Project 457180

SLE is a complex autoimmune disease that causes long-term distress, multi-organ damage, and occasional fatality in affected individuals. It also disproportionally affects women and individuals of African, Asian, or Hispanic descent. A complex network of disease factors is associated with SLE, ranging from genetic defects and hormonal dysregulation to environmental stimulations, medication and infection, which results in highly heterogeneous clinical manifestation and limited options for broadly effective therapeutic interventions. The cellular mechanisms driving the production of self-targeting antibody (autoantibodies), which induces recurrent inflammation in lupus, remain elusive and urge for extensive investigation. Studying how antibody secreting cells, which are the producers of autoantibodies, develop and differentiate under inflammatory environments are pertinent to understanding SLE disease progression. Here I propose to study the development and function of a lupus-associated B cell subset in mice with established autoantibody secreting potential, which are named DN2-like B cells. I hypothesize that the RNA sensor toll-like receptor-7 will be a main cellular driver for the activation and differentiation of DN2-like B cells into autoantibody secreting cells. I will establish and utilize a mouse model that allows the timely tracking of B cell kinetics to study the developmental trend and activation requirements of DN2-like B cells, to determine autoreactivity of DN2-like B cell-derived autoantibodies, and to define cellular precursors of DN2-like B cells. Utilizing a combination of clinically validated autoreactivity tests, advanced imaging and sequencing technologies, as well as fundamental immunology assays, this study will advance our current understanding of the fundamental biological circuitry behind inflammatory autoantibodies in lupus patients and point to potential future avenues for therapeutic development.