A Role for the CXCR3/CXCL10 Axis in Rasmussen Encephalitis

• Published in: Pediatric neurology Vol. 49; no. 6; pp. 451 - 457.e1
• Main Authors: Mirones, Isabel, PhD, de Prada, Inmaculada, MD, PhD, Gómez, Ana M., PhD, Luque, Alfonso, PhD, Martín, Roberto, Pérez-Jiménez, M. Ángeles, MD, PhD, Madero, Luis, MD, PhD, García-Castro, Javier, PhD, Ramírez, Manuel, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2013
• Subjects: Adolescent; Amides - pharmacology; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Brain - pathology; brain damage; Cells, Cultured; Chemokine CXCL10 - metabolism; chemokines; Child; Child, Preschool; Coculture Techniques; CXCL10; Dose-Response Relationship, Drug; Encephalitis - metabolism; Encephalitis - pathology; Female; Humans; Interferon Inducers - pharmacology; Male; Mice; Nerve Tissue Proteins - metabolism; Neurology; Pediatrics; Poly I-C - pharmacology; Quaternary Ammonium Compounds - pharmacology; rasmussen encephalitis; Receptors, CXCR3 - metabolism; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; T lymphocytes; CXCL10; rasmussen encephalitis; brain damage; chemokines
• ISSN: 0887-8994; 1873-5150
• DOI: 10.1016/j.pediatrneurol.2013.07.019

Abstract Background Rasmussen encephalitis is a devastating pediatric syndrome of unknown etiology that is characterized by progressive loss of neurological function and intractable focal epilepsy. Cytotoxic T lymphocytes have an active role in the pathogenic process of Rasmussen encephalitis. We studied the implication of CXCL10-CXCR3, a chemotactic axis involved in the pathogenesis of several cases of immune encephalitis. Methods We analyzed surgical specimens of children with Rasmussen encephalitis, and performed functional in vitro assays to test the implications of the pathological findings. Results We found that cytotoxic T lymphocytes infiltrating the damaged areas of primary biopsies expressed CXCR3, whereas neurons and astrocytes in the same areas expressed CXCL10. The in vitro assays demonstrated we found that astrocytes upregulated the expression of CXCL10 messenger RNA and the release of CXCL10 to the supernatants on stimulation with polyinosinic-polycyticylic acid, a synthetic double-stranded RNA that mimics infections with either RNA or DNA viruses. Activated T lymphocytes responded to the production of CXCL10 by astrocytes by increasing their migration in a transwell assay. Finally, the chemotaxis induced by the stimulated astrocytes was completely abrogated in the presence of a small molecule antagonist of CXCR3. Conclusions Our results suggest that the CXCR3-CXCL10 axis has a role in recruiting pathogenic T lymphocytes into the brains of patients with Rasmussen encephalitis. This chemotactic mechanism may be targeted pharmacologically.