Deletion of Ptpn2 in B cells contributes to development of autoimmunity
Autoimmunity arises when self-reactive B and T cells target the body's own tissues, with B cells contributing through antigen presentation to T cells and production of autoantibodies and pro-inflammatory cytokines. Genome wide association studies (GWAS) have suggested that single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor type 2 (PTPN2), which is ubiquitously expressed throughout the body, are associated with development of autoimmune diseases, such as rheumatoid arthritis (RA), Crohn's disease, and type 1 diabetes (T1D). While prior studies have focused on the role of Ptpn2 in T cells and other cell types, its function in B cells remains unknown. To test the B cell-intrinsic role of Ptpn2, we generated a B cell-specific deletion of Ptpn2 in mice (Mb1-Cre;Ptpn2fl/fl). We found that loss of Ptpn2 in B cells promotes organ inflammation, increases the frequency of autoimmune-associated B cells (ABCs) and plasmablasts in the periphery, and increases autoantibody levels in the serum. Moreover, we found that Ptpn2 acts as a negative regulator of the JAK/STAT and TLR7 pathways in B cells. In line with this, treatment of B cells from Mb1-Cre;PTPN2fl/fl mice with IFNy and TLR7 agonist leads to enhanced differentiation into ABCs. These findings highlight the critical role of Ptpn2 in B cell function and its potential as a key regulator in preventing B cell associated autoimmunity. Overall design: B cells were isolated from spleen from 5 control and 6 PTPN2 B cell knock out mice.