A mighty mouse: building a better model of multiple sclerosis

Abstract

The 2 cardinal cell populations mediating adaptive immunity are T and B lymphocytes. These cells play important but poorly understood roles in the immunopathological demyelinating disease multiple sclerosis (MS) and in a widely used animal model of human MS known as EAE. In the current issue of the JCI, 2 research teams report their parallel studies of double-transgenic mice expressing T and B cell receptors that recognize the same myelin protein (see the related articles beginning on pages 2385 and 2393). More than half of the double-transgenic mice spontaneously developed autoimmune demyelination in their spinal cords and optic nerves, exhibiting pathologies reminiscent of human MS. The studies describe an important new model for MS research.

Figure 1. A mighty mouse for MS research.

In this issue of the JCI, 2 research groups developed double-transgenic mice (TCR^MOG×IgH^MOG mice, or OSE mice) expressing T and B cell receptors that recognize the same myelin protein, MOG (2, 3). More than 50% of these mice developed inflammatory demyelinating lesions in their spinal cords and optic nerves, reminiscent of human MS. The studies suggest that B cells play a critical role as APCs in OSE mice. B cells are able to present antigen efficiently because (a) the antigen receptor concentrates antigen from very low levels; (b) engagement of the antigen receptor generates signals that upregulate costimulatory molecules like CD86; and (c) antigen is shuttled to a compartment where it competes well for binding to MHC class II for presentation to T cells. Activated T cells then express the proinflammatory cytokines IFN-γ and IL-17. MOG-specific B cells were also shown to undergo class switching to IgG1 in the presence of transgenic T cells; however, this occurred in all double-transgenic mice whether they were asymptomatic or had clinical EAE, suggesting that anti-MOG IgG1 antibodies are not required to trigger disease.