Therapeutic inhibitors of antigen presentation pathways in SLE

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 (MF s) and dendritic cells (DCs). In this pathway, antigen loaded B cells deliver their antigens to MFs and DCs, which amplify and activate autoimmune T cells, and initiate 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.

SR-A is a key membrane bound receptors on macrophages and dendritic cells. SR-A forms a trimeric surface structure that mediates a number of important cellular functions, including adhesion to B cells and the binding and the uptake of apoptotic cell debris by phagocytic cells. SR-A has two unique domains in the surface exposed structure, a cysteine rich domain (SRCR) and a collagenous-like domain proximal to the membrane. The biology of SR-A depends on the receptor’s ability to bind and acquire soluble ligands via either of the two domains. We have established high throughput screening systems to identify novel small molecule inhibitors (SMIs) of the SR-A domain implicated in autoimmunity. Our goal is to develop SMIs to specifically interfere with antigen transfer and subsequent downstream pathology created by this receptor. In accomplishing this goal, we have formed a unique collaboration with the Yale University Center for Molecule Discovery (http://ycmd.yale.edu/resources) with expertise in medicinal chemistry, molecular computational analyses, and fundamental SMI development and troubleshooting. As noted above, these studies will develop candidates that block SR-A mediated transfer and processing of autoantigens. Key screening strategies have been established and pilot studies have confirmed the feasibility of blocking SR-A mediated biology in treating an animal model of lupus autoimmunity. The sought after milestones for subsequent studies will focus on structure-activity relationships of compounds, toxicity of candidate compounds and in long term efficacy and potential therapeutic efficacy in models of autoimmunity.