Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation

Abstract

Individuals with spinal cord injury (SCI) are highly susceptible to infection. This post-traumatic immune suppression is thought to occur via alterations in sympathetic nervous system (SNS) or hypothalamic-pituitary-adrenal (HPA) axis function. Normally, the HPA axis and SNS help coordinate proper immune function. After SCI, the HPA axis becomes activated and descending input to sympathetic preganglionic neurons (SPNs) is impaired. Because lymphoid organs are innervated by SPNs distributed throughout the thoracolumbar spinal cord, we predicted leveldependent immune suppression after SCI due to activation of the HPA axis and loss of descending input to SPNs. We tested this hypothesis by measuring indices of HPA (circulating corticosterone; CORT) and SNS function (norepinephrine (NE) in spleen) as well as antigen-specific antibody synthesis against an exogenous non-self protein following high or low level SCI. Using a midthoracic (T9) spinal contusion injury model, we found that CORT was elevated after SCI with aberrant patterns of diurnal CORT synthesis evident through at least the first 24 hours post-injury. However, splenic NE and antibody synthesis were similar to uninjured controls. Injury severity did not change these parameters. Indeed, CORT, NE and antibody synthesis were similar after T9 contusion or transection SCI. In contrast, high level SCI (T3) caused sustained increases in CORT and splenic NE along with impaired antibody synthesis and elevated splenocyte apoptosis. The immunosuppressive effects of T3 SCI were caused by NE acting at β2-adrenergic receptors (β2AR) and could be reversed using β2AR blockers. Interestingly, impaired antibody after T3 SCI could be Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript mimicked after T9 SCI with a β2AR agonist. These data illustrate the immunosuppressive effects of the SNS after high-level SCI and indicate that immune deficits may be overcome using β-blockers.

CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice

“…It is likely that CD-1 and C57BL/6 mice respond differently to SCI such that reducing neutrophils in the injured spinal cord is detrimental to CD-1 recovery, but beneficial to C57BL/6 recovery. Furthermore it has also been reported that the immune response triggered by SCI may be different for high thoracic SCI (as performed in our study) compared to lower thoracic SCI (as performed in the study by Stirling and associates), as higher levels of SCI (T3-T6) impair sympathetic innervation of lymphoid tissue (Lucin et al, 2007;Popovich and McTigue, 2009). …”

Spinal Cord Injury Causes Chronic Liver Pathology in Rats

“…This is in contrast to previous work showing more severe effects after higher-level injuries on autonomic dysreflexia, inflammation, and cardiovascular problems. 16,66,67 Both injury levels used here, however, completely (cervical) or partially (thoracic) disrupt descending control of sympathetic neurons innervating the liver and, thus, differences in hepatic changes between cervical and thoracic injuries were subtle. To further test this, a cohort of animals received a lumbar SCI to spare sympathetic innervation to the liver.…”

Immune dysfunction and chronic inflammation following spinal cord injury

“…There is ample evidence demonstrating that despite an elevated inflammatory state, SCI is associated with a state of immunosuppression and a heightened susceptibility to infection. [6][7][8][9] Suppressed function of natural killer cells, neutrophils, macrophages and lymphocytes have each been documented following SCI. 6,10,11 The loss of motor and sensory function also contribute to this population's greater susceptibility to a number of acute infections, including urinary tract infection (UTI) and pressure ulcers, as well as metabolic disorders associated with a more sedentary lifestyle such as obesity, atherosclerosis and type 2 diabetes.…”

“…8 As lymphoid organs such as the spleen and adrenal gland are innervated by sympathetic neurons that originate from regions throughout the thoracolumbar spinal cord, an injury at or above this region may be expected to induce immune suppression. 9 Damage to the cervical spine would interfere with supraspinal control over preganglionic neurons below the injury, whereas damage at the mid-thoracic region would damage preganglionic sympathetic neurons directly. 7 Level-dependent impairment in B-cell function has been demonstrated in mice subjected to high (T3) versus mid-thoracic (T9) SCI.…”