Systemic Lupus Erythematosus (SLE) stands as a multifaceted autoimmune disorder, characterized by a spectrum of clinical manifestations and the generation of autoantibodies against self-antigens. Our focus was on the pivotal role of B cells in the development of SLE. The study also underscored the significant contribution of regulatory B (Breg) cells in the context of SLE, suggesting their potential as key regulators of the disease process. Our results provided a deeper understanding of the intricate interplay between B cells and SLE, offering insights that were valuable for both scientific research and future designs of therapeutic approaches. Cutting-edge single-cell RNA sequencing was employed to analyze the differences in splenic Breg subsets and their molecular profiles across different stages of lupus development in mice. Transcriptome-based changes in Bregs during active disease were confirmed through phenotypic analysis. These findings provided crucial insights into the dynamic role of B cells in the pathogenesis of SLE. In addition, we delved into the intricate connection between SLE and the gut microbiota. A literature review offered a comprehensive analysis of current research, with a particular emphasis on potential interactions between bacterial flagellin and Toll-Like Receptor 5 (TLR5) on immune cells. These interactions garnered substantial attention due to their potential implications in the pathogenesis of SLE. We synthesized existing research, providing valuable insights into the complex interplay between SLE and the microbiota and suggesting promising avenues for further investigation and potential therapeutic interventions. In the final study, we explored lupus-like disease in mice with global Tlr5 deletion, initially expecting disease attenuation. Surprisingly, the results revealed an exacerbation of lupus-like symptoms, particularly in female mice lacking Tlr5. Future research will seek to uncover the mechanisms by which Tlr5 deletion modulates interactions between the host and the gut microbiota, ultimately contributing to the exacerbation of lupus-like disease. / Doctor of Philosophy / Systemic Lupus Erythematosus (SLE) is characterized by a range of health issues and the body attacking itself. In this exploration, we journey through the intricate landscape of SLE, uncovering key players and unexpected twists. In this dissertation, we journeyed through the intricate landscape of SLE, uncovering key players and unexpected twists. In this dissertation, we closely examined these immune cells, revealing how different types of B cells contributed to SLE's development. We also introduced the enigmatic regulatory B (Breg) cells, which acted as potential peacekeepers in this autoimmune reaction. Our results illuminated the complex relationship between B cells and SLE, offering insights that benefited both researchers and those seeking new treatments. We employed cutting-edge technology, single-cell RNA sequencing, to scrutinize the genetic fingerprints of B cells in mice with SLE. The results unveiled changes in Breg cells during active disease, providing critical clues about how B cells impacted SLE progression. In addition, this dissertation took us into the microscopic world of our gut inhabitants, the microbiota. We dived into a treasure trove of research, focusing on how interactions between bacterial flagellin and various microbiota elements affected immune cells through a special receptor called Toll-Like Receptor 5 (TLR5). These interactions, like hidden clues, had piqued scientists' interest for their potential role in SLE development. We synthesized existing research, offering valuable insights into the complex interplay between SLE and our microbiota. The discussion also suggested promising paths for future research and potential therapies. In the final study, we encountered a plot twist. We anticipated that deleting the Tlr5 gene would improve lupus-like disease in mice. To our surprise, the opposite happened. Lupus-like symptoms worsened, especially in female mice lacking Tlr5. Clinical signs included enlarged spleens and lymph nodes, increased immune cell activity, and kidney inflammation. But Tlr5 deletion didn't change the mice's metabolism or the leaky gut. Instead, it reshaped their gut's microbial residents. Future research aimed to uncover how Tlr5 deletion altered the interactions between the host and gut microbes, ultimately making lupus-like disease more severe. In a nutshell, this journey through SLE's complex world provided a deeper understanding of its intricacies. We met the B cells, explored the microbiota, and encountered surprises along the way. These discoveries were vital pieces of the puzzle, bringing us closer to unlocking the secrets of SLE and, perhaps, finding new ways to manage and treat this challenging autoimmune disorder.