The Project

Backgroung

The acute traumatic spinal cord injury represents the onset of a lifelong disease and constitutes an individual and socioeconomic catastrophe for which there is no consistent approach for intervention (Siddiqui et al., 2015). Despite affecting the two main systems controlling body homeostasis the maladaptive systemic immune response including evolving autoimmunity after spinal cord injury is poorly understood. Moreover, the need to improve medical care for spinal cord injury patients is mirrored by a lack of improved long-term survival over the last three decade compared to the general population (Shavelle et al., 2015). Finally, fragmentation of preclinical research and clinical spinal cord injury care constitutes a roadblock impeding hypothesis-testing in the clinical realm. All of the above justify the need for a translational network aiming to unravel novel spinal cord injury disease mechanisms, which could qualify as therapeutic target.

Key objective of this proposal is to investigate whether patients displaying inferior neuronal recovery profiles (rehabilitation-non-responder) host distinct signatures of humoral post-traumatic autoimmunity evolving after spinal cord injury (humoral autoimmunity as outcome modifying factor)

The maladaptive systemic immune response after spinal cord injury can be characterized by at least two putatively interrelated immunological syndromes. First, the spinal cord injury-induced immune deficiency syndrome (Schwab et al., 2014, Meisel et al., 2005) considered a physiological response to prevent overt autoimmunity against central nervous system antigen. Second, post-traumatic autoimmunity developing against central nervous system neo-antigen perpetuated in case of blunted spinal cord injury-induced immune deficiency syndrome penetrance and/or spinal cord injury -associated infections. This hypothesis is in line with published evidence reporting that infections are associated with elevated auto-antibody titers against central nervous system antigen (Davies et al., 2007) and impaired functional outcome (Failli et al., 2012)

Our consortium focus on studying B-cell derived signatures of humoral autoimmunity dependent on spinal cord injury-induced immune deficiency syndrome (mettere link a spiegazione) penetrance and spinal cord injury -associated infections (mettere link a spiegazione). Substrate for screening analysis will be available serum samples from the prognostic “SCIentinel” study. Screening results will be re-assessed within the prospective “SCIentinel-Prolong” study, which will allow for CSF analysis and correlation with neurological and functional outcome measures up to one year after spinal cord injury.

Objectives

  • Deciphering patterns of humoral “de novo” autoimmunity after human spinal cord injury by proteomics and tissue/cell based approaches.
  • Identifying functionally relevant auto-antigens in a bed to bench side translation.
  • Linking autoimmunity to clinical diagnostics and outcome.
  • Lalidating the findings across pathologies.

We will address these aims based on published evidence and preliminary findings of the consortium members and their collaboration partners. We will use well characterized human specimen-banks (SCIentinel) as already established in a recent multi-national trial (Kopp et al., 2013) and samples collected in an upcoming follow-on trial (SCIentinel-prolong) in combination with existing experimental (spinal cord injury contusion model) and human (MUW Brain Bank) tissue repositories as well as experimental models of autoimmune disease (antibody transfer).

Our hypotheses

  • An auto-antibody response directed against Central Nervous System and Peripheric Nervous System antigen is emerging in a sub-cohort of spinal cord injury patients over the course from acute to chronic spinal cord injury.
  • Humoral autoimmunity is dependent on the severity of the spinal cord injury-induced immune deficiency syndrome penetrance during the acute spinal cord injury phase.
  • Infections, in particular spinal cord injury-associated pneumonia are associated with higher levels of auto-antibody synthesis.

The auto-antibody response is able to affect neurological and functional outcome parameters associated with central and peripheral channelopathies/neuropathies

Methodology

In order to validate preliminary evidence for post-traumatic autoimmunity, the SILENCE project combines existing data/sample repositories with a forthcoming trial and experimental models. Based on explorative pilot data from the SCIentinel trial (Kopp et al. 2013) specimen bank, the SILENCE-project will systematically screen for evolving autoimmunity (epitope spreading) using protein microarrays (WP2) and tissue or cell based assays (WP3). The antigens identified can be linked to the immunological phenotype of the trial participants to account for immunodepression (penetrance of the spinal cord injury-induced immune deficiency syndrome). Furthermore, the results inform antibody transfer models to explore the functional relevance of the identified antigens (WP3). Underlying cellular mechanisms will be investigated applying immunohistochemistry on markers of B-cell development. The upcoming SCIentinel prolong trial serves for confirmation of the autoimmunity screening and for extension of the autoimmune profiling to CSF samples as well as for long-term follow-up (1-year post- spinal cord injury). The current recruitment platform are specialized spinal cord injury centers in Germany and Switzerland. The SILENCE project will allow for extensions of the SCIentinel-prolong trial, which are highly relevant in terms of characterizing the identified underlying cellular mechanisms of humoral autoimmunity and to assess the clinical impact of the maladaptive systemic immune response (autoimmunity & spinal cord injury-induced immune deficiency syndrome). The extensions enabled by the proposed SILENCE project are:

1) B-cell phenotyping;

2) T-/B-cell functional (auto-)immunity assays (WP1);

3) clinical electrophysiology (WP4) and functional outcome assessment (WP5). Furthermore, the SILENCE project permits the incorporation of an additional trial center in Italy, which will also contribute as reference center for functional outcome evaluation (WP5). The SCIentinel prolong trial will receive additional funding from the Wings for Life Spinal Cord Research Foundation (WfL), which assures its feasibility. See the figure below.

Our interdisciplinary consortium includes five project partners, whose provide multiple individual contributions to each work package