Researchers identify a new regulator of the immune system

Mount Sinai Hospital researchers identify a new regulator of the immune system

Mount Sinai Hospital researchers have discovered a new molecular system that regulates our immune system, the body's primary defense system against infections. This work sheds new light on how immune T cells function to combat infectious diseases and cancer, and how genetic defect associated with this system may cause autoimmune diseases.

The findings were published in the February 8th issue of the prestigious scientific journal Nature. Dr. James Dennis, a Senior Research Scientist at Samuel Lunenfeld Research Institute (SLRI) and Professor of Molecular and Medical Genetics, University of Toronto led the research team. His co-authors are Drs. Michael Demetriou, Maria Granovsky, and Sue Quaggin who also work at the SLRI.

The researchers identified the Mgat5 gene and a family of sugar-binding proteins called galectins as a key regulator of T cells in the immune system. Mice lacking the Mgat5 gene developed hyperactive immune systems which resulted in skin hypersensitivity, kidney autoimmune disease and a susceptibility to multiple sclerosis.

"Our analysis of T cell receptors in the Mgat5-deficient mice lead to an exciting conceptual advance at the molecular level" said Dr. Dennis. The Mgat5 gene encodes an enzyme that adds sugar chains to the T-cell receptors. The study found that these sugar chains form a lattice network with sugar-binding proteins called galectins on the cell surface. This slows the movement of T cell receptors, which must break-out of the lattice and clusters, or huddle with one-another when they see "foreign" molecules. This huddling of receptor stimulates molecular signals inside for the cells to go into action, and is a very important physical event for many receptor-ligand systems in our body. When the Mgat5 sugar chains were lowered in mice lacking the gene, the T-cell receptors clustered more readily, in some cases reacting to "self" proteins, which resulted in autoimmune disease. The immune system must differentiate between invaders and the body's own cells, a fine balance that can be tipped toward "reaction against self" which is the cause of autoimmune disease.

Multiple genes and environmental factors contribute to chronic inflammatory and autoimmune diseases such as Multiple Sclerosis, asthma, and insulin-dependent diabetes, that cumulatively affect many people.

"Our knowledge of genes and their variant forms that lead to autoimmune diseases is currently quite limited. Our study identifies Mgat5 as a gene that when defective may increase susceptibility to autoimmune diseases in humans," said Dr. Dennis. "One's genetic makeup is an important factor in these diseases. Our study suggests that variant forms of Mgat5 gene may be present in some people and predispose them to autoimmune disease. This will be a focus of further studies in humans."

The finding also suggests that new drugs designed to stimulate Mgat5 could be used to dampen T cells in autoimmune disease, while inhibitors of Mgat5 might be used to sensitize the immune system in the treatment of cancer and infections. Dr Dennis' group reported last year that mice lacking Mgat5 show reduced growth in breast cancer.

"This is another example of the exemplary work carried out by researchers at the Samuel Lunenfeld Research Institute," said Joseph Mapa, President and CEO, Mount Sinai Hospital. "The implications of the Mgat5 research not only profoundly affects our understanding of the immune system but could also lead to new drug development and treatments for patients with autoimmune diseases, as well as cancer and HIV."

This research was supported by grants from the National Cancer Institute of Canada, the National Science and Engineering Council of Canada, the Ontario Research and Development Challenge Fund, GlycoDesign Inc. of Toronto.

Established in 1985, The Samuel Lunenfeld Research Institute (SLRI) in Toronto, Ontario Canada is one of the world's leading centres for health research. The SLRI is part of Mount Sinai Hospital, an internationally recognized 465-bed acute care academic health centre affiliated with the University of Toronto. The SLRI has 250 research, administrative and support staff, 100,000 square feet of laboratory space.

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