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Our research aims to understand the underlying mechanism of the maladaptive immune response triggered by spinal cord injury (SCI). SCI has been associated with both systemic immune deficiency syndrome and post-traumatic autoimmunity. Both maladaptive neuro-immunological syndromes are associated with inferior repair and serve as a target to improve neurological recovery. We apply a bedside-to-benchside translational approach to investigate clinical phenotypes with molecular techniques in order to develop novel treatments for patients suffering from spinal cord injury.

Background

The central nervous system (CNS) and the immune system are integrated supersystems that regulate physiological homeostasis. Although the CNS is normally immune privileged, upon injury, the immune system gets uncontrolled access and enters the CNS to clear debris and stimulate repair. Unfortunately, once the homeostasis is disrupted between these two systems, they can have detrimental effects on each other. Most research studying the immune system after SCI has focused on understanding the function of leukocytes at the site of injury. However, injury to the spinal cord also disrupts the CNS control over the immune system and endocrine or autonomic effector organs. This disruption of the sympathetic nervous system results in a spinal cord injury-induced immune depression syndrome (SCI-IDS) (Riegger et al., 2003, 2007; Kopp et al., 2023).

This means that immune suppression after SCI is partly “neurogenic” (originating from the nervous system). Neurogenic SCI-IDS is functionally relevant and propagates the susceptibility of infection in a lesion level dependent manner. Consequently, among paraparetic animals the bacterial load in the lung increases with lesion level height using a controlled model of experimental pneumonia (Brommer et al., 2016). A maladaptive neuroendocrine reflex has been identified as a major underlying neurogenic trigger which occurs in a lesion level dependent manner and results in elevated susceptibility for infections (pneumonia) (Prüss et al., 2017). The acquired a secondary, neurogenic immune deficiency syndrome is characterized by impaired cellular- (monocyte and lymphocytes) and humoral immunity (relative hypogammaglobulinaemia especially during the early phase) mirroring a combined cellular & humoral immune deficiency. Non-neurogenic mechanisms of immunosuppression also exist, including “systemic immune response syndrome” (SIRS) and “compensatory anti-inflammatory response syndrome” (CARS), which are general injury-induced. Together, both SCI-IDS and SIRS/CARS render the patient highly susceptible to infections, which are i) the leading cause of death after acute SCI ii) impair the metabolism at the SCI lesion site (Gallagher et al., 2018, Visagan et al., 2023) and iii) reduce neurological and functional recovery (Failli et al., 2012, Kopp et al., 2017) (Figure 1).

Figure 1. Acquired infections as neurological recovery-confounder after Spinal Cord Injury.

Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. (A) The mismatch (red) between the degree of recovery predicted from the initial lesion size and the final degree of recovery can be caused by the delayed emergence of acquired recovery-confounder, as such as acquired infections. (B) Functional outcome prediction after spinal cord injury (SCI) based on initial injury severity only (dashed arrow) ignores the variability that is introduced after initial injury (e.g. by acquired infections) and can affect the lesion-affected (red) and recovery-related networks (green). While the lesion-affected network increases, the recovery-related networks become reduced. Adapted from Nature Rev Neurol., 2021, 17:53-62.

Besides an acquired pneumonia or surgical site wound infection, also acquired pressure ulcers comprise supernumerary immunologically active lesions in addition to the SCI site and act as independent risk factor for poor neurological recovery, elevated mortality and morbidity (Kopp et al., 2024) (Figure 2).

Figure 2: Pressure Ulcer (PU+) associate with worse neurological outcome and are an independent risk factor for poor neurological recovery in SCI patients

A Cohort study included 1282 individuals with spinal cord injury, of which 594 (45.7%) developed PU during initial hospitalization. Illustrated is the percentage of SCI patients classified for injury severity (ASIA impairment scale, AIS) and comparing their respective recovery profiles (‘improving’ vs ‘stable/worsening’) with acquired PU(+) compared to those without (PU(-). ASIA impairment scale (AIS)-conversion over the first year after SCI is depicted. The AIS is a classification of injury completeness taking motor and sensory function into account. The total sample (AIS A, B, C) revealed less frequent upward AIS-conversions (dotted bars, positive y-axis) (n = 95 of 249; 38.2%) in the PU(+) compared with the PU(-) group (n = 157 of 264; 59,5%). This is further verified in all individual SCI injury severity groups AIS A, B, and C. Besides demonstrating reduced patients with improvements patient numbers not recovering or even worsening (black bar, negative y-axis) were increased in the SCI patients with PU (PU+) compared to those without (PU-). Abbreviations: AIS = ASIA impairment scale, ASIA = American Spinal Injury Association, PU = pressure ulcer. Adapted from JAMA Network, 2024, 2;7:e2444983.

