{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/38209"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/38209","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity","abstract":"The 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.","abstract_html":"The murine &lt;i&gt;lpr&lt;/i&gt; gene encodes for an aberrant form of Fas (CD95), a molecule involved in apoptosis. The mouse &lt;i&gt;gld&lt;/i&gt; gene leads to the expression of a defective Fasligand. Mice homozygous for &lt;i&gt;lpr&lt;/i&gt; or &lt;i&gt;gld&lt;/i&gt; 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 &lt;i&gt;lpr&lt;/i&gt; 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&lt;sup&gt;MEL-14&lt;/sup&gt;. The DN T cells constitutively transcribed perform, TNF-α and IFN-γ genes. Unlike the DN T cells from &lt;i&gt;lpr&lt;/i&gt; mice, similar cells from &lt;i&gt;gld&lt;/i&gt; 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 &lt;i&gt;lpr&lt;/i&gt; DN T cells can be activated via CD44 and gp-90&lt;sup&gt;MEL-14&lt;/sup&gt; 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 &lt;i&gt;lpr&lt;/i&gt; 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 &lt;i&gt;in vivo&lt;/i&gt; may trigger an inflammatory response and contribute to the vasculitis seen in &lt;i&gt;lpr&lt;/i&gt; and &lt;i&gt;gld&lt;/i&gt; 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.","abstract_has_math":false,"creators":["Hammond-McKibben, Denise M."],"institution":"Virginia Tech","degree_name":"Ph. D.","degree_level":"doctoral","degree_discipline":"Biology","degree_department":"Biology","school":null,"contributors":[],"advisors":[],"committee_chairs":["Nagarkatti, Prakash S."],"committee_members":["Nagarkatti, Mitzi","Schurig, Gerhardt G.","Holladay, Steven D.","Falkinham, Joseph O. III"],"year":1995,"date_issued":"1995-04-05","date_published":"1995-04-05","updated_at":"2026-07-22T22:20:18Z","subjects":["mutations"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["etd-06062008-162732"],"render_values":[{"text":"etd-06062008-162732","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/38209","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Nagarkatti, Prakash S."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Nagarkatti, Mitzi","Schurig, Gerhardt G.","Holladay, Steven D.","Falkinham, Joseph O. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph. D."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["BTD"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Nagarkatti, Prakash S."],"dc:contributor.committeemember":["Nagarkatti, Mitzi","Schurig, Gerhardt G.","Holladay, Steven D.","Falkinham, Joseph O. 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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."],"dc:description.degree":["Ph. D."],"dc:format.medium":["BTD"],"dc:format.mimetype":["application/pdf"],"dc:identifier.other":["etd-06062008-162732"],"dc:identifier.uri":["http://hdl.handle.net/10919/38209"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["mutations"],"dc:title":["Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity"],"dc:type":["Dissertation"],"dc:type.dcmitype":["Text"],"thesis:degree_discipline":["Biology"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Ph. 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