The effect of an autoimmune-associated allelic variant of protein tyrosine phosphatase nonreceptor 22 on B cell tolerance in a murine model. (P4066)

Abstract

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.