ABSTRACT
BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS. METHODS: Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP. RESULTS: Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS. DISCUSSION: Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.
Subject(s)
Multiple Sclerosis , Humans , Brain/metabolism , Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Endothelial Cells/metabolism , Leukocytes/metabolism , Leukocytes, Mononuclear , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Background: Patients with intractable seizures who are not candidates for focal resective surgery are indicated for a palliative surgical procedure, the callosotomy. This procedure is based on the hypothesis that the corpus callosum is an important pathway for interhemispheric spread of epileptic activity and, for drug resistant epilepsy. It presents relatively low permanent morbidity and an efficacy in the control of seizures. Based on literature, the corpus callosotomy improves the quality of life of patients that has the indication to perform this procedure because it allows reducing the frequency of seizures, whether tonic or atonic, tonic-clonic, absence or frontal lobe complex partial seizures. Aim: The aim of this literature review is discuss the technical details, modalities, risks, complications, results as well de prognosis of callosotomy based on critical literature review and the authors experience. Casuistry and Methods: It was performed bibliographical consultation, using the databases MEDLINE, LILACS, SciELO, utilizing language as selection criteria, choosing preferably recent articles in Portuguese, Spanish or English, with publication year higher than 2000. Conclusion: According to authors experience and references, callosotomy is a safe procedure when indicated to selected cases and the success rate is proportional to the extent of callosal resection. A greater resection can reduce the seizure frequency, however the morbidity may also be larger. There is no important study comparing VNS versus Callosotomy versus VNS plus callososotomy, what would be for future necessary for an important source of data about this topic.
Introducción: Los pacientes con convulsiones intratables que no son candidatos para la cirugía de resección focal están indicados para un procedimiento quirúrgico paliativo, la callosotomía. Este procedimiento se basa en la hipótesis de que el cuerpo calloso es una importante vía para la propagación interhemisférica de la actividad epiléptica y, para la epilepsia resistente a fármacos. Presenta relativamente baja morbilidad permanente y una eficacia en el control de las convulsiones. Sobre la base de la literatura, la callostomía mejora la calidad de vida de los pacientes que tiene la indicación para realizar este procedimiento, ya que permite reducir la frecuencia de las crisis, ya sean tónica o átona, tónico-clónicas, ausencia o lóbulo frontal crisis parciales complejas. Objetivo: El objetivo de esta revisión de la literatura es discutir los detalles técnicos, modalidades, riesgos, complicaciones, resultados y de pronóstico de callosotomía basado en la revisión crítica de la literatura y la experiencia de los autores. Casuística y Métodos: Se realizó la consulta bibliográfica, utilizando la base de datos MEDLINE, LILACS, SciELO, que utiliza el lenguaje como criterios de selección, la elección de los artículos recientes preferiblemente en portugués, español o Inglés, con el año de publicación superior a 2000. Conclusión: De acuerdo con la experiencia y las referencias del autor, callosotomía es un procedimiento seguro cuando indicado para casos seleccionados y la tasa de éxito es proporcional a la extensión de la resección del cuerpo calloso. A mayor resección puede reducir la frecuencia de las crisis, sin embargo, la morbilidad puede ser también mayor. No hay ningún estudio que compara la estimulación del nervio vago frente a frente callosotomía VNS más callososotomy, lo que sería la futura necesaria para una importante fuente de datos sobre este tema.