Our immune system works tirelessly to protect us from harmful infections by producing special proteins called antibodies. These antibodies are made by immune cells called B cells, which are essential for fighting off viruses and bacteria. However, sometimes B cells can mistakenly attack the body’s own tissues, leading to autoimmune diseases like lupus, type 1 diabetes, and multiple sclerosis. Scientists have discovered that certain B cells can recognize and bind to many different substances, including those found in both harmful pathogens and healthy tissues. This ability, known as “polyreactivity,” can help fight infections but may also increase the risk of autoimmunity. While our bodies have checkpoints to prevent B cells from attacking our own tissues, these safety mechanisms do not always work perfectly. Recent research shows that understanding how B cells behave and how these checkpoints fail could lead to better treatments for autoimmune diseases. By studying rare genetic conditions and using advanced technologies to analyze B cells, researchers hope to identify why some people develop autoimmunity and how to stop it. This work could pave the way for more personalized treatments, improving the lives of those affected by autoimmune diseases.

Despite the significant overlap in the antigenic composition and structural epitopes between those present on pathogens and those expressed on self-tissues, B cells have evolved the ability to undergo B cell receptor (BCR) rearrangements early in development in the bone marrow to generate diversity and later differentiate in the periphery to combat the inevitable antigenic similarities. While this diversity enables the recognition of any pathogen, it also poses a risk of self-recognition, leading to autoimmunity. Many layers of regulation are present during both the generation and activation of B cells to prevent this phenomenon, although they are evidently imperfect. Although the amount of polyreactive binding by IgG memory antibodies is normally low and nonpathogenic, somatic hypermutations are responsible for creating pathogenic antibodies in patients and mice with autoimmune diseases where the checkpoints that remove autoreactive B cells are altered. Previously it has been shown that patients with autoimmune conditions, such as systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis (RA) have an increase in polyreactive and autoreactive B cells in their blood compared to non-autoimmune individuals8. In fact, disease specific autoantibodies can be detected in these disorders with a long prodrome during which there are no clinical symptoms (i.e., anti-nuclear ab – ANA for SLE, anti-cyclic citrullinated peptide – CCP for RA, anti-insulin and glutamic acid decarboxylase – GAD for T1D). However, our lack of understanding as to how these self-reactive B cells become activated leading to participation in autoimmune disease pathogenesis constitute a significant hurdle for the development of 1) prognostic disease biomarkers and 2) novel therapeutic approaches. Autoimmune diseases such as SLE, MS, and T1D are characterized by the breakdown of B cell tolerance and the emergence of auto- and poly-reactive B cells. This proposal investigates the mechanistic underpinnings of B cell tolerance breakdown, focusing on whether auto- and poly-reactivity is germline derived or triggered by environmental exposure (i.e., infection, microbiota), driving promiscuous antigen binding and autoimmunity. We hypothesize that polyreactive B cells play a pathogenic role in driving and perpetuating autoimmune pathogenesis, particularly if cross-reactive with self-antigen and viral antigen product. Additionally, we posit that any B cell specific phenotype/repertoire traits we find in new onset (young) SLE, T1D, and MS patients may also be present in a portion of autoantibody (Aab+) asymptomatic donors, thus potentially earmarking them for increased risk of rapid progression. Through immune repertoire sequencing, single-cell transcriptomics, and functional assays, we aim to define the phenotypic and molecular signatures of auto- and poly-reactive B cells across autoimmune diseases. By studying shared immune repertoire traits and cross-reactive clonotypes, we seek to identify biomarkers for early disease prediction and develop targeted immunotherapies that deplete or modulate pathogenic B cells only.