Abstract Many diseases, both immune-mediated and non-immune, demonstrate strong association with particular alleles of the major histocompatibility complex (MHC). The mechanism underlying such associations is presently unknown. The existing paradigm, which had been theorized more than three decades ago, remains largely unverified to this day. As a result, our understanding of a fundamental biologic mechanism, which pertains to the health of millions, is out of step with modern scientific concepts. The proposal presented here will examine a new hypothesis, formulated based on current evidence. The underlying hypothesis proposed here is that class II MHC-encoded proteins encode signal transduction ligands that interact with cell surface receptors on other cells and trigger signaling events. Under certain circumstances, such interactions could provoke aberrant cellular events that may contribute to disease development, or to the severity of such diseases. The model system that will be studied here involves a recently discovered ligand encoded by certain HLA-DRB1 alleles and triggers oxidative stress in cells upon contact with a cell surface receptor that had been identified as calreticulin (CRT). In order to verify the underlying hypothesis, the potential contribution of this ligand-receptor interaction to the severity of atherosclerosis (AS) will be studied both in vitro and in vivo. For in vitro experiments, endothelial cell cultures will be treated with the ligand or its control reagents and the phenotypic and functional atherogenic consequences will be studied. The in vivo experiments will involve determination of accelerated AS features in transgenic mice expressing the MHC-encoded ligand. The role of CRT will be studied by conditional deletion of its encoding gene, or by knocking-in a mutated gene. The proposed research could introduce a paradigm shift thereby improve our knowledge, which in turn could help to design better therapies for many diseases.