Objective. Autoantibodies against ribosomal P proteins are linked to the neuropsychiatric manifestations of systemic lupus erythematosus (SLE). The present study was undertaken to assess how the specific brain-binding autoantibody anti-ribosomal P can induce a depression-type psychiatric disorder in mice.Methods. Mice were injected intracerebroventricularly with affinity-purified human anti-ribosomal P antibodies or IgG as control. Pharmacologic and immunologic treatments included the antidepressant drug fluoxetine, the antipsychotic drug haloperidol, and antiidiotypic antibodies. Behavior was assessed by the forced swimming test, motor deficits by rotarod, grip strength, and staircase tests, and cognitive deficits by T-maze alternation and passive avoidance tests.Results. Anti-ribosomal P antibodies induced depression-like behavior in the mice (mean ؎ SEM 147.3 ؎ 19.2 seconds of immobility versus 75.2 ؎ 12.1 seconds of immobility in IgG-injected control mice; P < 0.005). The anti-ribosomal P antibody-induced depression-like behavior was partially blocked by a specific antiidiotypic antibody and significantly blocked by long-term treatment with fluoxetine, but not by shortor long-term treatment with haloperidol. The depressive behavior was not associated with any motor or cognitive deficits. Anti-ribosomal P antibodies specifically stained neurons in the hippocampus, cingulate cortex, and the primary olfactory piriform cortex, compatible with the previously described binding to the membranebound P0 ribosomal protein.Conclusion. This is the first report of an experimental depression induced by a specific autoantibody. The results implicate olfactory and limbic areas in the pathogenesis of depression in general, and in central nervous system dysfunction in SLE in particular.The anti-ribosomal P antibodies are members of a polyspecific population of autoantibodies that target 3 highly conserved ribosomal phosphoproteins (1). These proteins comprise P0, P1, and P2 molecules that correspond to sizes of 38 kd, 19 kd, and 17 kd, respectively. P proteins are acidic phosphoproteins associated mainly with the 60S ribosomal subunit in eukaryotic cells. The existence of ribosome-free P proteins in the cytoplasm and the presence of P0 on the surface of the cell membrane have also been reported (2-4). The antiribosomal P antibody is specific to systemic lupus erythematosus (SLE) (1) and is detected predominantly in patients during the active phases of the disease (5,6). These autoantibodies in SLE recognize an epitope that is confined within the 22-carboxy-terminal amino acids, and this pattern is identical in P0, P1, and P2 proteins (7). According to observations in the literature, there is some variability regarding the prevalence of antiribosomal P in SLE patients, ranging from 6% to 36% (5,(8)(9)(10). The prevalence of anti-ribosomal P is higher in Asians than in blacks or whites (9), and genetic factors may account for the wide range of anti-ribosomal P frequencies among SLE patients (11).A link between anti-ribosomal P ...

Though many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in this disease. We review clinical data obtained from a large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white matter disease and behavioral changes in APS or linked to laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with beta2-glycoprotein I, a central autoantigen in APS, which induces persistent high levels of aPL. These mice develop hyperactive behavior after a period of four to five months as well as deficits in learning and memory and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. Another model we have developed, in which IgG from APS patients induce depolarization of brain synaptoneurosomes, may serve as a model for the pathogenesis of epilepsy in APS.

Thrombin, a central factor in thrombogenesis, affects cells in the brain through protease activated receptors. Low levels of thrombin activity are neuroprotective while higher levels are deleterious, and we have therefore developed a new method for its direct quantitative measurement in brain slices following stroke. Thrombin activity was measured by a fluorescent substrate on fresh coronal slices taken from the ipsilateral and contralateral hemispheres 24-72 h following permanent right middle cerebral artery occlusion. Prolyl endopeptidase and aminopeptidases were inhibited as a critical step to insure the specificity of the assay for thrombin detection. Infarct volume was assessed using TTC staining. Thrombin activity in the right ischemic hemisphere was significantly higher compared to the contralateral hemisphere (32 ± 6 and 27 ± 10 mU/ml, mean ± SE in the two most affected slices from the ischemic hemisphere vs. 21 ± 6 and 8 ± 2 mU/ml in corresponding contralateral slices; p < 0.05). Thrombin levels in the ischemic and contralateral hemispheres were significantly higher compared to healthy control mice and were above the range known to be protective to brain cells. A significant correlation was found between thrombin activity in the ischemic hemisphere and the infarct volume. Results of studies based on this method may translate into potential thrombin based therapies.

The antiphospholipid (Hughes) syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and beta2-glycoprotein I (beta2-GPI). Beta2-GPI immunized mice develop systemic manifestations of APS and we presently examined CNS manifestations in this APS model. Female BALB/c mice were immunized once with beta2-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A staircase test and a T-maze alternation test were performed to test behavior and cognition in independent groups of mice 6, 12 and 18 weeks following the immunization. The APS mice developed elevated levels of antibodies against negatively charged phospholipids and beta2-GPI. Neurological impairment was detected only 18 weeks after the induction of the APS and consisted of both cognitive (53 +/- 4 vs 71 +/- 3% correct choices in the T-maze alternation for APS vs control mice, P < 0.001) and behavioral changes (higher number of rears (18 +/- 2 vs 11 +/- 1, P < 0.006) and higher number of stairs climbed (12 +/- 2 vs 7 +/- 1, P < 0.02). This is the first report of cognitive deficits in this APS model and demonstrates the time course for the development of previously described behavioral changes. The mechanism involved in these CNS manifestations remains to be elucidated.