Anti-nuclear antibodies (ANA) are a hallmark feature of autoimmunity, but are found in ~20% of healthy women, most that will never develop pathogenic autoimmunity. Further, African American (AA) women are more likely to develop SLE compared to women of European (EA) background. Understanding changes in immune pathways between ANA+ healthy individuals and SLE subjects remains a crucial goal in understanding benign and pathogenic autoimmunity. To assess immune alterations in ANA+ healthy individuals, phenotyping by mass cytometry, plasma cytokine measurement by luminex and altered TCR and BCR phopho-specific signaling were evaluated in EA and AA individuals matched in 24 groups (n=72) as ANA- healthy, ANA+ healthy or SLE patients. Further, whole genome RNA-sequencing was performed on sorted T cells, B cells and monocytes. EA ANA+ controls exhibited greater immune regulation with reduced T and NK cell numbers, and increased expression of CD85j compared to ANA- controls. Further, modules associated with hematopoiesis, T cell activation, intrinsic apoptosis, and autophagy signaling pathways are expressed at higher levels in T cells of EA ANA+ individuals. In contrast, AA ANA+ controls had modules associated with the Th1 pathway and IFN signaling present that were expressed at the highest levels in SLE patient T cells. Following TCR stimulation, EA ANA+ T cells exhibited greater ERK phosphorylation that was absent in SLE patients suggesting early dysregulation leading to exhaustion. These results suggest that mechanisms of preclinical autoimmunity vary by ethnicity, and ANA+ European Americans may have more effective regulatory mechanisms in place to prevent transition to SLE.