The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury

Abstract

During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity.

Keywords: Adaptive immune response; Autoimmunity; Innate immune response; Spinal cord injury.

Figure 1. The CNS and immune system are integrated “supersystems” that regulate physiological homeostasis

The classical neuroimmunological perspective to research on SCI or other neurologic diseases has been to focus on leukocyte functions in brain and/or spinal cord, i.e., two immune-privileged sites. However, the modulatory effects of a CNS lesion on immune function were neglected (neurogenic immune ablation). For example, injury to the vegetative, sympathetic nervous system partly withdraws the control of the CNS on the immune and endocrine organs. Loss of this hardwiring has been designated as spinal cord injury-induced immune depression syndrome (SCI-IDS) and may increases the susceptibility to infection in a lesion height dependent manner and may also paradoxically promote autoimmunity. Non-neurogenic mechanisms of immune regulation including “systemic immune response syndrome” (SIRS) or “compensatory anti-inflammatory response syndrome” (CARS) are also elicited by injury and disease and likely increase incidence of infections. Infections are the major cause of death after SCI and have been identified as ‘disease modifying factor’ (DMF) characterized as independent risk factor for poor neurological recovery.

Figure 2. ‘Defective’ resolution of inflammation after SCI

Resolution efficacy is measured as the number of cells being cleared from the lesion site. The cell-specific resolution interval R_i can be determined from the curve at the time when cell numbers decreased by 50% (data points represents the mean of N = 5). Several leukocyte subsets persist indefinitely implying that a ‘resolution-deficit’ exists after SCI. T-cell infiltrates plateau early with ~10% of maximal cell numbers remaining at chronic post-injury intervals. Macrophage and B-cell numbers decrease more slowly. Indeed, even several weeks post-injury, ~45% of maximal macrophage numbers persist (as can be predicted with reasonable certainty from nonlinear regression analysis) after SCI exemplified after a thoracic-level 8 SCI-Model in Lewis rats.

Figure 3. Hallmarks of CNS autoimmunity displayed by T - and B-Lymphocytes after SCI

A. T-lymphocytes are enceophalitogenic after acute SCI. Pioneering reports were able to unravel that adoptive T cell transfer after SCI are encephalitogenic and able to breach in between the intact endothelium and cross the blood spinal cord barrier (BSB) to form classical infiltration clusters accumulating in the perivascular virchow-robin spaces as entry routes for invading T-cells (Popovich et al., 1996a). Permission for reprint will be requested. B. B-lymphocytes form aberrant clusters and align along ectopic ‘follicle-alike’ structures in adjacent areas of the SCI lesion site and represent neuroimmunological hallmarks of a non-selflimiting inflammatory response after SCI. Remaining B-cell parenchymal clusters constitute a source of (auto-)antibody generation implied in degenerative complement mediated axonal damage but also autoimmune pathophysiology. Oligoclonal band synthesis has been reported after experimental SCI and in human CNS injury (A & B, 50 μm).

Figure 4. Lesional and systemic maladaptive immune dysfunction after acute SCI is sustained and extends into the phase of chronic SCI

At the systemic level (upper row), initially after SCI the immune system is suppressed by ‘non-neurogenic’ (CARS/SIRS) and ‘neurogenic’ (SCI-IDS) mechanisms. With time after SCI, the imprint of SCI-IDS increases while the role of CARS/SIRS subsides in case of non-septic SCI-patients. The immune suppression facilitates the development of infections. Infections are the main cause of death in the acute and chronic phase after SCI and have been identified recently as an independent risk factor for poor neurological outcome in SCI patients. (Lower row). In the injured spinal cord, sustained, non-resolving inflammation occurs and is associated with indices of neurodegeneration, demyelinisation and autoimmunity and neurologic changes associated with maladaptive plasticity (e.g.,pain). (Middle row). Systemic and localized (intraspinal) immune dysfunction are interdependent. SCI-IDS could be protective by limiting excessive autoimmunity against CNS-epitopes shielded behind the intact blood-spinal cord barrier (BSB). The penetrance of SCI-IDS is sufficient to prevent classical CNS autoimmune disease (e.g., MS) but is not sufficient for eliminating activation of B- or T cell autoimmunity (See also Table 1). Infections generate excessive host and pathogen-specific RNA, DNA and cell membrane detritus – all are immunogenic and act as adjuvants that are able to boost inflammation including the non-resolved inflammatory cascades active in the injured spinal cord. Moreover, conserved microbial structural motifs, referred to as pathogen-associated molecular patterns (PAMPs), are able to bind to cognate receptors grouped as Toll-like receptors (TLRs) (Akira et al., 2006), which are expressed by neuron, astrocytes, microglia, and oligodendrocytes. Infection derived ligand recognition by TLR is a candidate mechanism to directly foster neuronal injury, neurodegneration, demyelinisation, autoimmunity and pain.