Balloon cells promote immune system activation in focal cortical dysplasia type 2B

Till S Zimmer; Diede W M Broekaart; Mark Luinenburg; Caroline Mijnsbergen; Jasper J Anink; Nam Suk Sim; Iliana Michailidou; Floor E Jansen; Peter C van Rijen; Jeong Ho Lee; Liesbeth François; Jonathan van Eyll; Stefanie Dedeurwaerdere; Erwin A van Vliet; Angelika Mühlebner; James D Mills; Eleonora Aronica

doi:10.1111/nan.12736

Balloon cells promote immune system activation in focal cortical dysplasia type 2B

Till S Zimmer, Diede W M Broekaart, Mark Luinenburg, Caroline Mijnsbergen, Jasper J Anink, Nam Suk Sim, Iliana Michailidou, Floor E Jansen, Peter C van Rijen, Jeong Ho Lee, Liesbeth François, Jonathan van Eyll, Stefanie Dedeurwaerdere, Erwin A van Vliet, Angelika Mühlebner, James D Mills, Eleonora Aronica

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Abstract

AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro-epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.

METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well-characterised FCD 2 cohort.

RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T-lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions.

CONCLUSION: We conclude that, next to mutation-driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b.

Original language	English
Pages (from-to)	826-839
Number of pages	14
Journal	Neuropathology and Applied Neurobiology
Volume	47
Issue number	6
Early online date	8 Jun 2021
DOIs	https://doi.org/10.1111/nan.12736
Publication status	Published - Oct 2021

Keywords

balloon cells
focal cortical dysplasia
immune system
inflammation

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Neuropathology Appl Neurobio - 2021 - Zimmer - Balloon cells promote immune system activation in focal cortical dysplasiaFinal published version, 3.3 MBLicence: CC BY-NC-ND

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Zimmer, T. S., Broekaart, D. W. M., Luinenburg, M., Mijnsbergen, C., Anink, J. J., Sim, N. S., Michailidou, I., Jansen, F. E., van Rijen, P. C., Lee, J. H., François, L., van Eyll, J., Dedeurwaerdere, S., van Vliet, E. A., Mühlebner, A., Mills, J. D., & Aronica, E. (2021). Balloon cells promote immune system activation in focal cortical dysplasia type 2B. Neuropathology and Applied Neurobiology, 47(6), 826-839. https://doi.org/10.1111/nan.12736

@article{965de74069a44f6f9c7cfe25f00a2699,

title = "Balloon cells promote immune system activation in focal cortical dysplasia type 2B",

abstract = "AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro-epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well-characterised FCD 2 cohort.RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T-lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions.CONCLUSION: We conclude that, next to mutation-driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b.",

keywords = "balloon cells, focal cortical dysplasia, immune system, inflammation",

author = "Zimmer, {Till S} and Broekaart, {Diede W M} and Mark Luinenburg and Caroline Mijnsbergen and Anink, {Jasper J} and Sim, {Nam Suk} and Iliana Michailidou and Jansen, {Floor E} and {van Rijen}, {Peter C} and Lee, {Jeong Ho} and Liesbeth Fran{\c c}ois and {van Eyll}, Jonathan and Stefanie Dedeurwaerdere and {van Vliet}, {Erwin A} and Angelika M{\"u}hlebner and Mills, {James D} and Eleonora Aronica",

note = "Funding Information: LF, JVE and SD were employees of UCB Pharma at the time of research. AE and JM are financially supported by an unrestricted grant from UCB Pharma. Funding Information: The research leading to these results has received funding from the European Union?s Seventh Framework Programme (FP7/2007?2013) under grant agreement no. 602391 (EPISTOP; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the European Union?s Horizon 2020 WIDESPREAD-05-2020?Twinning (EpiEpiNet; EA, EAvV), grant agreement no. 952455, the Dutch Epilepsy Foundation, project number 16-05, 20-11 (DWMB, EAvV) and 20-02 (AM, ML); the European Union?s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 722053 (EU-GliaPhD; TSZ, EA); ZonMw, Programme Translational Research no. 95105004 (EA); an unrestricted grant from UCB Pharma (AE, JM); Prinses Beatrix Spierfonds, Grant application no: W.OR14 to Frank Baas (IM). Funding Information: The research leading to these results has received funding from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602391 (EPISTOP; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the European Union{\textquoteright}s Horizon 2020 WIDESPREAD‐05‐2020–Twinning (EpiEpiNet; EA, EAvV), grant agreement no. 952455, the Dutch Epilepsy Foundation, project number 16‐05, 20‐11 (DWMB, EAvV) and 20‐02 (AM, ML); the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska‐Curie grant agreement no. 722053 (EU‐GliaPhD; TSZ, EA); ZonMw, Programme Translational Research no. 95105004 (EA); an unrestricted grant from UCB Pharma (AE, JM); Prinses Beatrix Spierfonds, Grant application no: W.OR14 to Frank Baas (IM). Publisher Copyright: {\textcopyright} 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society",

