. Recent findings suggest that SHIP-1 may also function in regulation of autonomous BCR signaling, particularly in B cell tolerance. SHIP-1 has been shown to translocate to the membrane during BCR signaling, but the mechanism by which this occurs and its functional consequences are not known. My studies addressed multiple aspects of SHIP-1 function in B cells, including the basis of its translocation following BCR stimulation, and its impact on tonic and antigen stimulated BCR signaling. I show here that SHIP-1 associates with PI(3,4,5)P₃ in vitro and may translocate to membranes enriched in PI(3,4,5)P₃. I further provide evidence that SHIP-1 functions to limit both tonic and antigen-initiated signaling in naïve B cells. Perhaps most interesting is the role of SHIP-1 in maintaining B cell tolerance. Many self-reactive B cells exist in the periphery in an unresponsive state that can be rapidly reversed by dissociation of autoantigen from BCR. Reversibility of anergy suggests that in chronically stimulated cells BCR transduce regulatory signals that maintain a non-durable state of unresponsiveness. Controversy exists regarding the biochemical nature of these signals. Candidate effectors include phosphatase and tensin homolog PTEN and SHIP-1, implicated in MD4.ML-5 anti-hen egg lysozyme (HEL) and Ars/A1 anti-chromatin models, respectively. Here I extend these studies showing definitively that SHIP-1 is required to maintain anergy in both models. In these studies I made the additional unexpected finding that SHIP-1 deficiency, while not affecting proliferation, licenses naïve high affinity anti-HEL (MD4) B cells to undergo much more efficient differentiation to plasma cells when transferred into antigen sufficient (ML-5) mice. Findings demonstrate a dynamic role for SHIP-1 in multiple signaling functions.
dc.identifierAkerlund_ucdenveramc_1639D_10218.pdf
dc.identifier.urihttp://hdl.handle.net/10968/1122
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 06/09/2017
dc.subjectSHIP-1
dc.subjectTolerance
dc.subjectMD4.ML-5
dc.subjectSignaling
dc.subject.meshClonal Anergy
dc.subject.meshReceptors, Antigen, B-Cell
dc.titleSHIP-1 regulation of B lymphocyte signaling
dc.typeText
dcterms.embargo.expires2017-06-09
thesis.degree.disciplineImmunology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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