{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/86452"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/86452","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"The Transcription Factor Ets1 Cooperates with IL-17 Receptor Subunit A to Prevent the Development of Autoimmunity and Immunodeficiency","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Sunshine, Alex; 0000-0002-7298-9474"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Garrett-Sinha, Lee Ann","Biochemistry"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-02-21T17:22:34Z","date_published":"2025-02-21T17:22:34Z","updated_at":"2026-07-27T19:05:32Z","subjects":["immunology"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/86452","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Garrett-Sinha, Lee Ann","Biochemistry"]},{"key":"dc:creator","label":"Author","values":["Sunshine, Alex; 0000-0002-7298-9474"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-02-21T17:22:34Z","2020"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["immunology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/86452"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Ets1 is a lineage-specific transcription factor that regulates B and T cell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice differentiate more readily to Th17 cells and secrete IL-17, a cytokine extensively implicated in autoimmune disease pathogenesis, and the immune responses to bacterial and fungal pathogens. To determine if increased IL-17 production contributes to the development of autoimmunity in Ets1 KO mice, I generated Ets1 and IL-17 Receptor double knock out (DKO) mice. I used a combination of flow cytometry, ELISA, ELISPOT, immunofluorescence, and in vitro differentiation assays to evaluate immune responses in DKO and control mice. These studies demonstrated that the absence of IL-17 signaling did not prevent or ameliorate the phenotype of Ets1 KO mice, but rather that DKO animals exhibited worse symptoms with striking increases in the numbers of Th2, Th17, and Tfh cells. DKO mice also developed an increased number of germinal center B cells, isotype-switched B cells, memory B cells, and plasma cells. During my studies, I noted that DKO mice began to develop skin lesions as they age, typically on the ventral surface of the neck. These lesions harbored Staphylococcus aureus (S. aureus) bacteria, and S. aureus could be recovered from the skin of DKO mice, even before lesions developed. Using a bioluminescent strain of S. aureus and IVIS imaging, I found that DKO mice experimentally infected with S. aureus on the back skin were unable to clear the bacteria. Interestingly, older DKO mice (4-6 months of age) had a more significant defect in clearing S. aureus than did younger mice (2-3 months of age). This lack of clearance to S. aureus indicates that an age-related alteration in the immune response underlies the susceptibility. Because DKO mice have strong autoimmune responses, they accumulate autoantibodies as they age. I found that DKO mice produce autoantibodies against the antimicrobial peptides, including cathelicidin-related antimicrobial peptide (CRAMP) and β-defensin 1 (DEFB1). They also produce autoantibodies that bind to the cytoplasm of neutrophils. Because these innate immune system components are essential in controlling bacterial infections, I theorized that autoantibody-mediated neutralization of these components might underlie the susceptibility to S. aureus that develops with age. To further test the roles of one of the antimicrobial peptides in the immune to S. aureus, I infected CRAMP KO with S. aureus, but I found that these mice were equally capable of clearing the infection as WT mice. My current model is that excessive immune activation leads to the production of autoantibodies that accumulate with age and that target innate immune effector mechanisms important for anti-bacterial immunity, thereby resulting in susceptibility to skin infections with S. aureus. My studies may have important implications in understanding the mechanisms that drive pathogenesis in human diseases characterized by both autoimmunity and immunodeficiency.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The Transcription Factor Ets1 Cooperates with IL-17 Receptor Subunit A to Prevent the Development of Autoimmunity and Immunodeficiency"]}]}],"canonical_facts":{"dc:contributor":["Garrett-Sinha, Lee Ann","Biochemistry"],"dc:creator":["Sunshine, Alex; 0000-0002-7298-9474"],"dc:date":["2025-02-21T17:22:34Z","2020"],"dc:description":["Ph.D.","Ets1 is a lineage-specific transcription factor that regulates B and T cell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice differentiate more readily to Th17 cells and secrete IL-17, a cytokine extensively implicated in autoimmune disease pathogenesis, and the immune responses to bacterial and fungal pathogens. To determine if increased IL-17 production contributes to the development of autoimmunity in Ets1 KO mice, I generated Ets1 and IL-17 Receptor double knock out (DKO) mice. I used a combination of flow cytometry, ELISA, ELISPOT, immunofluorescence, and in vitro differentiation assays to evaluate immune responses in DKO and control mice. These studies demonstrated that the absence of IL-17 signaling did not prevent or ameliorate the phenotype of Ets1 KO mice, but rather that DKO animals exhibited worse symptoms with striking increases in the numbers of Th2, Th17, and Tfh cells. DKO mice also developed an increased number of germinal center B cells, isotype-switched B cells, memory B cells, and plasma cells. During my studies, I noted that DKO mice began to develop skin lesions as they age, typically on the ventral surface of the neck. These lesions harbored Staphylococcus aureus (S. aureus) bacteria, and S. aureus could be recovered from the skin of DKO mice, even before lesions developed. Using a bioluminescent strain of S. aureus and IVIS imaging, I found that DKO mice experimentally infected with S. aureus on the back skin were unable to clear the bacteria. Interestingly, older DKO mice (4-6 months of age) had a more significant defect in clearing S. aureus than did younger mice (2-3 months of age). This lack of clearance to S. aureus indicates that an age-related alteration in the immune response underlies the susceptibility. Because DKO mice have strong autoimmune responses, they accumulate autoantibodies as they age. I found that DKO mice produce autoantibodies against the antimicrobial peptides, including cathelicidin-related antimicrobial peptide (CRAMP) and β-defensin 1 (DEFB1). They also produce autoantibodies that bind to the cytoplasm of neutrophils. Because these innate immune system components are essential in controlling bacterial infections, I theorized that autoantibody-mediated neutralization of these components might underlie the susceptibility to S. aureus that develops with age. To further test the roles of one of the antimicrobial peptides in the immune to S. aureus, I infected CRAMP KO with S. aureus, but I found that these mice were equally capable of clearing the infection as WT mice. My current model is that excessive immune activation leads to the production of autoantibodies that accumulate with age and that target innate immune effector mechanisms important for anti-bacterial immunity, thereby resulting in susceptibility to skin infections with S. aureus. My studies may have important implications in understanding the mechanisms that drive pathogenesis in human diseases characterized by both autoimmunity and immunodeficiency.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/86452"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["immunology"],"dc:title":["The Transcription Factor Ets1 Cooperates with IL-17 Receptor Subunit A to Prevent the Development of Autoimmunity and Immunodeficiency"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:32Z"}