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.
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.
Authors: Faiez Al Nimer; Ivan Jelcic; Christian Kempf; Tom Pieper; Herbert Budka; Mireia Sospedra; Roland Martin Journal: Neurol Neuroimmunol Neuroinflamm Date: 2017-12-08
Authors: Margaret J Landreneau; Michael T Mullen; Steven R Messé; Brett Cucchiara; Kevin N Sheth; Louise D McCullough; Scott E Kasner; Lauren H Sansing Journal: Ann Clin Transl Neurol Date: 2018-07-03 Impact factor: 4.511
Authors: Zuzana Liba; Martina Vaskova; Josef Zamecnik; Jana Kayserova; Hana Nohejlova; Matyas Ebel; Jan Sanda; Gonzalo Alonso Ramos-Rivera; Klara Brozova; Petr Liby; Michal Tichy; Pavel Krsek Journal: BMC Neurol Date: 2020-09-24 Impact factor: 2.474