P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance

Abstract

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a “de novo” variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.

Immune Infiltration Characteristics and a Gene Prognostic Signature Associated With the Immune Infiltration in Head and Neck Squamous Cell Carcinoma

“…P2RY8 (P2Y Receptor Family Member 8) was a Gα13-coupled receptor, which regulated the migration inhibition and growth of B cells. P2RY8 was frequently mutated in diffuse large B-cell lymphoma and Burkitt lymphoma ( Lu et al, 2019 ; He et al, 2022 ). P2RY10 (P2Y Receptor Family Member 10) was also a G-protein-coupled receptor.…”

“P2RY8-son” break of tolerance promotes SLE

“…Variable dysregulation of AKT and ERK pathways were also reported in germline gain-of-function PIK3CD mutations defining the activated PI3K-δ syndrome and in protein kinase C-δ deficiency, while SOCS1 and A20 refer to JAK/STAT or NFKβ signaling inhibition ( Li et al, 2020 ; Belot et al, 2013 ; Hadjadj et al, 2020 ); all these genetic conditions can drive lymphoproliferation and monogenic lupus (see figure). Actually, DLBCL shares more genetic anomalies with autoimmune disease than solid cancer ( Din et al, 2019 ), and, as exemplified in the current work of He et al (2021) , DLBCL and lupus may represent two sides of the same coin. Thus, it is likely that new germline susceptibilities to lupus will be recognized in genes identified with recurrent somatic mutation in DLBCL, as illustrated here with germline mutations of P2RY8 .…”

“…Third, P2RY8 expression restricts B cell autoreactivity. To explore the role of P2RY8 in the B cell negative selection,He et al (2021) took advantage of VH3H9 transgenic mice expressing a heavy (H) chain that was isolated from anti-dsDNA antibodies from MRL-lpr/lpr mice. Because the VH3H9 H chain can pair with endogenous lambda light (L) chains to generate anti-DNA reactive B cells, this model allows the analysis of B cell tolerance by measuring lambda (especially lambda-1)-expressing follicular B cells as a marker of DNA-specific autoreactivity.…”

“…In this issue of JEM , the Carola Vinuesa and Jason Cyster laboratories ( He et al, 2021 ) characterize the genetic contribution of germline P2RY8 variants to systemic lupus erythematosus (SLE) and further expand the role of P2RY8 in tolerance maintenance. P2RY8 serves as a G-protein receptor for S-geranyl-geranyl-L-glutathione (GGG) that drives B cell clustering inside germinal centers (GCs; Lu et al, 2019 ).…”

“…First, the authors identify P2RY8 germline variants associated with SLE or antiphospholipid syndrome. Using next generation sequencing, He et al (2021) depict two rare and one new genetic variants in P2RY8 in a total of eight patients with lupus or antiphospholipid syndrome. Among these genetic findings, the p.L257F variant is the most severe and best characterized variant.…”