Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

Abstract

Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function. These effects stem from maladaptive changes in the spinal cord after injury, including plasticity within the spinal sympathetic reflex circuit that results in exaggerated sympathetic output in response to peripheral stimulation below injury level. Such pathological activity is particularly evident after a severe high-level injury above thoracic spinal cord segment 6, greatly increasing the risk of the development of sympathetic hyperreflexia and subsequent disrupted regulation of lymphoid organs. Encouragingly, studies have presented evidence for promising therapies, such as modulation of neuroimmune activity, to improve regulation of peripheral immune function. In this review, we summarize recent publications examining (1) how various immune functions and populations are affected, (2) mechanisms behind SCI-induced immune dysfunction, and (3) potential interventions to improve SCI individuals' immunological function to strengthen resistance to potentially deadly infections.

Keywords: SCI-IDS; autonomic dysreflexia; immune dysfunction; spinal cord injury.

Figure 1

After spinal cord injury (SCI), both chronic systemic inflammation and immunosuppression result in SCI-induced immune depression syndrome (SCI-IDS). Altered immune function results in increased susceptibility to infection and exacerbated secondary complications of SCI. In turn, these secondary complications and infections may create a feedback loop which amplifies immune dysfunction. Created using BioRender.com accessed on 2 September 2021.

Figure 2

After a SCI, there is an acute drop in systemic norepinephrine (NE) and an increase in plasma glucocorticoids (GCs) released by the adrenal glands. Chronically, increased neural circuit plasticity results in sympathetic hyperreflexia and release of NE by sympathetic post-ganglionic neurons, including those targeting the spleen and other lymphoid organs such as the bone marrow. These changes after SCI result in measurable altered immune profile and function. Created using BioRender.com accessed on 2 September 2021.

Figure 3

Preclinical studies have revealed that pharmacological inhibition of sympathetic circuit plasticity, either through the use of high-dose gabapentin (GBP) or soluble TNFα inhibition, can reduce autonomic dysreflexia (AD) and improve splenic immune cell profile. Separately, studies have examined the modulation of gut microbiota, either through probiotic treatment or deletion of Pde4b, to improve microbiome composition after SCI, which in turn improves anti-inflammatory immune cell profile in gut-associated lymphoid tissues (GALTs), like mesenteric lymph nodes (MLNs), and reduces circulating markers of inflammation. Created using BioRender.com accessed on 2 September 2021.