THE ROLE OF MEMORY ADAPTIVE IMMUNITY IN MILD TBI

Approximately 1.7 million Americans sustain a traumatic brain injury per year. About 75% of these injuries are considered mild (mTBI), where only a brief loss of consciousness and change in cognitive function is initially observed. Despite the appearance of health, individuals that have recovered from mTBI may be susceptible to worse outcome after a subsequent second injury and may even result in sudden coma or death. More often, repeated mild TBI events even over extended durations are associated with cumulative decline in memory function, inability to concentrate, recurrent headaches, and dizziness. Alterations in brain energy metabolism, local neuroinflammation, and fluid balance are among mechanisms implicated for contributing to repeated TBI-related outcomes are modified by the interval, magnitude, and number of each repeated injury. Recently, it has been determined that the adaptive immune system can respond and develop memory to CNS injury and activate production of autoantibodies with pathogenic potential. However, the precise response and contribution of memory immune responses in pathogenesis after repeated mTBI events has not been investigated. Our goal in this project is to determine the role of memory components of the adaptive immune system in mTBI.We have recently profiled the immunological chemokine and cytokine responses that occur after CNS injury in rodent models. Interestingly, we recently observed a delayed and sustained induction of the primary CNS lymphocyte attractant (chemokine ligand 20, CCL20) after TBI. CCL20 is implicated as a necessary signal for entry of memory T cells into the CNS to become reactive. CCL20 also specifically promotes infiltration of memory B cells with capacity to produce autoantibodies. Furthermore, previous work has demonstrated that knockout of the CCL20 receptor CCR6 completely protects mice from autoimmune encephalomyelitis. However, there is a gap of understanding in what components of the adaptive immune system are beneficial or deleterious to the pathogenesis after TBI. A central characteristic of the adaptive immune system is the development of memory to illicit higher magnitude responses with repeated stimuli. This property may be the basis for cumulative damage from repeated injuries and is of clinical significance. Our hypothesis is that primary mTBI results in T and B lymphocytes memory and potentiates an increased pathogenic response to repeated mTBI.To test this hypothesis in this exploratory project, we propose two specific aims. In Aim 1, we will determine the response of the memory immune system to single mTBI and dual mTBI events that are separated by various intervals of time and correlate these responses to pathological outcomes. We will also inhibit specific pathways of memory immune system activation to determine their contribution to mTBI outcome. In Aim 2, we will isolate lymphocytes from mTBI subjects and identify the brain-associated antigens that are immunogenic and stimulatory. By completing this exploratory project, we will prove a greater understanding of the immunological response to mTBI injuries and identify novel therapeutic targets and strategies for improving outcomes for injured individuals and facilitating servicemember return to duty.