Exploring the Complex Immune Microenvironment of Rasmussen EncephalitisExploring the Complex Immune Microenvironment of Rasmussen Encephalitis https://pediatricsnationwide.org/wp-content/uploads/2022/09/AdobeStock_117146752-HEADER-FOR-WEB-1024x587.jpg 1024 587 Lauren Dembeck Lauren Dembeck https://pediatricsnationwide.org/wp-content/uploads/2021/03/Dembeck_headshot.gif
- January 06, 2023
- Lauren Dembeck
Researchers used a multi-omics approach to gain a deeper understanding of aberrant cellular signaling leading to progression of a rare childhood neurological disease.
Rasmussen encephalitis is a very rare childhood neurological disease characterized by chronic progressive inflammation of one hemisphere of the brain, leading to loss of function, neurodegeneration, and drug-resistant epilepsy. Researchers have known that affected brain tissue harbors infiltrating cytotoxic T-cells and microglia; however, the cell type-specific mechanisms underlying the disease have remained unresolved.
To identify the cell populations involved in Rasmussen encephalitis, researchers at Nationwide Children’s Hospital used single-nucleus RNA-sequencing to assess gene expression across multiple cell types within brain tissue surgically resected from two children with Rasmussen encephalitis. The implementation of this new technology approach at Nationwide Children’s is being led by Katherine Miller, PhD, principal investigator in the Steve and Cindy Rasmussen Institute for Genomic Medicine and co-corresponding author of the paper. Their findings were recently published in Acta Neuropathologica Communications.
“Annually, approximately one in every five million children develop new-onset Rasmussen encephalitis, and because of its rarity, there haven’t been many opportunities to study this disease,” explains senior study author Tracy Bedrosian, PhD, principal investigator in the Institute for Genomic Medicine at Nationwide Children’s. “So, it was striking to us that we were treating two patients with Rasmussen encephalitis around the same time.”
Dr. Bedrosian and colleagues compared gene expression signatures of individual cells of resected brain tissue samples from the two children with Rasmussen encephalitis to those from two age-matched individuals with unaffected brain tissue and no history of epilepsy nor immune disease and those from two individuals with Type I focal cortical dysplasia with no known immunological pathology, which served as an epilepsy control.
They found the tissues from children with Rasmussen encephalitis not only contained more microglia — more than twice as many per amount of tissue — but also were enriched with distinct microglial populations compared with the tissues from the two other groups of children. Specifically, the team found that microglia in Rasmussen encephalitis tissues had increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation.
“Microglia can exist in different states, and they can be anywhere on a spectrum of activity from quiescent to activated. In this study, we were able to tease out these different populations of microglia within the diseased brain tissue and see that, based on their gene expression patterns, different subtypes are likely performing different functions,” explains Dr. Bedrosian.
The researchers then extended their findings using spatial proteomic analysis of tissue from four surgical resections collected from a biobank. This allowed them to examine the expression profiles of the microglia within their pathological context. They found that some microglia were spatially aggregated into nodules, which can be thought of as hot spots of immune activation, says Dr. Bedrosian, and have been reported previously as a key precedent to cytotoxic T-cell infiltration in Rasmussen encephalitis. These aggregated microglia showed increased expression of immune regulatory proteins, such as PD-L1, CD14, and CD11c, and T-cell activation markers, including CD40 and CD80. They were also physically located close to distinct CD4+ and CD8+ T-cell populations, which may be damaging the brain in these regions, adds Dr. Bedrosian.
“These findings serve as a stepping stone. The next step is to continue with the identification and characterization of the various cell populations and link them to differences in seizure activity and physiology,” says study co-author Jeffery Leonard, MD, chief of Pediatric Neurosurgery at Nationwide Children’s and professor of Neurological Surgery at The Ohio State University College of Medicine. “Our hope is that one day we will determine a treatment strategy that helps these children with this very debilitating disease.”
Westfall JJ, Schwind WN, Sran S, Navarro JB, Leonard J, Pindrik JA, Pierson CR, Boué DR, Koboldt DC, Ostendorf AP, Wilson RK, Mardis ER, Miller KE, Bedrosian TA. Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis. Acta Neuropathology Communications. 2022 Nov 21;10(1):168.
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