Investigating the mechanisms of lupus-associated CNS dysfunction
Systemic lupus erythemasus (SLE) patients report various neuropsychiatric symptoms; however, the underlying cause of these symptoms is unclear. In SLE, autoantibodies are secreted into the bloodstream by autoreactive B cells. These antibodies form immune complexes that deposit in tissues causing tissue damage and ultimately organ failure. The CNS is partially protected from antibody-mediated attack by the blood-brain-barrier (BBB), but BBB integrity can become compromised in disease. Antibody deposition in the CNS has been detected in SLE patients and in mouse models. Intriguingly, however, studies report that 40% of neuropsychiatric symptoms are present before or at the time of SLE diagnosis and 60% develop in the first year after diagnosis. Given the early onset of these symptoms, a compromised BBB may not be required for these symptoms to develop. In support of this idea, our preliminary data revealed microglial activation, reduced synapse density, and defects in adult neurogenesis in the absence of detectable immune complex deposition or lymphocyte infiltration in the brain in a lupus-like mouse strain. Interestingly, we observed concurrent increases in serum and CSF cytokines, several which are regulators of adult neurogenesis and synaptic plasticity. Thus, in this study, we will investigate the hypothesis that lupus-specific autoreactive B cells trigger CNS dysfunction in SLE via early changes in cytokines.
The proposed experiments address this hypothesis using the SLE-like 564Igi strain with transgenic autoreactive B cells that recognize the lupus-specific antigen, SSB/La. We will first ask how breakdown of B cell tolerance, one of the earliest events in SLE, affects CNS pathology and then investigate the role cytokines play in promoting CNS pathology. Other SLE mouse models also exhibit similar CNS defects; however, these phenotypes often develop before the brain fully matures (5-8 weeks), and in other studies of characterizing mice aged 4-5 months, IgG deposition and immune cell infiltration were apparent in the CNS. In the 564Igi mice, no CNS phenotypes emerged in 6-week-old mice, suggesting slower disease progression and normal CNS development. Also, CNS phenotypes developed in the absence of detectable IgG deposition. Thus, the 564Igi lupus-like strain represents a simplified system compared to other lupus models. Furthermore, our lab has techniques and tools to study transgenic 564Igi lupus-specific B cells. Using these tools, we found that IFN-a receptor inhibition reduced lupus-specific B cell frequency and autoantibodies levels in 564Igi mice. In our preliminary studies, the same treatment prevented defects in adult neurogenesis and aberrant cytokine signaling. The long-term goal of this study is to identify novel therapeutic targets in the treatment of neuropsychiatric lupus, and our preliminary findings suggest that targeting cytokines such as IFN-a may be an effective approach which may be translatable to humans.