year = "2021",

month = oct,

doi = "10.1111/nan.12736",

language = "English",

volume = "47",

pages = "826--839",

journal = "Neuropathology and Applied Neurobiology",

issn = "0305-1846",

publisher = "Wiley-Blackwell",

number = "6",

}

Zimmer, TS, Broekaart, DWM, Luinenburg, M, Mijnsbergen, C, Anink, JJ, Sim, NS, Michailidou, I, Jansen, FE, van Rijen, PC, Lee, JH, François, L, van Eyll, J, Dedeurwaerdere, S, van Vliet, EA, Mühlebner, A, Mills, JD & Aronica, E 2021, 'Balloon cells promote immune system activation in focal cortical dysplasia type 2B', Neuropathology and Applied Neurobiology, vol. 47, no. 6, pp. 826-839. https://doi.org/10.1111/nan.12736

TY - JOUR

T1 - Balloon cells promote immune system activation in focal cortical dysplasia type 2B

AU - Zimmer, Till S

AU - Broekaart, Diede W M

AU - Luinenburg, Mark

AU - Mijnsbergen, Caroline

AU - Anink, Jasper J

AU - Sim, Nam Suk

AU - Michailidou, Iliana

AU - Jansen, Floor E

AU - van Rijen, Peter C

AU - Lee, Jeong Ho

AU - François, Liesbeth

AU - van Eyll, Jonathan

AU - Dedeurwaerdere, Stefanie

AU - van Vliet, Erwin A

AU - Mühlebner, Angelika

AU - Mills, James D

AU - Aronica, Eleonora

N1 - Funding Information: LF, JVE and SD were employees of UCB Pharma at the time of research. AE and JM are financially supported by an unrestricted grant from UCB Pharma. Funding Information: The research leading to these results has received funding from the European Union?s Seventh Framework Programme (FP7/2007?2013) under grant agreement no. 602391 (EPISTOP; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the European Union?s Horizon 2020 WIDESPREAD-05-2020?Twinning (EpiEpiNet; EA, EAvV), grant agreement no. 952455, the Dutch Epilepsy Foundation, project number 16-05, 20-11 (DWMB, EAvV) and 20-02 (AM, ML); the European Union?s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 722053 (EU-GliaPhD; TSZ, EA); ZonMw, Programme Translational Research no. 95105004 (EA); an unrestricted grant from UCB Pharma (AE, JM); Prinses Beatrix Spierfonds, Grant application no: W.OR14 to Frank Baas (IM). Funding Information: The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602391 (EPISTOP; EA, FJ) and no. 602102 (EPITARGET; EAvV, EA), the European Union’s Horizon 2020 WIDESPREAD‐05‐2020–Twinning (EpiEpiNet; EA, EAvV), grant agreement no. 952455, the Dutch Epilepsy Foundation, project number 16‐05, 20‐11 (DWMB, EAvV) and 20‐02 (AM, ML); the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska‐Curie grant agreement no. 722053 (EU‐GliaPhD; TSZ, EA); ZonMw, Programme Translational Research no. 95105004 (EA); an unrestricted grant from UCB Pharma (AE, JM); Prinses Beatrix Spierfonds, Grant application no: W.OR14 to Frank Baas (IM). Publisher Copyright: © 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society

PY - 2021/10

Y1 - 2021/10

N2 - AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro-epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well-characterised FCD 2 cohort.RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T-lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions.CONCLUSION: We conclude that, next to mutation-driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b.

AB - AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro-epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well-characterised FCD 2 cohort.RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T-lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions.CONCLUSION: We conclude that, next to mutation-driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b.

KW - balloon cells

KW - focal cortical dysplasia

KW - immune system

KW - inflammation

UR - http://www.scopus.com/inward/record.url?scp=85107551902&partnerID=8YFLogxK

U2 - 10.1111/nan.12736

DO - 10.1111/nan.12736

M3 - Article

C2 - 34003514

SN - 0305-1846

VL - 47

SP - 826

EP - 839

JO - Neuropathology and Applied Neurobiology

JF - Neuropathology and Applied Neurobiology

IS - 6

ER -

Balloon cells promote immune system activation in focal cortical dysplasia type 2B

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