Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRLโlpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRLโlpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokineโdriven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11โ15 weeks of age) MRLโlpr/lpr mice contained high levels of interleukin (IL)โ6 and interferonโฮณ (IFNฮณ) mRNA, which became even more pronounced in old (22โ30 weeks of age) autoimmune mice. mRNA levels for the cytokines ILโ1ฮฒ and ILโ10 were elevated in the cerebellum of old, but not young, MRLโlpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for ILโ3 and tumor necrosis factorโฮฑ were comparable in autoimmune and normal mice, indicating that enhanced gene expression of ILโ6, IFNฮณ, ILโ1ฮฒ, and ILโ10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE. J. Neurosci. Res. 64:26โ33, 2001. ยฉ 2001 WileyโLiss, Inc.