Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity

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dc.contributor.authorHammond-McKibben, Denise M.en
dc.contributor.committeechairNagarkatti, Prakash S.en
dc.contributor.committeememberNagarkatti, Mitzien
dc.contributor.committeememberSchurig, Gerhardt G.en
dc.contributor.committeememberHolladay, Steven D.en
dc.contributor.committeememberFalkinham, Joseph O. IIIen
dc.contributor.departmentBiologyen
dc.date.accessioned2014-03-14T21:13:20Zen
dc.date.adate2008-06-06en
dc.date.available2014-03-14T21:13:20Zen
dc.date.issued1995-04-05en
dc.date.rdate2008-06-06en
dc.date.sdate2008-06-06en
dc.description.abstractThe murine <i>lpr</i> gene encodes for an aberrant form of Fas (CD95), a molecule involved in apoptosis. The mouse <i>gld</i> gene leads to the expression of a defective Fasligand. Mice homozygous for <i>lpr</i> or <i>gld</i> mutations develop severe lymphoproliferative and autoimmune disease characterized by the accumulation of unique CD4⁻CD8⁻ (double-negative, DN) T cells. Because of these poor functions in vitro, the nature and significance of DN T cells in the autoimmune disease process is not clear. In the current study we found that <i>lpr</i> DN T cells could mediate spontaneous lysis of certain tumor cells as well as mediate redirected lysis of various tumor targets when stimulated through the CD3/αβTCR complex and certain adhesion molecules, such as, CD44 and gp90<sup>MEL-14</sup>. The DN T cells constitutively transcribed perform, TNF-α and IFN-γ genes. Unlike the DN T cells from <i>lpr</i> mice, similar cells from <i>gld</i> mice failed to exhibit spontaneous cytotoxicity despite expression of similar levels of cytokines and adhesion molecules. Furthermore, lpr DN T cells could mediate redirected lysis of Fas⁺ but not Fas⁻ target cells. Together, these studies suggested that lysis of target cells by DN T cells was dependent on the interaction between Fas and Fas-ligand. The fact that <i>lpr</i> DN T cells can be activated via CD44 and gp-90<sup>MEL-14</sup> suggested that these T cells may be able to mediate lysis of endothelial cells which bear the ligand for these adhesion molecules. Further studies revealed that the <i>lpr</i> DN T cells could mediate spontaneous lysis of endothelial cells and that CD44-hyaluronate interactions were important for endothelial cell lysis. Thus, interactions between DN T cells and endothelial cells <i>in vivo</i> may trigger an inflammatory response and contribute to the vasculitis seen in <i>lpr</i> and <i>gld</i> mice. We also addressed the hypothesis that acquired immunodeficiency syndrome (AIDS) may be a consequence of destabilization of the idiotypic network. These studies demonstrated that auto- or allo-immunizations involving recognition of class II MHC antigens can trigger an anti-HIV response and such possibilities should be taken into consideration while delineating the pathogenesis of AIDS.en
dc.description.degreePh. D.en
dc.format.extentxi, 166 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-06062008-162732en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-06062008-162732/en
dc.identifier.urihttp://hdl.handle.net/10919/38209en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V856_1995.H366.pdfen
dc.relation.isformatofOCLC# 32912354en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectmutationsen
dc.subject.lccLD5655.V856 1995.H366en
dc.titleEffect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunityen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineBiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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