Elucidate Consequences of Autoimmune Response to Protease-modified GFAP in TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是全球人群死亡和残疾的主要原因，美国每年报告约200万例TBI事件。在TBI后的第一天内发生显著的细胞死亡，导致脑蛋白及其分解产物大量释放到生物流体如脑脊液（CSF）和循环血液中，这是由受损的脑血屏障促进的。我们最近进行了一项试验性的无偏调查，以检查TBI后患者血清是否含有与TBI后一种或多种脑特异性蛋白反应的自身抗体。相当出乎意料地，我们发现TBI患者的亚急性血清的显著部分含有对主要星形胶质细胞蛋白GFAP的显性自身抗体应答，所述主要星形胶质细胞蛋白GFAP被蛋白水解修饰为GFAP分解产物（GFAP-BDP）。我们推测，这种蛋白酶修饰的GFAP可以打破自身耐受性，并作为显性自身抗原触发TBI后的自身免疫反应。为了检验这一假设，我们建议进行一项转化研究，该研究将测试临床样品和进行小鼠体内自身免疫研究相结合，如下所示：特异性目的1将鉴定和表征TBI后人CSF和血清中蛋白酶修饰的GFAP和伴随的自身抗体。具体目标2将检查主动GFAP-BDP抗原免疫后小鼠的全身免疫应答和脑病理学后果。最后，具体目标3将探索作为抗GFAP-BDP自身免疫与实验性TBI结合的结果的小鼠病理学变化。所产生的数据将为TBI的致病机制提供有价值的见解，并可能支持旨在减少TBI后公共卫生负担的治疗策略的潜在发展。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of death and disability in the human population worldwide, with approximately 2 million reported TBI events occurring in the US annually. Significant cell death occurs within the first days following TBI, resulting in a substantial release of brain proteins and their breakdown products into biofluids such as cerebrospinal fluid (CSF) and circulating blood as facilitated by the compromised brain blood barrier. We recently performed a pilot unbiased investigation to examine if post-TBI patient serum contains autoantibody reactive to one or more brain-specific proteins after TBI. Rather unexpectedly, we found that a significant portion of TBI patients' subacuet sera contains a dominant autoantibody response to a major astrocyte protein GFAP that is proteolytically modified as GFAP breakdown product (GFAP-BDP). We hypothesize that such protease modified GFAP could breakdown the self-tolerance and serve as the dominant autoantigen to trigger autoimmune response following TBI. To examine this hypothesis, we propose to conduct a translational study that combines testing clinical samples and conducting mouse autoimmune studies in vivo as the following: Specific Aim 1 will identify and characterize protease-modified GFAP and accompanied autoantibodies in human CSF and sera post-TBI. Specific Aim 2 will examine systemic immune response and brain pathological consequences in mice following active GFAP-BDP antigen immunization. Lastly, Specific Aim 3 will explore mouse pathological changes as a result of anti-GFAP-BDP autoimmunity in conjunction with experimental TBI. The data generated would provide valuable insight into the pathogenic mechanisms of TBI and likely to support potential development of treatment strategies aimed at reducing the public health burden that follows TBI.