Agonists and Antagonists of Neuropsychiatric Lupus Project Summary Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common and potentially lethal form of lupus. Two abnormalities have consistently been linked to NPSLE: the presence of autoantibodies and the presence of pro-inflammatory cytokines. However, the role of individual autoantibodies as well as specific cytokines remains controversial and the relationship between these two abnormalities is relatively unexplored. In our previously funded R21 proposal, we hypothesized that cell death coupled with the release of nucleoproteins resulted in the formation of immune complexes that stimulate Toll like receptors (TLRs) to produce high local concentrations of type 1 IFN (and perhaps other cytokines). In preliminary data, we have indeed observed that cerebrospinal fluid (CSF) from NPSLE patients have significantly higher interferon (IFN)-a inducing potential compared to controls and that, normalized for IgG concentrations, the IFN inducing activity was 800-fold higher than serum. The high IFN inducing activity of autoantibodies in CSF relative to serum was explained by the low concentration of certain protein inhibitors in CSF. In the current proposal, we will ask the following questions: 1) Does the IFN-a or other cytokine inducing activity of immune complexes correlate with autoantibody specificity, disease subsets or CNS injury in patients with NPSLE? Cytokine inducing capacity of serum and CSF from well characterized NPSLE patients will be compared between the 19 case definitions of NPSLE, between different autoantibody specificities as determined by a proteomic array and correlations determined with markers of brain cell injury. In the pediatric population, we will examine whether IFN-a inducing activity is associated with neurocognitive defects or MRI changes. 2) In the second Aim, we ask what are the mechanisms whereby two identified serum factors inhibit IFG activity? At least two serum factors have been identified that suppress IFN-a inducing activity by autoantibodies in CSF. We will identify the cell type and receptors that the inhibitors act on and then investigate the mechanism of inhibition. Relevance: Even when the most common (but least specific) subtypes of NPSLE are excluded, NPSLE occurs in about half of pediatric cases of SLE and a high proportion of cases with adult SLE. We have documented the potent inflammatory potential of autoantibodies in the CSF of NPSLE patients and have identified protein inhibitors. The ready availability of these inhibitors will allow us to consider therapeutic uses in the future. PUBLIC HEALTH RELEVANCE: Agonists and Antagonists of Neuropsychiatric Lupus Project Narrative The cause(s) of most cases of lupus affecting the brain are unknown, but there is good evidence to suggest that certain types of antibodies may play a role. We have documented that these antibodies in brain fluid can cause the production of certain inflammatory proteins. Here, we determine which types of neurological disease are associated with specific inflammatory proteins and we determine how certain protein inhibitors can be used to dampen the inflammation.
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