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W217 - Systems Immunology Approaches Identify Potential Drug Targets to Prevent Brain Inflammation in Refractory Epilepsy

Wednesday, June 21, 2023
7:30 AM – 7:30 PM  
Salvatore Albani – Director, Translational Immunology Institute (TII), SingHealth-DukeNUS; Thaschawee Arkachaisri – KK Women's and Children's Hospital, Singapore; nursyuhadah Binte Sutamam – Translational Immunology Institute (TII), SingHealth-DukeNUS; Derrick Chan – KK Women's and Children's Hospital, Singapore; Florent Ginhoux – 5Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.; Zeng Li – 8Department of Neurosurgery, National Neuroscience Institute, Singapore; Amanda Lim – Translational Immunology Institute (TII), SingHealth-DukeNUS; jocelyn Lim – KK Women's and Children's Hospital, Singapore; Simon Ling – KK Women's and Children's Hospital, Singapore; David Low – KK Women's and Children's Hospital, Singapore; adeline Ngoh – KK Women's and Children's Hospital, Singapore; sharifah Nur Hazirah – Translational Immunology Institute (TII), SingHealth-DukeNUS; Su Li Poh – Translational Immunology Institute (TII), SingHealth-DukeNUS; Enrico pretretto – DUKE-NUS Medical School, Singapore; Eng-King Tan – Department of Neurosurgery, National Neuroscience Institute, Singapore; Jing Yao – Translational Immunology Institute (TII), SingHealth-DukeNUS; Joo Guan Yeo – KK Women's and Children's Hospital, Singapore; Tong Hong Yeo – KK Women's and Children's Hospital, Singapore
Abstract Text: Epileptogenesis is a pathological process that causes spontaneous recurrent seizures in Epilepsy. Patients non-responsive to antiepileptic drugs are categorized as drug-refractory epilepsy (DRE). Epileptogenic triggers are multifactorial and not well understood. We aimed to address here the hypothesis that inappropriate, immunologically driven pro-inflammatory mechanisms contribute to the pathogenesis of refractory epilepsy in humans
We used single cell Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) to dissect the architecture of the immuno-transcriptome of the diseased epileptic human brain. Systems and Network biology methods were used to analyze the cellular network facilitating immune cell infiltration into the brain. Ligand Receptor network analysis was performed to show intercellular communication and to identify potential drug targets.
Our approach uncovered a surprisingly well organized pro-inflammatory microenvironment pivoting on activated, pro-inflammatory microglia in a closely-knit network where resident cells attract and manipulate in a pro-inflammatory fashion infiltrating innate and adaptive immune cells. Furthermore, for the first time we showed physically interacting microglia with infiltrating immune cells that co-enhances proinflammatory capacity of interacting cells. Moreover, we discovered potential Ligand receptor interaction that could be blocked to prevent brain inflammation by available approved therapeutics
Altogether, our study characterizes the DRE focus in the human brain as an immunologically competent and pro-inflammatory micro-environment and unravels the potential mechanism of immune cell infiltration in the epileptic brain lesions.