{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/136878"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/136878","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Early Growth Response Protein 2 (EGR2) regulation of B cell differentiation in lupus-prone mice","abstract":"Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with an unidentified cause and no suitable treatment. It involves abnormal activation of B cells, which produce pathogenic autoantibodies that contribute to inflammation and tissue damage in multiple organs. Therapeutic depletion of B cells in human lupus patients had mixed success due to the complex heterogeneity of B cell subsets, differences in autoantibody production, and the persistence of antibody-secreting plasma cells (PCs). Our laboratory reported that the transcription factor Early Growth Response 2 (EGR2), a key regulator of immune cell function, was markedly upregulated in murine and human lupus lymphocytes. Further, we reported that conditional deletion of Egr2-/- in lymphocytes in lupus-prone B6/lpr mice suppressed pathogenic anti-dsDNA autoantibodies. Notably, Egr2-/- B6/lpr mice exhibited an increased germinal center B (GCB) cell population but a decreased PC subset, suggesting that GCB cells fail to progress into fully differentiated PCs. This finding reveals a novel and unexpected role of EGR2 in the transition from GCB cells to antibody-secreting PCs. These findings provide compelling evidence that EGR2 functions aberrantly in lupus, contributing to disease pathology by facilitating the generation of autoreactive PCs. To further investigate the novel role of EGR2 on B cells. In this project, we conducted extensive experiments using newly developed CD2Cre-Egr2-/- MRL-MpJ- Fas lpr mice, in which Egr2 is selectively deleted in CD2-expressing lymphocytes primarily in T cells and a subset of activated or mature B cells that express CD2. Our findings show that egr2 deletion in MRL/lpr mice leads to a significant reduction in marginal zone B cells and a trend reduction in antibody-secreting plasma cells, while follicular B cells remain largely unaffected. Germinal center B cells were found to be increased, mirroring previous results observed in Egr2-/- B6/lpr mice. However, we observed only a slight decrease in serum anti-dsDNA autoantibodies in Egr2-/- MRL/lpr mice, which was different from what we observed in Egr2-/- B6/lpr mice. Collectively, our data indicate that EGR2 plays a pivotal and previously underappreciated role in regulating late-stage B cell development in lupus. These findings suggest that EGR2 may contribute to lupus pathogenesis by facilitating the differentiation of autoreactive B cells into plasma cells, and it may represent a novel therapeutic target for modulating pathogenic B cell responses in SLE.","abstract_html":"Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with an unidentified cause and no suitable treatment. It involves abnormal activation of B cells, which produce pathogenic autoantibodies that contribute to inflammation and tissue damage in multiple organs. Therapeutic depletion of B cells in human lupus patients had mixed success due to the complex heterogeneity of B cell subsets, differences in autoantibody production, and the persistence of antibody-secreting plasma cells (PCs). Our laboratory reported that the transcription factor Early Growth Response 2 (EGR2), a key regulator of immune cell function, was markedly upregulated in murine and human lupus lymphocytes. Further, we reported that conditional deletion of Egr2-/- in lymphocytes in lupus-prone B6/lpr mice suppressed pathogenic anti-dsDNA autoantibodies. Notably, Egr2-/- B6/lpr mice exhibited an increased germinal center B (GCB) cell population but a decreased PC subset, suggesting that GCB cells fail to progress into fully differentiated PCs. This finding reveals a novel and unexpected role of EGR2 in the transition from GCB cells to antibody-secreting PCs. These findings provide compelling evidence that EGR2 functions aberrantly in lupus, contributing to disease pathology by facilitating the generation of autoreactive PCs. To further investigate the novel role of EGR2 on B cells. In this project, we conducted extensive experiments using newly developed CD2Cre-Egr2-/- MRL-MpJ- Fas lpr mice, in which Egr2 is selectively deleted in CD2-expressing lymphocytes primarily in T cells and a subset of activated or mature B cells that express CD2. Our findings show that egr2 deletion in MRL/lpr mice leads to a significant reduction in marginal zone B cells and a trend reduction in antibody-secreting plasma cells, while follicular B cells remain largely unaffected. Germinal center B cells were found to be increased, mirroring previous results observed in Egr2-/- B6/lpr mice. However, we observed only a slight decrease in serum anti-dsDNA autoantibodies in Egr2-/- MRL/lpr mice, which was different from what we observed in Egr2-/- B6/lpr mice. Collectively, our data indicate that EGR2 plays a pivotal and previously underappreciated role in regulating late-stage B cell development in lupus. These findings suggest that EGR2 may contribute to lupus pathogenesis by facilitating the differentiation of autoreactive B cells into plasma cells, and it may represent a novel therapeutic target for modulating pathogenic B cell responses in