Breakthrough in understanding autoimmune disease development

T-cell Receptors (gold, upper) on the surface of T-cells selectively bind the lipid antigen presenting molecule on dendritic cells, CD1b (lower), presenting a rare cellular phospholipid (gold), over common phospholipids found in membranes (pink, cyan and green), which in turn induces an autoimmune response.

Phospholipids – fat molecules that form the membranes found around cells – are highly abundant, but when it comes to autoimmune diseases, their role has largely been overlooked. Recent research has pointed to a role for lipids in numerous diseases, including psoriasis, contact hypersensitivities and allergies. The development of autoimmune diseases such as these is now better understood thanks to researchers from the Australian Research Council Centre of Excellence in Advanced Molecular Imaging (Imaging CoE) and Brigham and Women’s Hospital at Harvard Medical School in the USA.

The interplay between key proteins in our immune system and lipid molecules in our cells has been described in a new study published in Science Immunology, by Imaging CoE immunologists based at the Monash Biomedicine Discovery Institute, Monash University, and Brigham and Women’s Hospital at Harvard University. Using key techniques in immunology and molecular imaging, the three-dimensional structures of specific immune proteins interacting with lipids have been generated, which allows a better understanding of autoimmune diseases they mediate.

Leading author, Dr Adam Shahine, a researcher at the Imaging CoE has shown how a protein, denoted as CD1b, on the surface of dendritic cells –  binds to lipid antigens, a molecule that can trigger our immune system. This newly bound CD1b and lipid then binds to a vital T cell receptor found on T cells that activate an immune response.

“The advanced imaging facilities of the Australian Synchrotron have allowed us to generate three-dimensional structures of T-cell receptor interaction against CD1b and lipid antigens.  These results highlight the role of CD1b in a phospholipid-mediated immune response, and provide a deeper understanding of the mechanisms of lipid-based autoimmune disease.”

Co-corresponding author D. Branch Moody, MD, a principal investigator in the Division of Rheumatology, Immunology and Allergy, Harvard Medical School said lipids have been underappreciated in immunology.

“ The search for the particular molecules that trigger autoimmune diseases has focused on proteins and peptides, but we should also be thinking about lipids as candidate antigens for autoimmune disease.”

The work has implications for specific forms of autoimmune disease, including lupus. Previous studies have found that patients with lupus have antibodies that bind to phospholipids, which cause clotting and strokes. The new study shows that T cells also recognize phospholipids, opening up new perspectives on T cell and antibody cooperation in this disease.

“Our discovery science reveals how our immune system can respond to specific lipids that are uncommon in the human immune system, thereby triggering an autoimmune response” added corresponding author Prof. Rossjohn, ARC Laureate Fellow.

Science Immunology journal publication: “A molecular basis of human T cell receptor autoreactivity towards self-phospholipids” Shahine et al