SCI-induced systemic maladaptive immune response and autoimmunity to CNS (SILENCE)

Up to 7 Million patients worldwide live with the debilitating consequences of spinal cord injury (SCI). The results of recent studies suggest that inferior neurological and functional recovery may be associated with a maladaptive autoimmune response such as the formation of autoantibodies against CNS-antigens or a SCI-induced immune deficiency syndrome. Autoantibodies to surface receptor antigens have not been studied in SCI patients. Due to their serological features (autoantibodies to membrane antigens can only be detected when the three-dimensional conformation of the targeted epitope is preserved) they so far escape detection with classical methods such as immunoblot or ELISA. Thus, little is known regarding their occurrence in post-traumatic SCI, their relation to different clinical complications, and neurological outcome. These questions will be addressed in our current project. We have started to systematically analyze serum samples of SCI patients over the course from acute to chronic SCI for anti-neuronal and anti-glial surface receptor antibodies. Our results, obtained so far, indicate that a sub-cohort of patients develop auto-antibodies to surface antigens of the dorsal horn of the spinal cord. The immunoreactivity against these antigens occurred four to five weeks after trauma. Aim of the present project is to decipher the role of post-traumatic humoral autoimmunity against antigens of the central nervous system (CNS) and investigate whether this response affects the neurological and functional outcome of patients. To address these questions, detailed autoantibody screening to cerebral and spinal cord antigens in serum and CSF samples obtained from well-characterized SCI specimen banks from prospective multicenter trials will be performed. Additional aims of the present project are to investigate the type of tissue injury in SCI lesions using a rodent SCI contusion model and human autopsy tissue, which allows defining the predominant pathogenic pathways leading to tissue injury and repair. Occurrence of autoantibodies against CNS antigens in SCI patients may be a correlate of clinical complication such as autonomic dysregulation or neuropathic pain and may be the rationale for individualized effective immune-modulatory treatment.

The variability of the limited natural recovery after spinal cord injury (SCI) is insufficiently explained. A maladaptive systemic immune response after SCI - possibly triggered by an emerging immune reaction against components of the central nervous system (CNS) or CNS injury-induced immune deficiency - might play a role. In longitudinal neuroimmunological and neuropathological studies, we address the objectives whether i) autoimmunity against spinal cord tissue may raise over time, ii) the perilesional area may represent an immunological risk to trigger autoimmunity and iii) dynamic induction of Nogo-A in perilesional plasticity regions after human SCI may occur. We investigated a large cohort of 22 SCI autopsies from different time points with clinical information. We found a sustained neurotoxicity up to months/years after SCI that may contribute to ongoing neuronal damage and impaired rehabilitation. Moreover, we found a dynamic expression of NogoA in perilesional areas in chronic stages after SCI. This suggests a therapeutic window for anti-Nogo-A treatment beyond 4 weeks in patients after SCI. In neuroimmunological studies we developed a spinal cord tissue-based assays applied in combination with dorsal root ganglia neuronal cultures both representing a screening-tool to interrogate and localize antibody-mediated autoimmunity directed against 3-D conformational epitopes. Emerging autoimmunity against spinal cord tissue and live neuronal cell epitopes 10 weeks after acute injury was restricted to SCI patients (16%, 9/55, serum) while being absent in controls suffering vertebral trauma without SCI (0%, 0/19). Autoantibody-binding to the spinal cord was observed in the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration. Analyses to identify the specific target of the antibody binding in TBA and estimate their outcome relevance are ongoing. The autoantibody synthesis commencing after human SCI suggest the existence of "para-traumatic CNS autoimmune syndromes" (in analogy to "para-neoplastic syndromes") and may offer new treatment perspectives for a subpopulation of spinal cord injured patients.