Alterations in Immune Cell Phenotype and Function after Experimental Spinal Cord Injury

Popovich, Phillip G.; Stuckman, Scott; Gienapp, Ingrid E.; Whitacre, Caroline C.

doi:10.1089/089771501750451866

Cited by 76 publications

(53 citation statements)

References 32 publications

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“…Popovich and colleagues found no significant proliferation of splenic T-lymphocytes when stimulated with MBP, suggesting that T-cells do not elicit a significant autoreactive response against MBP after thoracic SCI in rats. 56 It is, however, difficult to truly compare the differing results between our study and that of Popovich and colleagues because our stimulation protocols are substantially different. Here we chose to stimulate with total homogenate from the injured spinal cord rather than MBP because the exact antigens that could stimulate the spleen after cSCI are unknown.…”

Section: Discussionmentioning

confidence: 65%

Characterization of the Antibody Response after Cervical Spinal Cord Injury

Ulndreaj

Τζέκου

Mothe

et al. 2017

Journal of Neurotrauma

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The immune system plays a critical and complex role in the pathobiology of spinal cord injury (SCI), exerting both beneficial and detrimental effects. Increasing evidence suggests that there are injury level-dependent differences in the immune response to SCI. Patients with traumatic SCI have elevated levels of circulating autoantibodies against components of the central nervous system, but the role of these antibodies in SCI outcomes remains unknown. In rodent models of mid-thoracic SCI, antibody-mediated autoimmunity appears to be detrimental to recovery. However, whether autoantibodies against the spinal cord are generated following cervical SCI (cSCI), the most common level of injury in humans, remains undetermined. To address this knowledge gap, we investigated the antibody responses following cSCI in a rat model of injury. We found increased immunoglobulin G (IgG) and IgM antibodies in the spinal cord in the subacute phase of injury (2 weeks), but not in more chronic phases (10 and 20 weeks). At 2 weeks post-cSCI, antibodies were detected at the injury epicenter and co-localized with the astroglial scar and neurons of the ventral horn. These increased levels of antibodies corresponded with enhanced activation of immune responses in the spleen. Higher counts of antibodysecreting cells were observed in the spleen of injured rats. Further, increased levels of secreted IgG antibodies and enhanced proliferation of T-cells in splenocyte cultures from injured rats were found. These findings suggest the potential development of autoantibody responses following cSCI in the rat. The impact of the post-traumatic antibody responses on functional outcomes of cSCI is a critical topic that requires further investigation.

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Section: Discussionmentioning

confidence: 65%

Characterization of the Antibody Response after Cervical Spinal Cord Injury

Ulndreaj

Τζέκου

Mothe

et al. 2017

Journal of Neurotrauma

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“…[24][25][26] There is also evidence in rodent models that SCI results in B-cell expansion with increased circulating IgG antibodies. 2,27 These antibodies target auto-antigens (eg, myelin basic protein, actin, nuclear proteins).…”

Section: Discussionmentioning

confidence: 99%

B-Cell Maturation Antigen, A Proliferation-Inducing Ligand, and B-Cell Activating Factor Are Candidate Mediators of Spinal Cord Injury-Induced Autoimmunity

Saltzman¹,

Battaglino

Salles

et al. 2013

Journal of Neurotrauma

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Autoimmunity is thought to contribute to poor neurological outcomes after spinal cord injury (SCI). There are few mechanism-based therapies, however, designed to reduce tissue damage and neurotoxicity after SCI because the molecular and cellular bases for SCI-induced autoimmunity are not completely understood. Recent groundbreaking studies in rodents indicate that B cells are responsible for SCI-induced autoimmunity. This novel paradigm, if confirmed in humans, could aid in the design of neuroprotective immunotherapies. The aim of this study was to investigate the molecular signaling pathways and mechanisms by which autoimmunity is induced after SCI, with the goal of identifying potential targets in therapies designed to reduce tissue damage and inflammation in the chronic phase of SCI. To that end, we performed an exploratory microarray analysis of peripheral blood mononuclear cells to identify differentially expressed genes in chronic SCI. We identified a gene network associated with lymphoid tissue structure and development that was composed of 29 distinct molecules and five protein complexes, including two cytokines, a proliferation-inducing ligand (APRIL) and B-cell-activating factor (BAFF), and one receptor, B-cell maturation antigen (BMCA) involved in B cell development, proliferation, activation, and survival. Real-time polymerase chain reaction analysis from ribonucleic acid samples confirmed upregulation of these three genes in SCI. To our knowledge, this is the first report that peripheral blood mononuclear cells produce increased levels of BAFF and APRIL in chronic SCI. This finding provides evidence of systemic regulation of SCI-autoimmunity via APRIL and BAFF mediated activation of B cells through BMCA and points toward these molecules as potential targets of therapies designed to reduce neuroinflammation after SCI.

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“…Previously, we demonstrated SCI-induced elevations of serum CORT in a rat model of SCI (Popovich et al, 2001). Here, we extend those findings to mice using a similar model of spinal contusion injury.…”

Section: Sci Activates the Hpa Axis But Disrupts Circadian Cort Synthmentioning

confidence: 90%

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

Lucin

Sanders

Jones

et al. 2007

Experimental Neurology

173

217

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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.

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Alterations in Immune Cell Phenotype and Function after Experimental Spinal Cord Injury

Cited by 76 publications

References 32 publications

Characterization of the Antibody Response after Cervical Spinal Cord Injury

Characterization of the Antibody Response after Cervical Spinal Cord Injury

B-Cell Maturation Antigen, A Proliferation-Inducing Ligand, and B-Cell Activating Factor Are Candidate Mediators of Spinal Cord Injury-Induced Autoimmunity

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

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