TY - JOUR
T1 - Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica
AU - Shimizu, Fumitaka
AU - Schaller, Kristin L.
AU - Owens, Gregory P.
AU - Cotleur, Anne C.
AU - Kellner, Debra
AU - Takeshita, Yukio
AU - Obermeier, Birgit
AU - Kryzer, Thomas J.
AU - Sano, Yasuteru
AU - Kanda, Takashi
AU - Lennon, Vanda A.
AU - Ransohoff, Richard M.
AU - Bennett, Jeffrey L.
N1 - Funding Information:
We thank A. Navarro for assistance in animal injections and perfusions, K. Blauth and Y. Liu for assistance in confocal microscopy, and H. Schumann and K. Hickey for assistance in rAb production (all from the University of Colorado Denver, School of Medicine). We thank G. Marsh (Biogen) for providing us with primary MECs from human kidney or lung. Funding: This work was funded with support from the Guthy-Jackson Charitable Foundation (to J.L.B. and R.M.R.), the NIH (EY022936 to J.L.B., NS072141 to G.P.O., K2471540 to R.M.R., and UM1AI110498 to J.L.B. and G.P.O.), and the National Multiple Sclerosis Society (to J.L.B. and G.P.O.).
Publisher Copyright:
© Copyright 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017/7/5
Y1 - 2017/7/5
N2 - Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell-targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) frompatients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs). Exposure of BMECs to these rAbs resulted in nuclear translocation of nuclear factor κB p65, decreased claudin-5 protein expression, and enhanced transit of macromolecules. Unbiased membrane proteomics identified glucose-regulated protein 78 (GRP78) as the rAb target. Using immobilized GRP78 to deplete GRP78 antibodies from pooled total immunoglobulin G (IgG) of 50 NMO patients (NMO-IgG) reduced the biological effect ofNMO-IgG onBMECs. GRP78 was expressed on the surface ofmurineBMECs in vivo, and repeated administration of a GRP78-specific rAb caused extravasation of serum albumin, IgG, and fibrinogen into mouse brains. Our results identify GRP78 antibodies as a potential component ofNMO pathogenesis and GRP78 as a candidate target for promoting central nervous system transit of therapeutic antibodies.
AB - Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell-targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) frompatients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs). Exposure of BMECs to these rAbs resulted in nuclear translocation of nuclear factor κB p65, decreased claudin-5 protein expression, and enhanced transit of macromolecules. Unbiased membrane proteomics identified glucose-regulated protein 78 (GRP78) as the rAb target. Using immobilized GRP78 to deplete GRP78 antibodies from pooled total immunoglobulin G (IgG) of 50 NMO patients (NMO-IgG) reduced the biological effect ofNMO-IgG onBMECs. GRP78 was expressed on the surface ofmurineBMECs in vivo, and repeated administration of a GRP78-specific rAb caused extravasation of serum albumin, IgG, and fibrinogen into mouse brains. Our results identify GRP78 antibodies as a potential component ofNMO pathogenesis and GRP78 as a candidate target for promoting central nervous system transit of therapeutic antibodies.
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U2 - 10.1126/scitranslmed.aai9111
DO - 10.1126/scitranslmed.aai9111
M3 - Article
C2 - 28679661
AN - SCOPUS:85021950257
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 397
M1 - aai9111
ER -