Insights into lupus heterogeneity by single-cell profiling of B cell activation
Lupus is a complex disease with both genetic and environmental causes. There are over 100 regions in our DNA with potential alternations (genetic variants) that make us susceptible to this disease. However, we do not know how most of the genetic variants cause lupus. B cells are important cells in lupus development since they produce the autoantibodies that cause organ damage. Many of the genetic susceptibility regions contain genetic information that is important for B cell development and function, such as the B cell receptor (BCR) and Toll-like receptor 7 (TLR7). Both BCRs and TLR7 are important in B cell responses and control antibody and autoantibody production. This grant will be used to study how both the BCR and TLR7 affect human B cells and influence the different lupus symptoms that are seen in the clinic. Dr. Gutierrez-Arcelus and her team will use the latest state-of-the-art technology to look at genetic material (RNA) and proteins in B cells from both healthy individuals and lupus patients.
What this study means for people with lupus
To find more effective and personalized treatments for lupus patients, there is a need to understand why the disease is so heterogeneous – differing widely from person to person – and how this disease develops in each patient. This project is expected to add valuable information on how lupus develops and how its causes different symptoms in different people. Findings from this study may also aid in directing lupus patients to the most relevant clinical trials and personalized therapies.
Systemic lupus erythematosus (SLE) is an autoimmune disease for which only one new drug has been approved in over 60 years. Design of future therapies will require new insights into disease pathogenesis. An important challenge in SLE is its high phenotypic heterogeneity. However, we know that the genetic contribution to SLE susceptibility is high (up to 66%), and that B cell dysfunction is a main driver of disease. Within the >100 susceptibility loci for SLE, a number of them harbor genes with functions in B cell receptor (BCR) signaling and Toll-like receptor (TLR) signaling. Our preliminary work has shown the importance of studying immune cells in multiple activation states in order to understand mechanisms of autoimmune diseases. Additionally, our preliminary analyses indicate that a BCR polygenic risk score (PRS), capturing the effects of multiple risk alleles in the BCR pathway, causes dysregulation of key processes in immortalized B cells. We hypothesize that part of the heterogeneity in SLE could be driven by variability in the contribution of BCR and TLR7 signaling to B cell dysfunction. In order to test this we will assess how BCR-PRS and TLR7-PRS cause B cell dysregulation during activation of each pathway by performing a large-scale study with single-cell profiling at the RNA and protein levels, and how they might lead to clinical heterogeneity in SLE, including response to therapy. Ultimately, we envision that BCR and TLR7 genetic footprints could aid in patient stratification for clinical trials and personalized therapies.