| A common genetic variant in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22-C1858T) has been linked to a wide range of autoimmune disorders. Although a B cell-intrinsic role in promoting disease has been reported, the mechanism(s) through which this variant functions to alter the pre-immune B cell repertoire remains unknown. Using a series of polyclonal and transgenic self-reactive models harboring the analogous mutation in murine Ptpn22, we show evidence for enhanced BCR, BAFFR and CD40 co-receptor programs, leading to broadly enhanced positive selection of B cells at two discrete checkpoints in the bone marrow and spleen. We further identified a bias for selection of self-reactive B cells into the follicular (FM) vs. marginal zone (MZ) B cell compartment. Using a biomarker to track a self-reactive heavy chain in peripheral blood, we found evidence of similarly enhanced positive selection in human carriers of the PTPN22-C1858T variant. Our combined data supports a model whereby the risk variant augments the BCR and co-receptor programs throughout B cell development to bias self-reactive specificities into the FM compartment, thereby likely increasing the risk for seeding of autoimmune B cell responses. |
