Linking the microbiome and the B cell repertoire to lupus nephritis
Our microbiome, made up of trillions of micro-organisms, plays a crucial role in maintaining our overall health. Studies have found that there are microbial changes in people with lupus and lupus nephritis, but it is not known whether changes in the microbiome influence or cause lupus. In a mouse model with lupus nephritis, Dr. Lambrecht has seen that lupus disease severity may change based on the animals’ microbiome. Using this grant from LRA, Dr. Lambrecht and his team will study how the microbiome influences B cells, which are immune cells that normally produce antibodies to protect against infection. In lupus patients, B cells produce the autoantibodies that attack the organs and cause complications such as lupus nephritis. Through experiments with individual types of bacteria (monocolonization), the research team will look at how individual bacterial strains may affect lupus. Additionally, Dr. Lambrecht’s team will collect blood and microbiome samples from lupus nephritis patients to study how the microbiome affects B cells, autoantibody production and dysregulated IgA responses in humans.
What this study means for people with lupus
Understanding how changes in the microbiome affect B cells and/or promote autoimmune diseases like lupus will help us develop more effective preventive approaches for individuals at increased risk of developing lupus, as well as better therapies for lupus patients.
Systemic lupus erythematosus (SLE) is an autoimmune disease affecting 0.2% of the population. Despite substantial disease heterogeneity, lupus nephritis is a universal and major concern in patients with SLE, often leading to impaired kidney function or end-stage renal disease even with aggressive treatment. Because of unknown drivers of disease, current treatments for lupus nephritis fail to target the underlying pathophysiology and new approaches are urgently needed. We hypothesize that the microbiome is an important driver of disease that could be modified. Literature reports microbial alterations to be associated with SLE and lupus nephritis, but is unknown whether this association is causal. Our preliminary data suggest that the disease manifestations of A20DC-KO mice, which spontaneously develop an autoimmune disease resembling SLE including lupus nephritis, due to a mutation in the lupus associated gene Tnfaip3, depend on the microbiology status of the mouse colony. First, we will investigate the lupus phenotype of A20DC-KO mice in specific-pathogen free and germ-free conditions. Using phage immunoprecipitation and single cell RNA sequencing, we will investigate how the microbiome shapes the auto-antibody repertoire. Secondly, we will recolonize A20DC-KO mice with distinct microbiomes, assess key lupus features and perform 16S rRNA sequencing. Thirdly, we will perform monocolonization experiments to investigate the disease-modifying role of unique bacterial strains and confirm our key mechanistical findings in an alternative B6.Sle1.Sle2.Sle3 mouse lupus model. Finally, we will translate the implications of dysregulated IgA responses in human lupus nephritis patients. If the microbiome indeed has a disease-modifying effect on SLE, modulation of the microbial composition may offer a promising new preventive and therapeutic opportunity.