The OX40L-OX40 axis in lupus pathogenesis
Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to nuclear antigens. Mouse studies with lupus models have demonstrated that T follicular helper (Tfh) cells play a major pathogenic role in lupus, and inhibition of the generation and/or activity of Tfh cells is beneficial for disease prevention and treatment. Supporting evidence was also obtained in studies of human SLE. However, little is known regarding the mechanism involved in aberrant Tfh responses in SLE. Our recent study shows that a TNF ligand family molecule expressed by myeloid APCs contributes to the aberrant Tfh response in SLE and therefore provides a rationale to block this axis as a therapeutic and/or preventive strategy for SLE. However, much remains to be determined to bring this concept into the clinic. The three aims in this study are: AIM 1: To identify molecular mechanisms by which signaling through the specific molecule induces the expression of Tfh molecules by human Th cells. AIM 2: To identify the range of immune cells expressing the specific molecule at inflamed tissues in SLE. AIM 3: To determine the role of the immune complex for the expression of the specific molecule. Our study will establish how this novel mechanism contributes to lupus pathogenesis.