SLE.","abstract_has_math":false,"creators":["Islam, Mahfuzul"],"institution":"Virginia Tech","degree_name":"Master of Science","degree_level":"masters","degree_discipline":"Biomedical and Veterinary Sciences","degree_department":"Biomedical and Veterinary Sciences","school":null,"contributors":[],"advisors":[],"committee_chairs":["Ahmed, S. A."],"committee_members":["Reilly, Christopher Michael","Luo, Xin","Dai, Rujuan"],"year":2025,"date_issued":"2025-07-22","date_published":"2025-07-22","updated_at":"2026-07-22T22:19:31Z","subjects":["EGR2","B cell differentiation","Germinal center B cells","Plasma cells","Autoantibodies"],"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":["vt_gsexam:44413"],"render_values":[{"text":"vt_gsexam:44413","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/136878","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Ahmed, S. 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It involves abnormal activation of B cells, which produce pathogenic autoantibodies that contribute to inflammation and tissue damage in multiple organs. Therapeutic depletion of B cells in human lupus patients had mixed success due to the complex heterogeneity of B cell subsets, differences in autoantibody production, and the persistence of antibody-secreting plasma cells (PCs). Our laboratory reported that the transcription factor Early Growth Response 2 (EGR2), a key regulator of immune cell function, was markedly upregulated in murine and human lupus lymphocytes. Further, we reported that conditional deletion of Egr2-/- in lymphocytes in lupus-prone B6/lpr mice suppressed pathogenic anti-dsDNA autoantibodies. Notably, Egr2-/- B6/lpr mice exhibited an increased germinal center B (GCB) cell population but a decreased PC subset, suggesting that GCB cells fail to progress into fully differentiated PCs. This finding reveals a novel and unexpected role of EGR2 in the transition from GCB cells to antibody-secreting PCs. These findings provide compelling evidence that EGR2 functions aberrantly in lupus, contributing to disease pathology by facilitating the generation of autoreactive PCs. To further investigate the novel role of EGR2 on B cells. In this project, we conducted extensive experiments using newly developed CD2Cre-Egr2-/- MRL-MpJ- Fas lpr mice, in which Egr2 is selectively deleted in CD2-expressing lymphocytes primarily in T cells and a subset of activated or mature B cells that express CD2. Our findings show that egr2 deletion in MRL/lpr mice leads to a significant reduction in marginal zone B cells and a trend reduction in antibody-secreting plasma cells, while follicular B cells remain largely unaffected. Germinal center B cells were found to be increased, mirroring previous results observed in Egr2-/- B6/lpr mice. However, we observed only a slight decrease in serum anti-dsDNA autoantibodies in Egr2-/- MRL/lpr mice, which was different from what we observed in Egr2-/- B6/lpr mice. Collectively, our data indicate that EGR2 plays a pivotal and previously underappreciated role in regulating late-stage B cell development in lupus. These findings suggest that EGR2 may contribute to lupus pathogenesis by facilitating the differentiation of autoreactive B cells into plasma cells, and it may represent a novel therapeutic target for modulating pathogenic B cell responses in SLE."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease. In lupus, the body's immune system, which usually defends against infections, becomes overactive and mistakenly attacks its healthy tissues and organs. This misguided attack leads to the production of harmful antibodies called autoantibodies. These autoantibodies target the body's cells, resulting in widespread inflammation and tissue damage. Lupus can affect multiple parts of the body, including the skin, joints, kidneys, heart, lungs, blood vessels, and brain. This widespread involvement can manifest as symptoms, including fatigue, joint pain, rash, and fever. The clinical severity of systemic lupus erythematosus (SLE) is highly variable, ranging from mild, intermittent symptoms in some patients to severe, potentially life-threatening organ complications in others. Lupus predominantly affects females, especially during their reproductive years, typically between the ages of 15 and 44. Lupus tends to involve some racial and ethnic groups more than others, with higher rates seen in African Americans, Asians, Hispanics, and Native Americans. While the exact cause of lupus is unknown, it is believed to involve a combination of genetic, environmental, and hormonal factors. Diagnosing lupus can be challenging because its symptoms often mimic those of other diseases. There is currently no cure for lupus, but treatments are available to help manage symptoms, reduce inflammation, and prevent organ damage. Current treatments often involve the use of immunosuppressive drugs, which can have significant side effects as they suppress the entire immune system. Therefore, there is a need for more targeted therapies that can specifically block the production of autoantibodies, the root cause of tissue damage in lupus, without suppressing the immune system broadly. Lupus is estimated to affect approximately 1.5 million Americans, and about 1600 new cases are added each year, of which most are women. The lifelong and incapacitating nature of lupus incurs enormous healthcare costs, reduces