Abstract
Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.
Highlights
Involvement of the humoral and cellular effector arms of the adaptive immune system in seizures associated with infection and autoimmunity is well established [1,2,3,4]
We used a NanoString® immune cell profiling oligonucleotide array to measure the expression of immune genes in resected brain tissue from 53 pediatric patients presenting with intractable epilepsy who underwent surgery to control their seizures
From clinical and pathological evaluation, seizures were associated with tuberous sclerosis complex (TSC) (n= 20), focal cortical dysplasia (FCD) (n= 20), RE (n= 5), perinatal arterial ischemic stroke (PAIS) (n= 5), and HME (n=3) (Table S1)
Summary
Involvement of the humoral and cellular effector arms of the adaptive immune system in seizures associated with infection and autoimmunity is well established [1,2,3,4]. Higher numbers of CD8 T cells were reported in sections from FCD type II brain tissue compared with FCD I brain specimens; T cells were observed in close proximity to dysmorphic neurons and balloon cells [8], a distinguishing pathological feature of FCD type II compared with FCD type I [9]. More recently Xu et al reported that immune cells isolated from resected brain tissue from pediatric epilepsy surgeries comprised antigen experienced CD4, CD8 and Th17 gd T cells [10]. In agreement with these observations, we found that effector memory T cells are present in brain tissue that has been removed to treat seizures associated with cortical malformations including FCD, TSC and HME [11]. Almost half of the CD45+ immune cells isolated from the HME brain tissue comprised CD69+ CD4 ab T cells (25.6%) and CD69+ CD8 ab T cells (21.3%), suggesting an antigen driven T cell trafficking to the brain in this HME patient
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