Abstract The C1858T allelic variant of tyrosine phosphatase PTPN22 (resulting in an R620W change of protein product, LYP) is strongly associated with multiple autoimmune diseases. Contradictory findings suggest the LYP-R620W variant exhibits either gain- or loss-of-function activity in antigen-receptor signaling. To model this risk allele in mice, we generated knock-in mice expressing the analogous R619W mutation in the murine ortholog, PEP. While the variant protein exhibits normal stability, its expression significantly alters lymphocyte function and aged knock-in mice exhibit effector T and, transitional, germinal center and age-related B cell expansion, autoantibodies and systemic autoimmunity. Further, PEP-R619W impacts B cell selection and, strikingly, B lineage-restricted variant expression is sufficient to promote autoimmunity. In the current project, we initiated a detailed study of the impact of variant expression on B cell tolerance mechanisms. Our studies were designed to test the hypothesis that while negative selection is intact, peripheral B cells expressing the variant exhibit increased positive selection, culminating in a skewed, autoreactive naïve B cell repertoire that promotes autoimmune pathogenesis. Preliminary data utilizing single cell BCR cloning and deep sequencing technologies to assess autoreactivity and V(D)J family usage in naïve B cell subsets, as well as characterization of negative and peripheral selection using in vivo models, will be presented.