Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier

Sivan Gelb; Ariel D. Stock; Shira Anzi; Chaim Putterman; Ayal Ben-Zvi

doi:10.1016/j.jaut.2018.03.001

Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier

Sivan Gelb, Ariel D. Stock, Shira Anzi, Chaim Putterman, Ayal Ben-Zvi

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

51 Scopus citations

Abstract

The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/fas ^lpr/lpr ). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease.

Original language	English
Pages (from-to)	34-44
Number of pages	11
Journal	Journal of Autoimmunity
Volume	91
DOIs	https://doi.org/10.1016/j.jaut.2018.03.001
State	Published - Jul 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Funding

These studies were supported by research grants from the Abisch-Frenkel Foundation ( 15/H1 ) and the Leona M. and Harry B. Helmsley Charitable Trust ( 2015PG-ISL007 ) to A. Ben-Zvi; a RO1 grant from the National Institute of Arthritis and Musculoskeletal Diseases ( AR065594 ) to C. Putterman; and training grant T32-GM007288 to A. Stock from the NIH .

Funders	Funder number
National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR065594, T32-GM007288
Leona M. and Harry B. Helmsley Charitable Trust
Abisch-Frenkel-Stiftung	15/H1

Keywords

Autoantibodies
Blood-CSF barrier (BCSFB)
Blood-brain barrier (BBB)
Choroid plexus (CP)
Lupus
Neuropsychiatric-lupus (NPSLE)

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title = "Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier",

abstract = " The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/fas lpr/lpr ). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease.",

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author = "Sivan Gelb and Stock, {Ariel D.} and Shira Anzi and Chaim Putterman and Ayal Ben-Zvi",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

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doi = "10.1016/j.jaut.2018.03.001",

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AU - Ben-Zvi, Ayal

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AB - The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/fas lpr/lpr ). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease.

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KW - Blood-brain barrier (BBB)

KW - Choroid plexus (CP)

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Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier

Abstract

Bibliographical note

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Keywords

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