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.

Public Health Relevance

The research proposed here will examine a novel hypothesis that could provide new insight into the mechanism of many diseases. It is based on recent findings, showing that certain proteins, coded by genes called the major histocompatibility complex, activate oxidative stress in cells that line the inner side of blood vessels. The findings could explain the mechanism of many diseases, including atherosclerosis, a major cause of disability and death in the US.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-CBB-7 (EU))
Program Officer
Marino, Pamela
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Ling, Song; Cline, Erika N; Haug, Timothy S et al. (2013) Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum 65:618-26
Holoshitz, Joseph; Liu, Ying; Fu, Jiaqi et al. (2013) An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity. J Immunol 190:48-57
Fu, Jiaqi; Ling, Song; Liu, Ying et al. (2013) A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol 191:2096-103
Naveh, Shirly; Tal-Gan, Yftah; Ling, Song et al. (2012) Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads. Bioorg Med Chem Lett 22:493-6
de Almeida, Denise E; Ling, Song; Holoshitz, Joseph (2011) New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Lett 585:3619-26
Holoshitz, Joseph (2010) The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol 22:293-8
Ling, Song; Cheng, Andrew; Pumpens, Paul et al. (2010) Identification of the rheumatoid arthritis shared epitope binding site on calreticulin. PLoS One 5:e11703
Holoshitz, Joseph; De Almeida, Denise E; Ling, Song (2010) A role for calreticulin in the pathogenesis of rheumatoid arthritis. Ann N Y Acad Sci 1209:91-8
De Almeida, Denise E; Ling, Song; Pi, Xiujun et al. (2010) Immune dysregulation by the rheumatoid arthritis shared epitope. J Immunol 185:1927-34