Researchers have made another important step in the progress towards being able to block the development of multiple sclerosis (MS) and other autoimmune diseases.
Published today in the journal Nature Communications, the researchers at the University of Adelaide have identified a key protein involved in a ‘super-inflammatory’ immune response that drives the progression of MS and other autoimmune diseases.
The protein is a specific ‘chemokine receptor’ involved in moving the body’s immune response cells, the T-cells, around the body when they are in the super-inflammatory mode needed to fight persistent infections or conversely, as in the case of autoimmune diseases like MS, attacking the body’s own tissues. This chemokine receptor, called CCR2, is a different receptor than was widely assumed to be involved.
“Everybody has been focussing on the CCR6 receptor as the one to target to control this inflammatory response,” says project leader Professor Shaun McColl, Director of the Centre for Molecular Pathology at the University of Adelaide.
“We’ve now shown that the receptor to target is actually CCR2. Blocking CCR6 makes the disease worse. If we can find an antagonist to block the CCR2 receptor specifically on these T-cells, we should be able to control the progression of MS.”
MS is an incurable neurodegenerative disease, currently affecting 23,000 people in Australia and the most common disease of the central nervous system in young adults.
“We still can’t control MS well, there’s a great need for new therapies,” says Professor McColl.
The University of Adelaide research was conducted by PhD student Ervin Kara under the supervision of Professor McColl and research fellow Dr Iain Comerford, also in the University’s School of Biological Sciences.
Another potential benefit of the research is in making improved vaccines to fight infection.
“Unlike in autoimmune diseases, where the body’s immune response is destroying its own cells and the aim is to block T-cell migration, with persistent infection we want to turn on the super-inflammatory response and enhance the migration of the immune cells to sites where they are needed,” says Professor McColl. “This research may help guide development of vaccines that can better force that immune response.”
Funding: The research has been supported by the National Health and Medical Research Council.
Source: Shaun McColl – University of Adelaide
Image Credit: The image is in the public domain.
Original Research: Full open access research for “CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells” by Ervin E. Kara, Duncan R. McKenzie, Cameron R. Bastow, Carly E. Gregor, Kevin A. Fenix, Abiodun D. Ogunniyi, James C. Paton, Matthias Mack, Diana R. Pombal, Cyrill Seillet, Bénédicte Dubois, Adrian Liston, Kelli P. A. MacDonald, Gabrielle T. Belz, Mark J. Smyth, Geoffrey R. Hill, Iain Comerford and Shaun R. McColl in Nature Communications. Published online October 29 2015 doi:10.1038/ncomms9644
Abstract
CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells
IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6−CCR2+) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.
“CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells” by Ervin E. Kara, Duncan R. McKenzie, Cameron R. Bastow, Carly E. Gregor, Kevin A. Fenix, Abiodun D. Ogunniyi, James C. Paton, Matthias Mack, Diana R. Pombal, Cyrill Seillet, Bénédicte Dubois, Adrian Liston, Kelli P. A. MacDonald, Gabrielle T. Belz, Mark J. Smyth, Geoffrey R. Hill, Iain Comerford and Shaun R. McColl in Nature Communications. Published online October 29 2015 doi:10.1038/ncomms9644