In addition to systemic immune suppression, there is also emerging evidence that a subpopulation of SCI patients develop autoimmunity directed against neurons (Schwab et al., 2023), making the interplay between these two systems more complex. A series of recent experiments provided immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient-subpopulation characterized by early neuropathic pain development. The emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes – in analogy to paraneopastic syndromes (Figure 3).

Figure 3. Emerging antibody-mediated autoimmunity after human spinal cord injury detects spinal cord epitopes

Antibody Binding of Sera of Patients With Spinal Cord Injury (SCI) to Native Spinal Cord Epitopes can be Detected by Tissue-Based Assays (TBA) and emerges over time after SCI. TBA are an established and validated diagnostic mean to determine autoantibodies in neurologic disease (Pruss, 2021). Sera of patients with SCI are applied to native rat spinal cord sections and incubated for 3 hours at 37°C (1:200 in blocking solution). (A) Representative SCI patient serum from the acute phase (1-week post-SCI) illustrates a negative staining pattern. (B) In contrast, by 10 weeks after SCI, de novo neuropil labeling of the Rexed Laminae (II/III) in the dorsal horn becomes apparent (arrowheads). Newly synthesized antibodies detect epitopes of the substantia gelatinosa, a less myelinated region characterized by high synaptic density, which receives input from A-delta (mechanoreceptor) or C fibers (nociceptor). The dorsal horn is considered crucial for sensory-motor integration and serves as an entry gate for propriospinal information mediating considerable effects of neurorehabilitation. Last, corresponding dorsal horn laminae contain Calcitonin Gene-Related Peptide positive fibers as candidates involved in neuropathic pain sensitation as well as autonomic control. Of note, the subpopulation of SCI patients with developing antibody synthesis also demonstrated early onset of neuropathic pain development. Scale bar A–F = 500 μm. Collaboration & Courtesy R. Hoeftberger. Adapted from Neurol. Neuroimmunol. Neuroinflamm. 10:e200099.

Figure 4. Emerging antibodies after human spinal cord injury bind to living neurons

SCI-associated, emerging antibodies bind to Living Neurons. Besides autoantibodies recognizing spinal cord epitopes in tissue based assays (TBA) (Figure 3), antibodies also bind to living primary dorsal root ganglia (DRG) cells in cell based assays (CBA). Immunopositivity in both TBA and CBA is considered relevant for functional relevance (Pruss, 2021). The presence of autoantibodies in sera from SCI patients binding to the membrane-epitopes of DRG neurons and glia cells as visualized by antihuman IgG antibodies (AF488, green) and counterstained with DAPI (blue). (A) Sera from patients with SCI demonstrate binding of human IgG antibodies to the DRG cells. (B) The surface staining pattern is absent in the serum of a control patient (Vertebra fracture without SCI). Collaboration & Courtesy R. Hoeftberger. Adapted from Neurol. Neuroimmunol. Neuroinflamm. 10:e200099.

Figure 5. Human Spinal Cord injury: A heterogenous & dynamic neuroimmunological interphase

Blood-brain spinal cord barrier breach and intrathecal antibody synthesis in a SCI patient subpopulation. Consecutive cerebrospinal fluid (CSF) diagnostics over time in a 55-year-old female patient with motor-sensory complete SCI of the neurologic level C4 illustrated and plotted as Reiber diagram. (A) Three weeks after SCI, despite a remaining mild disturbance of the blood-spinal cord barrier (BSCB), no intrathecal antibody synthesis can be detected. (B) Within the subsequent 4 weeks, a dynamic autoimmune process develops at the lesion site until week 7. Evolving post-traumatic CNS autoimmunity is characterized by a (1) reopening of the BSB (3-fold albumin CSF/serum ratio) indicative for a mild BBB disturbance and (2) remarkable de novo antibody synthesis detected in the CSF compartment only (IgG, IgA, and IgM CSF/serum ratios are substantially increased (not shown). A predominant IgM class response confirms its novel onset (de novo synthesis, blue arrow). This indicates intrathecal antibody synthesis as a characteristic hallmark of CNS-autoimmunity. SCI patients with increasingly disturbed Blood-Spinal Cord Barrier (BSCB) and intrathecal antibody synthesis represent a distinct cohort from a neuroimmunological perspective compared to those with closing BSCB.  Adapted from Neurol. Neuroimmunol. Neuroinflamm. 10:e200099.

In contrast to a diminished systemic immunity, at the lesioned spinal cord local non-resolving inflammation occurs (Zrzavy et al., 2021) (Figure 6). This sustained, smoldering inflammation is known driveneurodegeneration, demyelination, and can also facilitate the development of autoimmunity (see above).

