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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Hicks, Ramona R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Schwab, Jan M; Zhang, Yi; Kopp, Marcel A et al. (2014) The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Exp Neurol 258:121-9
Gilbert, Ryan J; Rivet, Christopher J; Zuidema, Jonathan M et al. (2011) Biomaterial design considerations for repairing the injured spinal cord. Crit Rev Biomed Eng 39:125-80
Donnelly, Dustin J; Longbrake, Erin E; Shawler, Todd M et al. (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci 31:9910-22
Zhang, Yi; Popovich, Phillip (2011) Roles of autoantibodies in central nervous system injury. Discov Med 11:395-402
Awad, Hamdy; Ankeny, Daniel P; Guan, Zhen et al. (2010) A mouse model of ischemic spinal cord injury with delayed paralysis caused by aortic cross-clamping. Anesthesiology 113:880-91
Killedar, Smruti; Dirosario, Julianne; Divers, Erin et al. (2010) Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response. J Neuroinflammation 7:39
Ankeny, Daniel P; Popovich, Phillip G (2010) B cells and autoantibodies: complex roles in CNS injury. Trends Immunol 31:332-8
Ankeny, Daniel P; Guan, Zhen; Popovich, Phillip G (2009) B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J Clin Invest 119:2990-9
Alexander, Jessica K; Popovich, Phillip G (2009) Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection and regeneration. Prog Brain Res 175:125-37
Lucin, Kurt M; Sanders, Virginia M; Popovich, Phillip G (2009) Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury. J Neurochem 110:1409-21

Showing the most recent 10 out of 18 publications