KSCHIRT: Defining the Role of B Cells in Adaptive Immune Response to Contusion TBI

Abstract Contusions are a common pathoanatomical type within the spectrum of traumatic brain injuries (TBIs), presenting as focal regions of tissue damage, often accompanied by intraparenchymal hemorrhage, blood- brain barrier (BBB) disruption and edema. Attendant excitotoxicity and cytokine release trigger early neuroinflammation, which is followed by infiltration of myeloid cells. The dynamics and roles of innate immune cells such as neutrophils and monocytes/macrophages has been extensively studied in TBI. Far less is known about the nature of the adaptive immune response following head trauma. Studies in stroke and spinal cord injury suggest that B cell-mediated adaptative immunity plays a significant role in the evolution of CNS injury for potentially months after injury. Clinically, autoantibodies to CNS antigens are detectable in serum after TBI, implicating peripheral B cell activation. However, evidence for B cell diapedesis into brain after TBI is woefully incomplete, and the potential role of B cells in modulating the progression of neuronal injury and neurobehavioral impairment in TBI is unknown. We have provocative preliminary data demonstrating delayed B cell diapedesis into the contused cortex. Further, our early work suggests that B cells may aggregate into structures akin to germinal centers or ectopic lymphoid structures and may differentiate into antibody- producing plasma cells. Because B cells direct both beneficial and detrimental events in the CNS during conditions of injury or disease, it is essential to investigate the functional consequences of post-traumatic B cell diapedesis. The studies outlined in this proposal will pursue three specific aims to (1) conduct a comprehensive examination of B cell diapedesis after contusive TBI, examining multiple time points and brain regions in both male and female mice, (2) provide the first insights into the role of endogenous B cells in modulating neuronal injury and plasticity as well as neurobehavioral function after TBI by using a B cell depletion strategy, and (3) test postinjury administration of an FDA-approved drug, which increases the subset of IL-10 producing B cells, for its therapeutic efficacy in attenuating post-traumatic neuroinflammation, tissue damage, and motor and cognitive impairment. These novel studies leverage the complementary TBI, stroke, and B cell neuroimmunology expertise of three experienced investigators in order to begin to unravel the role B cells play in brain after TBI and to develop translationally relevant intervention strategies to promote beneficial B cell-mediated adaptive immune responses.