the quality of life, increases the risk of losing the ability to work, and can be fatal. While there have been notable advances in the understanding and clinical management of lupus, there is still an urgent need for a deeper understanding of the disease process and the design of newer therapeutic approaches. Our research focuses on the role of transcription factors in regulating the function of immune cells. One such factor is Early Growth Response 2 (EGR2), EGR2 has also been shown to play a crucial role in the immune system, especially in T cells, where it is highly induced upon activation. It is essential for maintaining immune tolerance and for preventing autoimmunity. While the role of EGR2 in T cells is well established, its function in B cells remains poorly understood, particularly in systemic lupus erythematosus (SLE). To build on our understanding of EGR2's role in lupus, we first referred to previously published studies from our laboratory. So the first question we asked was: Is EGR2 expression changed in lupus-prone mice? To answer this, we analyzed three different lupus-prone mouse strains with distinct genetic backgrounds and disease progression: B6/lpr – which develops a mild lupus-like disease, B6sle123- which develops moderate to severe disease; and MRl/lpr which develops severe disease. We also compared our findings with human peripheral blood mononuclear cells (PBMCs) from lupus patients compared to healthy donors. Interestingly, we observed that EGR2 expression was consistently elevated across all three lupus-prone mouse strains and in human PBMCs. This suggests that the observations made in mouse models have relevance to human disease. Having established that EGR2 is upregulated during lupus, our next question was, what happens if we delete the Egr2 gene in lupus-prone mice? In our first study using B6/lpr mice, we found that Egr2 deletion resulted in a significant reduction in autoantibody production, a hallmark of lupus. After observing a protective effect of Egr2 deletion in the B6/lpr model, which develops a relatively mild form of lupus, we wanted to explore what happens in a more severe disease MRL/lpr mouse model. This study focuses on investigating the role of early growth response protein 2 (EGR2) in B cell development and its progression in lupus. Our findings indicate that EGR2 may represent a promising therapeutic target. However, additional clinical studies in humans are required to assess its therapeutic potential and efficacy."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Early Growth Response Protein 2 (EGR2) regulation of B cell differentiation in lupus-prone mice"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Ahmed, S. A."],"dc:contributor.committeemember":["Reilly, Christopher Michael","Luo, Xin","Dai, Rujuan"],"dc:contributor.department":["Biomedical and Veterinary Sciences"],"dc:creator":["Islam, Mahfuzul"],"dc:date.accessioned":["2025-07-23T08:00:33Z"],"dc:date.available":["2025-07-23T08:00:33Z"],"dc:date.issued":["2025-07-22"],"dc:description.abstract":["Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with an unidentified cause and no suitable treatment. It involves abnormal activation of B cells, which produce pathogenic autoantibodies that contribute to inflammation and tissue damage in multiple organs. Therapeutic depletion of B cells in human lupus patients had mixed success due to the complex heterogeneity of B cell subsets, differences in autoantibody production, and the persistence of antibody-secreting plasma cells (PCs). Our laboratory reported that the transcription factor Early Growth Response 2 (EGR2), a key regulator of immune cell function, was markedly upregulated in murine and human lupus lymphocytes. Further, we reported that conditional deletion of Egr2-/- in lymphocytes in lupus-prone B6/lpr mice suppressed pathogenic anti-dsDNA autoantibodies. Notably, Egr2-/- B6/lpr mice exhibited an increased germinal center B (GCB) cell population but a decreased PC subset, suggesting that GCB cells fail to progress into fully differentiated PCs. This finding reveals a novel and unexpected role of EGR2 in the transition from GCB cells to antibody-secreting PCs. These findings provide compelling evidence that EGR2 functions aberrantly in lupus, contributing to disease pathology by facilitating the generation of autoreactive PCs. To further investigate the novel role of EGR2 on B cells. In this project, we conducted extensive experiments using newly developed CD2Cre-Egr2-/- MRL-MpJ- Fas lpr mice, in which Egr2 is selectively deleted in CD2-expressing lymphocytes primarily in T cells and a subset of activated or mature B cells that express CD2. Our findings show that egr2 deletion in MRL/lpr mice leads to a significant reduction in marginal zone B cells and a trend reduction in antibody-secreting plasma cells, while follicular B cells remain largely unaffected. Germinal center B cells were found to be increased, mirroring previous results observed in Egr2-/- B6/lpr mice. However, we observed only a slight decrease in serum anti-dsDNA autoantibodies in Egr2-/- MRL/lpr mice, which was different from what we observed in Egr2-/- B6/lpr mice. Collectively, our data indicate that EGR2 plays a pivotal and previously underappreciated role in regulating late-stage B cell development in lupus. These findings suggest that EGR2 may