Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Current Knowledge of Microglia in Traumatic Spinal Cord Injury

Microglia are the resident immune cells in the central nervous system (CNS). After traumatic spinal cord injury (SCI), microglia undergo activation, proliferation, and changes in gene and protein expression and morphology, with detrimental and beneficial effects. Activated microglia cause secondary neuronal injury via the production of proinflammatory cytokines, reactive oxygen species, and proteases. However, activated microglia also promote neuronal repair through the secretion of anti-inflammatory growth factors and cytokines. Proinflammatory cytokines increase endothelial permeability, promote A1 astrocyte activation and axonal demyelination, and reduce neural stem/progenitor cells (NSPCs), leading to the exacerbation of neuronal injury. In contrast, anti-inflammatory factors facilitate angiogenesis, reduce reactive astrocytes, and promote axonal remyelination and the propagation of NSPCs, contributing to tissue repair and locomotor recovery. Due to its limited regenerative capacity, the CNS requires beneficial microglia for continuous protection against injury. Understanding and regulating microglial activation status are beneficial to reducing detrimental effects and promoting repair behaviors and to obtain more information on efficient therapies for traumatic SCI. This review discusses microglial activation and the differences between microglia and similar immune cells, microglial interactions with other cells in the spinal cord, and the progress in the development of therapies targeting microglia in SCI.

Enriched Environment Regulates Dendritic Cells to Alleviate Inflammation in Cerebral Infarction Lesions

Objective. The aim was to investigate the role that enriched environment (EE) plays in the regulation of inflammation in cerebral infarction (CI) lesions and further explore the relationship between this regulation and dendritic cells (DCs). Methods. 72 Sprague-Dawley rats were randomly divided into sham operation group (CON group, n = 24 ) and CI model group ( n = 48 ). On completion of the establishment of CI rat models by Longa’s method, rats in the models group were further assigned to standard environment group (NC group, n = 24 ) and EE group ( n = 24 ). HE staining was utilized for evaluation of neuronal injury in the lesions. The number of CD74- and integrin αE-positive cells was detected by immunofluorescence. The expression of the IL-1β, IL-6, and TNF-α in the brain tissue and serum of rats was measured by immunohistochemistry and ELISA, respectively. Results. In comparison with the CON group, the NC and EE groups showed significant increases in neuronal injury, CD74- and Integrin αE-positive cells, DC content, as well as IL-1β, IL-6, and TNF-α expression in brain tissue and serum. According to the further comparison between the NC group and EE group, the latter showed decreases in each indicator, and these decreases were in a time-dependent manner. Conclusion. EE avoids the accumulation of DCs in the lesions and reduces the contents of IL-1β, IL-6, and TNF-α, consequently promoting the recovery of CI. And better recovery results can be obtained through increasing the time to stay in EE.

The Nuclear Factor-Kappa B Signaling Pathway is Involved in Transient Receptor Potential Vanilloid 4-Mediated Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus

The blockage of transient receptor potential vanilloid 4 (TRPV4) greatly reduces hippocampal neuronal injury in mice with temporal lobe epilepsy through inhibiting inflammation. NF-κB signaling pathway is activated during epilepsy, leading to enhanced inflammation and neuronal injury. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1β, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. We conclude that TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. Meanwhile, blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the neuroprotective ability of TRPV4 blockage in mice with PISE.