P2RY8 Variants in Lupus Patients Uncover a Role for the Receptor in Immunological Tolerance

Exaggerated PI3K/AKT signaling abrogates B cell tolerance and results in autoimmunity. P2RY8 is a repressor of AKT-mediated B cell activation that also restrains cell migration. Here we identified a de novo, novel P2RY8 missense variant in a child with severe lupus nephritis, an ultrarare variant in a proband with antiphospholipid syndrome, and a less rare missense variant in six lupus patients. These variants impaired protein expression and function, leading to increased AKT and ERK activity and cell migration, and diminished follicular confinement. By contrast, P2RY8 overexpression restrained plasma cell (PC) development and reinforced negative selection of DNA-reactive developing mouse B cells. Remarkably, P2RY8 was downregulated in most SLE patients. Environmental factors including TLR7 ligation and DNA damage caused P2RY8 downregulation. Low P2RY8 correlated with lupus nephritis and increased PC and double negative B cells, suggesting that loss of P2RY8-mediated immunological tolerance contributes to lupus pathogenesis.