AI-13 Therapeutic inhibitors of antigen presentation pathways in SLE

Abstract

Background The Mamula laboratory has identified and characterized a novel pathway of antigen presentation in autoimmune disease. In particular, B cells that acquire specific autoantigens can play an important role in triggering autoimmunity in both a direct and indirect manner. First, B cells can directly process autoantigen in triggering T cell autoimmunity. Therapeutics such as Rituxan and Belimumab have been developed to interfere with these direct functions of B cells. In the indirect pathway, autoantigen-bearing B cells form high affinity interactions with scavenger receptor A (SR-A), which is expressed primarily on macrophages (MΦs) and dendritic cells (DCs). After receiving antigen from B cells, MΦs and DCs are then highly competent in activating autoimmune T cells and initiating pathology in models of disease. Our working hypothesis is that identifying small molecules that inhibit the latter pathway will provide leads for developing a new treatment for autoimmunity. Methods and results In brief, we have utilized probes to follow antigen presenting pathways between human B cells and MΦs or DCs. As illustrated in the figure 1, B cells make direct contact with DCs and transfer antigen via a SR-A mediated pathway. We have also identified small molecule inhibitors (SMIs) that interfere with SR-A interactions and interrupt the transfer of autoantigen between B cells and DCs. MRL mice were treated with SMIs of SR-A and the onset and progression of autoimmunity (autoantibodies and autoreactive T cells) were assessed over time. SMI treatment of MRL mice greatly reduced autoAbs and T cell activation as well as tissue pathology. Conclusions This study identifies a novel SR-A dependent pathway of antigen presentation between human B cells and MΦs and DCs. Inhibition of this pathway reduces T cell activation, reduces the production of autoantibodies, and ameliorates kidney and skin pathology of SLE in a murine model.