Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1169-1186 |
| Number of pages | 18 |
| Journal | Journal of Experimental Medicine |
| Volume | 215 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2018 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy. / Xu, Dan; Robinson, Andrew P.; Ishii, Toshiyuki; Duncan, D'Anne S.; Alden, Tord D; Goings, Gwendolyn E.; Ifergan, Igal; Podojil, Joseph Robert; Penaloza-MacMaster, Pablo; Kearney, Jennifer A; Swanson, Geoffrey T; Miller, Stephen D; Koh, Sookyong.
In: Journal of Experimental Medicine, Vol. 215, No. 4, 01.04.2018, p. 1169-1186.Research output: Contribution to journal › Article
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 Robert
AU - Penaloza-MacMaster, Pablo
AU - Kearney, Jennifer A
AU - Swanson, Geoffrey T
AU - Miller, Stephen D
AU - Koh, Sookyong
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.
UR - http://www.scopus.com/inward/record.url?scp=85044820342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044820342&partnerID=8YFLogxK
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 -