Rethinking Repair: Long-Term Adaptive Immunity Supports Functional Recovery for Stroke Patients

Within hours after stroke onset, there is a massive inflammatory response in the brain that contributes to neuronal and vascular injury. However, clinical trials to minimize post-stroke inflammation failed, highlighting the need to better understand inflammatory and neuroprotective mechanisms within the central nervous system (CNS) after stroke. My lab focuses on investigating the interactions between lymphocytes and neurons after CNS injury. My previously AHA-funded studies in a mouse model of stroke found that endogenous neuroprotection coincided with lymphocyte autoimmune responses to CNS antigen (Ag). This would suggest that neuronal and myelin autoimmune responses could, in fact, be beneficial during recovery, but this benefit most likely depends upon the responding lymphocyte subsets and timing of activation. It is particularly critical to understand long-term autoimmune responses after clinical brain injury as functional recovery requires months to years for completion. Thus, the overarching hypothesis of this Established Investigator Award is that long-term plasticity requires specific autoreactive T and B cell responses. Our preliminary data confirmed novel neuronal autoimmune responses in pediatric stroke patients. We will confirm CNS-directed autoreactivity in adult stroke patients and use in vitro and ex vivo assays from patient-derived lymphocytes to test the mechanisms of CNS-targeted autoimmunity on neuronal survival and immunosuppression. Finally, we will use long-term neuroimaging and assessment of clinical recovery to identify potentially beneficial neuronal autoimmunity. Stroke is the main contributor to long-term adult disability in the United States. Greater understanding of immunoplasticity during CNS injury and repair could lead to novel immunomodulating therapeutics that harness the beneficial effects of autoreactivity on plasticity, and improve quality of life for millions during recovery.