Aberrant cytokine gene expression in the hippocampus in murine systemic lupus erythematosus.

Cytokines are important mediators of immune regulation and have been implicated in the pathogenesis of the neurological disturbances, which occur in up to sixty percent of patients with systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, including native DNA. Cytokines are thought to drive autoantibody production in lupus. Certain of the derangements in memory and learning described in human and experimental SLE map to the hippocampus. The current study examines the expression of cytokine genes in the hippocampus in lupus, using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop a SLE-like illness accompanied by disturbances in spatial learning. Our results suggest a potential role for proinflammatory cytokines in the cognitive aberrations observed in lupus.

Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus.

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 MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/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 cytokine-driven 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 (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.