Figure 6 Smoldering non-resolving inflammation at the spinal lesion site in SCI patients

Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury. Chronic, non-resolving inflammation is characterized p22phox (NADPH)+ microglia/macrophage and associates with intense oxidized phospholipids in neurons. (A-D) Early chronic – chronic stages (3 months to 1.5 years) after human SCI demonstrates a cystic cavitation (syrinx, asterisk) at the initial lesion site as well as surrounding scar formation composed of an hypercellular rim. (B) The scar contains non-resolving, activated CD68+ macrophages, which form an inflammatory ‘layer’ confined to the immediate border between the hypercellular and hypocellular regions with declining cell numbers towards the syrinx core. Non-resolving lipid-laden (foamy) CD68+ macrophages form compartmentalized clusters ‘locked’ into the immediate scar (arrow). CD68+ monocytes/macrophages also form clusters in Virchow-Robin-alike spaces pointing to a chronic immunological activation or drainage. (C & D) The lesional rim illustrates massive reactive GFAP+ astrogliosis with some remaining evenly distributed CD68+ macrophages. Of note, also the rim represents an area of higher immune alertness characterized by higher numbers of CD68+ myeloid cells even until chronic stages. (E–G) Oxidative injury after SCI affects spinal neurons. Presence of oxidized phospholipids (e06 immunoreactivity) in neurons is associated with beading and fragmentation of cell processes in the human CNS and occurs after SCI. (E) Intense e06 immunoreactivity in a neuron demonstrating signs of degeneration and beading/fragmentation of cell processes. (F) Massive accumulation of oxidized phospholipids (e06+) in a degenerating neuron surrounded from and in contact with pro-inflammatory p22phox+ microglia (blue). (G) e06+ neuron undergoing central chromatolysis in contact with activated pro-inflammatory p22phox+ microglia. Scale bars = 125mm in A, B, 250mm C & D and 25mm in E-F. Adapted from Brain, 2021, 144:144-161. Courtesy R. Hoeftberger.

Local and systemic immune dysfunction occur acutely after SCI and persist into the chronic phase of SCI, comprising a substrate for propagated neurodegeneration. (Schwab et al., 2014, 2023, Zrzavy et al., 2021).

Topics & Main Projects

1. Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS)

SCI disrupts the interplay between the immune system and the CNS (Meisel et al., 2005), leaving patients vulnerable to infections such as pneumonia and urinary tract infections. Patients with acute SCI who suffer from infections have a worse prognosis for neurological repair. Our lab is interested in understanding the trigger and implications of the immunodepression syndrome induced by SCI (SCI-IDS). Using different models of SCI and pneumonia, we can investigate what functional deficits result from infection after SCI and explore the underlying mechanisms for these deficits. The impact of acquired infections on the lesion affected and recovery associated networks is under investigation. Our lab strives to identify novel clinical strategies to combat SCI-IDS, using a bench-to-bedside and bedside-to-bench approach. This includes immunotropic approaches to stabilize the immune-system, as well as non-antibiotic treatments to reduce infection susceptibility.

2. Spinal Cord Injury-induced autoimmunity

Another aspect of the maladaptive immune response after SCI is SCI-induced autoimmunity. Despite systemic reductions in immunity, at the site of injury there is non-resolving inflammation (Prüss et al., 2011, Zrzavy et al.,2021). This ongoing inflammation may cause maladaptive priming of lymphocytes against self-antigens. We are interested in understanding the presence and function of these autoreactive T cells and B-cell-mediated autoantibodies after SCI. The emerging auto-antibody formation in a SCI patient subpopulation directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes – in analogy to paraneopastic syndromes. Paratraumatic CNS autoimmune syndrome are a candidate driver to aggravate spasticity, neuropathic pain, fatigue or even interfere with the response to neurorehabilitation

3. Protecting outcome ‘at risk’ – tackling treatable recovery confounder

Acquired infections after spinal cord injury (SCI) associate with significantly reduced neurological recovery. Having established a clinical phenotype of poor neurological recovery, we apply a bed-to-benchside translational approach to decipher underlying mechanism and identify novel molecular targets for intervention of translational value to protect the endogenous recovery potential from the deleterious impact of acquired infections. Novel neuroprotective therapies targeting infection-triggered pathways represent an innovative novel strategy to tackle an unaddressed, prevalent pathological condition and unmet medical need.

The Schwab Lab is affiliated with the Belford Center for Spinal Cord Injury and the Center for Brain and Spinal Cord Repair (CBSCR) at the Ohio State University. 

 

References

Brommer B, Engel O, Kopp MA, Watzlawick R, Müller S, Prüss H, Chen Y, DeVivo MJ, Finkenstaedt FW, Dirnagl U, Liebscher T, Meisel A, Schwab JM (2017). Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain 139:692-707.

Failli V, Kopp MA, Gericke C, Martus P, Klingbeil S, Brommer B, Laginha I, Chen Y, DeVivo MJ, Dirnagl U, Schwab JM (2012). Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain 135:3238-3250.

