TY - JOUR
T1 - Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy
AU - Xu, Dan
AU - Robinson, Andrew P.
AU - Ishii, Toshiyuki
AU - Duncan, D'Anne S.
AU - Alden, Tord D.
AU - Goings, Gwendolyn E.
AU - Ifergan, Igal
AU - Podojil, Joseph R.
AU - Penaloza-MacMaster, Pablo
AU - Kearney, Jennifer A.
AU - Swanson, Geoffrey T.
AU - Miller, Stephen D.
AU - Koh, Sookyong
N1 - Funding Information:
We acknowledge S. Swaminathan, P. Mehl, and C. Ostiguin at Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility for the assistance of data acquisition. We thank J. Rappoport and C. Arvanitis at Northwestern University Center for Advanced Microscopy for their support in data acquisition. We acknowledge the important contribution of the patients and their guardians who have donated resected brain and blood samples for our study. We thank Miller laboratory members for all the support and insightful comments. This work was supported by National Institutes of Health grants R01 NS073768 and R21 NS094999 to S.D. Miller and S. Koh and Epilepsy Foundation fellowships 262243 to D. Xu and 1K22 AI118421 to P. Penaloza-MacMaster
Publisher Copyright:
© 2018 Xu et al.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.
AB - The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity. Conversely, numbers of regulatory T (T reg) cells inversely correlated with disease severity. Correspondingly, using the kainic acid model of status epilepticus, we show ameliorated seizure activity in both γδ T cell- and IL-17RA-deficient mice and in recipients of T reg cells, whereas T reg cell depletion heightened seizure severity. Moreover, both IL-17 and GM-CSF induced neuronal hyperexcitability in brain slice cultures. These studies support a major pathological role for peripherally derived innate and adaptive proinflammatory immune responses in the pathogenesis of intractable epilepsy and suggest testing of immunomodulatory therapies.
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U2 - 10.1084/jem.20171285
DO - 10.1084/jem.20171285
M3 - Article
C2 - 29487082
AN - SCOPUS:85044820342
VL - 215
SP - 1169
EP - 1186
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -