Project Summary Systemic lupus erythematosus (SLE) is a heterogeneous, systemic autoimmune disease that causes significant morbidity and early mortality, especially in minority populations and in women of child-bearing age. By the time patients reach SLE classification, the majority exhibit organ/tissue damage and ongoing, aggressive inflammatory processes. Preventing SLE would reduce the risk of irreversible organ damage and treatment-related toxicities, but requires identification and validation of drivers and restraints of disease progression during this pre-/early-clinical time period. Our research groups have made important progress toward deciphering aspects of preclinical autoimmunity. A few findings include showing: autoantibodies occur in linked-subsets years before clinical disease, demonstrating humoral epitope spreading and peripheral immune dysregulation in preclinical autoimmune transition, defining immune endotypes of autoantibody positive healthy individuals, identifying activated B cell and select myeloid cell subsets preceding SLE disease flare, and establishing viral reactivation preceding SLE disease onset. Through our newly formed ADAPTS consortium, we will address these gaps with twelve available, complementary pre-disease unique collections that span this continuum from benign autoimmunity to active SLE, which includes clinical data, questionnaire information, biospecimens, autoantibody and other experimental data from nearly 11,000 participants. A subset of the highest-risk individuals earlier in this continuum will be followed for autoimmune and clinical progression. These cross-sectional collections are augmented with longitudinal transitional cohorts which include over 400 individuals who transition to SLE with pre-disease samples and clinical data. Our investigative team members bring strengths in clinical investigation, innate immunology, cell-free nucleic acid sensing, soluble mediator characterization, multi-omic analyses, cellular immunology, immune metabolism, systems immunology, bioinformatics and strong, productive collaborations. Building on our published and new preliminary data, our ADAPTS consortium of clinical and basic scientists will assess potentially independent or complementary mechanisms of disease progression and immune restraint by testing the roles of RNA-sensing pathways, cell-free nucleic acids, age-associated B cells and autoantibody characteristics, myeloid cell subsets, T cell lymphopenia and lymphopenia-induced proliferation, T cell immunometabolism, as well as select environmental (microbiome, virome), genomic and innate and adaptive immune responses as drivers of SLE disease. We will also validate and refine predictive models of clinical SLE disease development to inform future prevention trials and assist the field through molecular and clinical endotype identification of the preclinical time periods. Data from this integrated research program will inform targeted immune-mediated prevention trial development, selection of cellular/molecular and pathway-directed therapies, and the design of longitudinal SLE natural history or prevention studies.

Project Narrative Autoimmune diseases afflict up to 12% of the US and lupus, as one autoimmune disease, remains a leading cause of medical death in young women of child-bearing age. This program is testing a number of potential drivers and protectors of autoimmune disease using unique patient cohorts and broad investigator expertise.