Deciphering the role of Epstein-Barr virus in SLE pathogenesis
This award is partially supported by AstraZeneca.
The exact cause of SLE is not well understood; however, genetic and environmental factors play important roles in the development of the disease. While Epstein-Barr Virus (EBV) infection has been strongly linked to SLE, how EBV infection causes SLE is unclear. B cells are an immune cell type that produce antibodies, which protect us from infection by recognizing foreign pathogens. In the case of SLE, B cells become autoreactive and produce autoantibodies that falsely recognize a patient’s own cells, triggering other immune cell types to mount an attack. Dr. Younis predicts that EBV infection enables B cells to become autoreactive and produce autoantibodies, contributing to the development of SLE. To investigate this, Dr. Younis has developed an innovative tool to examine molecular changes in individual EBV-infected B cells from SLE patients to understand how EBV triggers B cells to become pathogenic, or disease-causing, in SLE and identify the specific pathways involved in the development of SLE.
Dr. Younis will first compare EBV-infected and non-infected B cells from SLE patients and healthy individuals to determine what molecular changes occur upon EBV infection. Identifying specific markers on EBV-infected B cells can enable the targeting and elimination of these cells in SLE. Dr. Younis will then investigate the antibodies encoded by EBV-infected B cells to determine whether they are autoreactive, meaning they recognize a patient’s own cells, promoting autoimmunity. B cells are professional antigen-presenting cells, meaning they detect, engulf, and display foreign pathogens on their surface to indicate infection to other immune cell types and boost the immune response. Dr. Younis will test the hypothesis that EBV infection causes B cells to become more effective antigen-presenting cells, leading to a more robust immune response and stimulating autoimmunity. Ultimately, Dr. Younis aims to understand how EBV infection contributes to the development of SLE and enable the development of fundamental therapies.
What this study means for people with lupus:
Results from Dr. Younis’ study will highlight how EBV infection promotes the development of SLE. As EBV is linked to other autoimmune disorders, including multiple sclerosis, the findings can potentially transform our understanding of SLE and lead to developing therapies for SLE and other autoimmune diseases.
Epstein-Barr virus (EBV) is suggested to play a central role in the pathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases. EBV is a B cell tropic herpes virus that infects and immortalizes B cells. B cell dysregulation and production of autoantibodies against intracellular antigens are hallmarks of SLE. Nevertheless, the mechanisms by which EBV promote SLE pathogenesis remains poorly understood. Research on the mechanisms by which EBV promotes SLE disease progression has been hampered by multiple biological and technological difficulties. For instance, direct analysis of individual EBV+ B cells in SLE patients is challenging due to the rare EBV+ B cell frequencies and low-level of EBV gene expression. During my initial postdoctoral period, I overcome this obstacle by developing single cell RNA- sequencing (scRNA-seq) methods to detect EBV genes and non-coding RNAs to characterize EBV+ B cells in SLE. The preliminary results revealed high expression of EBER1 and B cell activation genes in EBV+ CD27+ B cells derived from SLE patients. The overarching goal of this proposal is to leverage the unique EBV-specific scRNA-seq methods that I developed to analyze dysregulated transcriptional pathways in EBV-transformed B cells of SLE patients as compared to healthy controls. I propose to examine the hypothesis that EBV promotes the development of SLE through activation of pathogenic B cells, and through molecular mimicry between EBV antigens with self-antigens. In particular, I will characterize the ability of EBV-transformed B cells to mediate autoreactive T cell activation, and investigate a role for EBV related molecular mimicry in SLE. During this award, I will: (1) characterize EBV-infected B cells in SLE using EBV-specific scRNA-seq methods that I developed to characterize dysregulated transcriptional pathways in EBV+ B cells in SLE; (2) sequence the paired heavy and light chain antibody repertoires in EBV+ and EBV- B cells in SLE and, and use antigen arrays to identify their EBV and self-antigen targets; (3) apply integrated informatics to develop a human gene transcriptional classifier that defines EBV+ B cells in SLE; (4) characterize the ability of EBV+ B cells to mediate T cell activation using tonsil organoids as a model system along with the EBV and self-antigens identified during the aim 1. I will conduct molecular studies to define the role of exosome-contained EBER1 in the pathogenesis of SLE. Further, I will utilize my EBV+ B cell transcriptional classifier, and apply it to publicly available datasets to gain insight into the potential role of EBV+ B cells in SLE and other autoimmune diseases. Collectively, success of this proposal will elucidate the mechanisms by which EBV mediates to the pathogenesis of SLE, which could lead to development of fundamental therapies.