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

T.S. Zimmer; D.W.M. Broekaart; M. Luinenburg; C. Mijnsbergen; J.J. Anink; N.S. Sim; I. Michailidou; F.E. Jansen; P.C. van Rijen; J.H. Lee; L. François; J. van Eyll; S. Dedeurwaerdere; E.A. van Vliet; A. Mühlebner; J.D. Mills; E. Aronica

doi:https://doi.org/10.1111/nan.12736

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

T.S. Zimmer, D.W.M. Broekaart, M. Luinenburg, C. Mijnsbergen, J.J. Anink, N.S. Sim, I. Michailidou, F.E. Jansen, P.C. van Rijen, J.H. Lee, L. François, J. van Eyll, S. Dedeurwaerdere, E.A. van Vliet, A. Mühlebner, J.D. Mills, E. Aronica

Research output: Contribution to journal › Article › Academic › peer-review

12 Citations (Scopus)

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	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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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{21fa3751ef9847f1bc6f0d5881d3a460,

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 = "T.S. Zimmer and D.W.M. Broekaart and M. Luinenburg and C. Mijnsbergen and J.J. Anink and N.S. Sim and I. Michailidou and F.E. Jansen and {van Rijen}, P.C. and J.H. Lee and L. Fran{\c c}ois and {van Eyll}, J. and S. Dedeurwaerdere and {van Vliet}, E.A. and A. M{\"u}hlebner and J.D. Mills and E. Aronica",

note = "With supplementary file",

year = "2021",

month = oct,

doi = "https://doi.org/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, T.S.

AU - Broekaart, D.W.M.

AU - Luinenburg, M.

AU - Mijnsbergen, C.

AU - Anink, J.J.

AU - Sim, N.S.

AU - Michailidou, I.

AU - Jansen, F.E.

AU - van Rijen, P.C.

AU - Lee, J.H.

AU - François, L.

AU - van Eyll, J.

AU - Dedeurwaerdere, S.

AU - van Vliet, E.A.

AU - Mühlebner, A.

AU - Mills, J.D.

AU - Aronica, E.

N1 - With supplementary file

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 - https://pure.uva.nl/ws/files/64033577/nan12736_sup_0001_supinfo.zip

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

U2 - https://doi.org/10.1111/nan.12736

DO - https://doi.org/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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