Role of novel metabolite-receptor pathway in protection from lupus
B cells are immune cells that produce antibodies to fight infections. However, in autoimmune conditions such as lupus, some B cells produce autoantibodies which cause the destruction of a person’s own organs. Dr. Cyster and his research team recently found that a small number of lupus patients have a mutated form of the receptor P2RY8, a protein on the surface of B cells that receives signals from the surrounding environment. However, it remains unknown how deficiency in P2RY8 on B cells affects patients with lupus. Dr. Cyster and his team will therefore look at a larger group of lupus patients to see what percentage of patients have the mutated form of P2RY8 or mutations in genes that function in the P2RY8 signaling pathway. They will also look closely at those patients who have the mutated form of P2RY8 to see if that plays a role in B cell autoantibody development and the severity of lupus symptoms.
What this study means for people with lupus
This project will provide novel information to better understand the genetic causes of lupus and potentially identify novel targets for therapeutic purposes in a subset of lupus patients.
We have recently identified disruptive mutations in P2RY8, a G-protein coupled receptor that responds to a novel metabolite S-geranylgeranyl-L-glutathione (GGG), in several lupus patients. Moreover, some patients without P2RY8 mutations show reduced P2RY8 expression in their lymphocytes. Mouse model studies indicate that P2RY8 promotes increased negative selection of DNA-reactive B cells and that it restrains plasma cell accumulation. The long-term objectives of the proposed work are to establish the extent of P2RY8 pathway disruption in systemic autoimmune disease patients, to determine whether P2RY8 pathway disruption informs about disease heterogeneity, and to perform mechanistic studies that define how P2RY8 helps maintain immunological tolerance. The Specific Aims of the proposal are to: (1) Define the extent of P2RY8 pathway mutation in SLE and in Sjogren’s syndrome, a related autoimmune condition that can co-occur with SLE. (2) Determine the basis for reduced P2RY8 expression in SLE patients without P2RY8 coding mutations; this includes testing patients for elevated circulating amounts of GGG. (3) Characterize P2RY8-expressing mice and P2RY8-deficient humanized mice to determine how the P2RY8 pathway helps maintain tolerance. This includes use of CRISPR gene-editing in human stem and progenitor cells and reconstitution of immune deficient mice to study P2RY8 -deficient and -sufficient B cells from the same donors, permitting mechanistic interrogation of P2RY8 function in immune tolerance. Defining the role of P2RY8 and its metabolite ligand in immune tolerance will lay the foundation for future development of small molecule agonists to augment P2RY8 pathway activity and reduce the generation of autoreactive lymphocytes and autoantibody producing cells.