Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving genetic and environmental factors and resulting in destructive tissue injury to multiple organ systems, including the central nervous system. Central nervous system symptoms include headache, cognitive dysfunction and psychiatric disorders and may be among the earliest signs of SLE. However, these non-specific symptoms make diagnosis/treatment of disease problematic. Although a number of sources have been proposed, currently there is no known cause of central nervous system symptoms in SLE. Here we suggest that microglia, immune cells in the brain that act as first responders to damage and infections to restore/maintain homeostasis, are defective in some SLE patients. Thus, we will examine microglia from both a mouse model of SLE as well as microglia-like cells from cerebrospinal fluid of patients with SLE to understand how this disease occurs. Our mouse model has a cell-specific genetic deletion of a protein involved in death and suppression of inflammation and deletion of this protein extends to microglia. Studies on neurodegenerative disease in mice show that microglia are composed of two populations, with one population potentially having anti-inflammatory and regulatory functions. Although we observe these same two microglia populations in our model, the regulatory population is reduced. Our model shows learning and memory defects as well as difficulties in coordination and balance. These behavioral issues correspond to evidence of leakiness into the brain and immune cell infiltration into what is normally a tightly preserved space. This infiltration resembles a model of traumatic brain injury, wherein physical damage to the brain promotes leakage of the blood-brain barrier. However, in our case, this breach is the direct result of our genetic deletion. Here, we hypothesize that central nervous system symptoms occur in SLE patients from an inability to maintain a regulatory population of microglia. We will determine if a defect in microglia subsets is the main mechanism of disease, and we also intend to examine global gene expression of the microglia subsets prior to and during disease to uncover possible functional deficiencies. We will then compare these functional deficiencies among other models of SLE and microglia-like cells from cerebrospinal fluid of SLE patients with central nervous involvement to potentially identify a common “disease signature.” Since SLE patients with central nervous system involvement often fail to achieve remission using current immunosuppressive and biologic therapies and side effects from treatment are great, the ultimate goal is to use these research discoveries to assist in diagnostic marker discovery and in the development of safer and more effective therapies.
|Effective start/end date||3/1/20 → 2/28/22|
- Alliance for Lupus Research (Agmt 03/01/2020)