Lymphocyte Functions in the Injured Spinal Cord

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DESCRIPTION (provided by applicant): Spinal cord injury (SCI) activates immune cells that cause tissue damage in the CNS. To date, most studies in this area have focused on the injurious effects of macrophages and T cells. However, antibodies that bind CNS proteins accumulate in sera and cerebrospinal fluid of people with SCI, suggesting that activated B cells may contribute to post-traumatic inflammatory damage. During the last five years, we have shown that SCI triggers B cell activation and autoantibody synthesis. Importantly, mice without B cells have smaller lesions and improved recovery after SCI. In this renewal application, we will test the hypothesis that antibodies produced after SCI exacerbate neuron and glial pathology thereby limiting functional recovery. Three specific aims are proposed. In Aim1, we will use proteomics to reveal the identities of proteins that activate B cells after SCI. In Aim 2, we will investigate the biological effects of purified antibodies obtained from SCI mice at different times after injury. This will be accomplished by injecting purified antibodies into specific regions of the spinal cord followed by behavioral and electrophysiological analysis of spinal cord function. Antibody-mediated changes in neuron/glial survival, axon pathology and/or demyelination will be documented using standard immunohistochemical techniques. Also in Aim 2, we will evaluate the mechanisms responsible for any detrimental effects caused by intraspinal antibody injection. This will be accomplished by injecting antibodies into mice that have been genetically modified such that they lack key proteins that known to mediate the effects of antibodies. In Aim 3, we will determine if two key B cell survival factors are responsible for the chronic intraspinal activity of B cells after SCI. Specifically, we will document spatiotemporal induction patterns and sources of BAFF and APRIL after SCI. To determine if these growth factors can be manipulated to stem B cell and antibody-mediated pathology after SCI, we will infuse the injury site with decoy receptors that will block BAFF and APRIL signaling. Collectively, the experiments in this proposal will provide novel information about the contributions of antibody-producing B cells to the tissue damage caused by SCI. Moreover, these studies will likely reveal novel therapeutic targets for treating SCI. PUBLIC HEALTH RELEVANCE This proposal will determine the identities of proteins that activate B cells, causing them to produce pathogenic autoantibodies after spinal cord injury (SCI). Moreover, the mechanisms responsible for autoantibody-mediated injury in the spinal cord will be determined and new strategies to block SCI-mediated B cell activation will be developed. Data from these studies will be used to develop novel clinical therapies to treat SCI in humans.