Multiple sclerosis (MS) is a clinically and pathologically heterogeneous inflammatory/demyelinating disease of the central nervous system (CNS). Many patients first present with isolated optic neuritis. In some variants of MS, like Devic's disease or neuromyelitis optica (NMO), lesions are predominantly found in the optic nerves and spinal cord but not in the brain. The immunological bases of the different forms of MS are unknown. Here, we summarize our published findings on two mouse models: 2D2 myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic mice, which develop spontaneous isolated optic neuritis, and 2D2 mice crossed with MOG-specific IgH knockin (TH) mice, which spontaneously develop a severe form of experimental autoimmune encephalomyelitis (EAE) with a selective distribution of meningeal and parenchymal inflammatory lesions in the spinal cord and optic nerves similar to that found in human Devic's disease.