Drug Discovery Opinion

Multiple sclerosis (MS) is an autoimmune disorder in which T-cells attack and damage the fatty myelin sheaths around the axons of the brain and spinal cord, disrupting the conduction of electrical signals along the nerve fibres. Although both genetic factors and viral infections have been suggested to contribute to the development of MS, no single virus has been conclusively linked to the disease and other mechanisms could also play a role. Animal models induced by CD8⁺ T-cells show similarities to human MS, and researchers at the University of Washington investigating the causes of MS have engineered mice that over-express CD8⁺ T-cells that recognise myelin basic protein (MBP), a candidate autoantigen in MS.

When infected with vaccinia virus engineered to produce MBP, the infection should activate the CD8⁺ T-cells to attack virally infected cells and also other cells that produce MBP. As expected, mice infected with the engineered virus developed MS-like disease but, surprisingly, symptoms were also triggered by infection with wild-type virus. This suggested that the engineered CD8⁺ T cells expressed a second receptor that recognised wild-type virus and subsequent cross-breeding experiments confirmed that some of the CD8⁺ T cells did indeed have receptors for both MBP and wild-type virus. Once activated by the virus, the dual-receptor CD8⁺ T cells were than able to attack cells producing MBP.

The study suggests a role for dual-receptor cells in autoimmune diseases and could explain how infection with a common virus triggers MS in genetically predisposed people, whilst having no lasting effects in most of the population. In the ‘dual-receptor model’, autoimmune activation could be triggered by a chance event leading to T-cells that recognise both MBP and a viral antigen. The prevalence of dual-receptor T cells is presently unclear and the team plan to assess whether they are more common in MS patients.

The study is published in Nature Immunology.

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