Fouad K, Popovich PG, Kopp MA, Schwab JM (2021). The neuroanatomical-functional paradox in spinal cord injury. Nat Rev Neurol. 17:53-62.

Gallagher MJ, Zoumprouli A, Phang I, Schwab JM, Kopp MA, Liebscher T, Papadopoulos MC, Saadoun S (2018). Markedly Deranged Injury Site Metabolism and Impaired Functional Recovery in Acute Spinal Cord Injury Patients With Fever. Crit Care Med. 46:1150-1157.

Kopp MA, Finkenstaedt FW, Schweizerhof O, Grittner U, Martus P, Watzlawick R, Brienza D, Failli V, Chen Y, DeVivo MJ, Schwab JM (2024). Hospital-Acquired Pressure Ulcers and Long-Term Motor Score Recovery in Patients With Acute Cervical Spinal Cord Injury. JAMA Netw Open 7:e2444983.

Kopp MA, Meisel C, Liebscher T, Watzlawick R, Cinelli P, Schweizerhof O, Blex C, Lübstorf T, Prilipp E, Niedeggen A, Druschel C, Schaser KD, Wanner GA, Curt A, Lindemann G, Nugeva N, Fehlings MG, Vajkoczy P, Cabraja M, Dengler J, Ertel W, Ekkernkamp A, Rehahn K, Martus P, Volk HD, Unterwalder N, Kölsch U, Brommer B, Hellmann RC, Baumgartner E, Hirt J, Geurtz LC, Saidy RRO, Prüss H, Laginha I, Failli V, Grittner U, Dirnagl U, Schwab JM (2023). The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study. Brain 146:3500-3512.

Kopp MA, Watzlawick R, Martus P, Failli V, Finkenstaedt FW, Chen Y, DeVivo MJ, Dirnagl U, Schwab JM (2017). Long-term functional outcome in patients with acquired infections after acute spinal cord injury. Neurology 28;88:892-900.

Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U (2005). Central nervous system injury-induced immune deficiency syndrome. Nature Reviews Neuroscience 6:775-786.

Prüss H (2021). Autoantibodies in neurological disease. Nat Rev Immunol. 21:798-813.

Prüss H, Tedeschi A, Thiriot A, Lynch L, Loughead SM, Stutte S, Mazo IB, Kopp MA, Brommer B, Blex C, Geurtz LC, Liebscher T, Niedeggen A, Dirnagl U, Bradke F, Volz MS, DeVivo MJ, Chen Y, von Andrian UH, Schwab JM (2017). Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex. Nature Neuroscience 20(11):1549-1559

Prüss H, Kopp MA, Brommer B, Gatzemeier N, Laginha I, Dirnagl U, Schwab JM (2011). Non-Resolving Aspects of Acute Inflammation after Spinal Cord Injury (SCI): Indices and Resolution Plateau. Brain Pathology 21:652-660.

Riegger T, Conrad S, Liu K, Schluesener HJ, Adibzahdeh M, Schwab JM (2007). Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur J Neurosci 25 :1743-7.

Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, Gerstein J, Dietz K, Abdizahdeh M, Schwab JM (2009). Immune depression syndrome following human spinal cord injury (SCI): a pilot study. Neuroscience 158:1194-9.

Riegger T, Schluesener HJ, Conrad S, et al (2003). Hematologic Cellular Inflammatory Response Following Human Spinal Cord Injury: 48th Annual Meeting of the German Society for Neuropathology and Neuroanatomy. Berlin: Acta Neuropathol 392.

Schwab JM, Zhang Y, Kopp MA, Brommer B, Popovich PG (2014). The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Experimental Neurology 258:121-129.

Schwab JM, Haider C, Kopp MA, Zrzavy T, Endmayr V, Ricken G, Kubista H, Haider T, Liebscher T, Lübstorf T, Blex C, Serdani-Neuhaus L, Curt A, Cinelli P, Scivoletto G, Fehlings MG, May C, Guntermann A, Marcus K, Meisel C, Dirnagl U, Martus P, Prüss H, Popovich PG, Lassmann H, Höftberger R (2023). Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury. Neurol Neuroimmunol Neuroinflamm. 10:e200099.

Visagan R, Kearney S, Blex C, Serdani-Neuhaus L, Kopp MA, Schwab JM, Zoumprouli A, Papadopoulos MC, Saadoun S (2023). Adverse Effect of Neurogenic, Infective, and Inflammatory Fever on Acutely Injured Human Spinal Cord. J Neurotrauma 40:2680-2693.

Zrzavy T, Schwaiger C, Wimmer I, Berger T, Bauer J, Butovsky O, Schwab JM, Lassmann H, Höftberger R (2021). Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury. Brain 144:144-161.