Somatic Mutations in Non-Ig Loci in Autoreactive B Cells as Drivers of Lupus Pathogenesis and Disease Heterogeneity
Abstract
Abnormal activity of B cells, one of the cells of the immune system, is critical to the development and progression of the autoimmune disease lupus. Uncontrolled activity of an enzyme normally found in B cells has been shown to cause gene mutations that lead to B cell cancers. In B cells from lupus patients, this same enzyme also shows uncontrolled activity. Based upon this observation, we hypothesize that uncontrolled activity of this enzyme may also cause gene mutation in B cells that result in abnormal B cell function and thus, contribute to the development and progression of lupus. Furthermore, we speculate that the occurrence of specific gene mutations in B cells in some lupus patients may explain why some patients develop specific symptoms associated with lupus and/or why lupus affects certain organs in some patients, why lupus flares occur, and why the disease progresses more rapidly in some patients than others. We think that B cell mutations impact lupus symptoms and disease progress by altering the expression of various genes that are essential for normal B cell development, growth, and function. To explore these ideas, we will analyze the DNA sequence of B cells from a mouse model of lupus that is very similar to human lupus and search for mutations in these DNA sequences. We will also examine gene expression and gene mutations in B cells from mice with aggressive lupus and those with mild lupus and correlate these with various lupus symptoms. Using a mouse model allows us to perform our study in a simplified system so we can more easily find potentially important gene mutations in B cells and correlate them with the severity of different symptoms of lupus and differences in the onset and progression of the disease. Finally, we will also identify mutations in the DNA of B cells from lupus patients experiencing a disease flare. This proposal is focused on exploring a novel idea that may help to explain the variability that we see in the symptoms and severity of disease in lupus patients. The basis for this variability, as well as how we can better detect it and best care for lupus patients based upon this variability, is one of the Focus Areas for fiscal year 2022 in the Lupus Research Program (LRP). The work proposed here has the potential to identify the cause of some of this variability as well as lead to the development of novel therapies to treat lupus patients based upon new ways to classify patients with respect to their risk for developing certain lupus symptoms and progressive disease. In addition, because the proposed studies will investigate the role gene mutations in B cells as drivers of lupus symptoms and disease progression, this application also focuses on a new potential disease mechanism in lupus. Thus, this proposal also addressed a second Focus Area of the LRP–understanding the biological mechanism of lupus disease. The idea that such gene mutations occur in B cells and contribute to lupus has never been examined, and thus the idea being studied in this proposal is completely novel. If our hypothesis is correct, and we detect gene mutations in B cells that correlate with clinical features or lupus disease severity, then our finding would have major implications for the study and treatment of lupus. In cancer care, screening for the presence of specific gene mutations is now very common because it allows physicians to more accurately classify a patient’s cancer type, determine prognosis, and predict response to various types of therapies. In addition, highly effective targeted molecular therapies have even been developed that effectively treat cancers with specific gene mutations. If our hypothesis that gene mutations in B cells contributes to lupus is correct, then our studies could pave the way for completely new methods to classify lupus disease subtypes and to identify patients with these subtypes. Of utmost importance, our work would also pave the way for the developm
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310402
Entities
People
- Karen Gould
Organizations
- United States Army
- University of Nebraska Medical Center