contribute to lupus pathogenesis by facilitating the differentiation of autoreactive B cells into plasma cells, and it may represent a novel therapeutic target for modulating pathogenic B cell responses in SLE."],"dc:description.abstractgeneral":["Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease. In lupus, the body's immune system, which usually defends against infections, becomes overactive and mistakenly attacks its healthy tissues and organs. This misguided attack leads to the production of harmful antibodies called autoantibodies. These autoantibodies target the body's cells, resulting in widespread inflammation and tissue damage. Lupus can affect multiple parts of the body, including the skin, joints, kidneys, heart, lungs, blood vessels, and brain. This widespread involvement can manifest as symptoms, including fatigue, joint pain, rash, and fever. The clinical severity of systemic lupus erythematosus (SLE) is highly variable, ranging from mild, intermittent symptoms in some patients to severe, potentially life-threatening organ complications in others. Lupus predominantly affects females, especially during their reproductive years, typically between the ages of 15 and 44. Lupus tends to involve some racial and ethnic groups more than others, with higher rates seen in African Americans, Asians, Hispanics, and Native Americans. While the exact cause of lupus is unknown, it is believed to involve a combination of genetic, environmental, and hormonal factors. Diagnosing lupus can be challenging because its symptoms often mimic those of other diseases. There is currently no cure for lupus, but treatments are available to help manage symptoms, reduce inflammation, and prevent organ damage. Current treatments often involve the use of immunosuppressive drugs, which can have significant side effects as they suppress the entire immune system. Therefore, there is a need for more targeted therapies that can specifically block the production of autoantibodies, the root cause of tissue damage in lupus, without suppressing the immune system broadly. Lupus is estimated to affect approximately 1.5 million Americans, and about 1600 new cases are added each year, of which most are women. The lifelong and incapacitating nature of lupus incurs enormous healthcare costs, reduces the quality of life, increases the risk of losing the ability to work, and can be fatal. While there have been notable advances in the understanding and clinical management of lupus, there is still an urgent need for a deeper understanding of the disease process and the design of newer therapeutic approaches. Our research focuses on the role of transcription factors in regulating the function of immune cells. One such factor is Early Growth Response 2 (EGR2), EGR2 has also been shown to play a crucial role in the immune system, especially in T cells, where it is highly induced upon activation. It is essential for maintaining immune tolerance and for preventing autoimmunity. While the role of EGR2 in T cells is well established, its function in B cells remains poorly understood, particularly in systemic lupus erythematosus (SLE). To build on our understanding of EGR2's role in lupus, we first referred to previously published studies from our laboratory. So the first question we asked was: Is EGR2 expression changed in lupus-prone mice? To answer this, we analyzed three different lupus-prone mouse strains with distinct genetic backgrounds and disease progression: B6/lpr – which develops a mild lupus-like disease, B6sle123- which develops moderate to severe disease; and MRl/lpr which develops severe disease. We also compared our findings with human peripheral blood mononuclear cells (PBMCs) from lupus patients compared to healthy donors. Interestingly, we observed that EGR2 expression was consistently elevated across all three lupus-prone mouse strains and in human PBMCs. This suggests that the observations made in mouse models have relevance to human disease. Having established that EGR2 is upregulated during lupus, our next question was, what happens if we delete the Egr2 gene in lupus-prone mice? In our first study using B6/lpr mice, we found that Egr2 deletion resulted in a significant reduction in autoantibody production, a hallmark of lupus. After observing a protective effect of Egr2 deletion in the B6/lpr model, which develops a relatively mild form of lupus, we wanted to explore what happens in a more severe disease MRL/lpr mouse model. This study focuses on investigating the role of early growth response protein 2 (EGR2) in B cell development and its progression in lupus. Our findings indicate that EGR2 may represent a promising therapeutic target. However, additional clinical studies in humans are required to assess its therapeutic potential and efficacy."],"dc:description.degree":["Master of Science"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:44413"],"dc:identifier.uri":["https://hdl.handle.net/10919/136878"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["EGR2","B cell differentiation","Germinal center B cells","Plasma cells","Autoantibodies"],"dc:title":["Early Growth Response Protein 2 (EGR2) regulation of B cell differentiation in lupus-prone mice"],"dc:type":["Thesis"],"thesis:degree_discipline":["Biomedical and Veterinary Sciences"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:31Z"}