High titers of autoantibodies against glutamic acid decarboxylase 65 (GAD65) are commonly observed in patients suffering from type 1 diabetes (T1D) as well as Stiff Person syndrome (SPS), a disorder that affects the central nervous system, and a variant of SPS, progressive encephalomyelitis with rigidity and myoclonus (PERM). While there is a considerable amount of data focusing on the role of GAD65-specific CD4+ T cells in T1D, little is known about their role in SPS. Here we show that mice possessing a monoclonal GAD65-specific CD4+ T cell population (4B5, PA19.9G11 or PA17.9G7) develop a lethal encephalomyelitis-like disease in the absence of any other T cells or B cells. GAD65-reactive CD4+ T cells were found throughout the CNS in direct concordance with GAD65 expression and activated microglia: proximal to the circumventricular organs at the interface between the brain parenchyma and the blood brain barrier. In the presence of B cells, high titer anti-GAD65 autoantibodies were generated but these had no effect on the incidence or severity of disease. In addition, GAD65-specific CD4+ T cells isolated from the brain were activated and produced IFN-γ. These findings suggest that GAD65-reactive CD4+ T cells alone mediate a lethal encephalomyelitis-like disease that may serve as a useful model to study GAD65-mediated diseases of the CNS
