GRP78 Antibodies Are Associated With Blood-Brain Barrier Breakdown in Anti–Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disorder

Abstract

Background and ObjectivesTo analyze (1) the effect of immunoglobulin G (IgG) from patients with anti–myelin oligodendrocyte glycoprotein antibody (MOG-Ab)–associated disorder on the blood-brain barrier (BBB) endothelial cells and (2) the positivity of glucose-regulated protein 78 (GRP78) antibodies in MOG-Ab–associated disorders.MethodsIgG was purified from sera with patients with MOG-Ab–associated disorder in the acute phase (acute MOG, n = 15), in the stable stage (stable MOG, n = 14), healthy controls (HCs, n = 9), and disease controls (DCs, n = 27). Human brain microvascular endothelial cells (BMECs) were incubated with IgG, and the number of nuclear NF-κB p65-positive cells in BMECs using high-content imaging system and the quantitative messenger RNA change in gene expression over the whole transcriptome using RNA-seq were analyzed. GRP78 antibodies from patient IgGs were detected by Western blotting.ResultsIgG in the acute MOG group significantly induced the nuclear translocation of NF-κB and increased the vascular cell adhesion molecule 1/intercellular adhesion molecule 1 expression/permeability of 10-kDa dextran compared with that from the stable MOG and HC/DC groups. RNA-seq and pathway analysis revealed that NF-κB signaling and oxidative stress (NQO1) play key roles. The NQO1 and Nrf2 protein amounts were significantly decreased after exposure to IgG in the acute MOG group. The rate of GRP78 antibody positivity in the acute MOG group (10/15, 67% [95% confidence interval, 38%–88%]) was significantly higher than that in the stable MOG group (5/14, 36% [13%–65%]), multiple sclerosis group (4/29, 14% [4%–32%]), the DCs (3/27, 11% [2%–29%]), or HCs (0/9, 0%). Removal of GRP78 antibodies from MOG-IgG reduced the effect on NF-κB nuclear translocation and increased permeability.DiscussionGRP78 antibodies may be associated with BBB dysfunction in MOG-Ab–associated disorder.

Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases

“…The mechanism by which the anti-GRP78 antibodies break the permeability of the BBB involves their binding to the scGRP78 on the brain microvascular endothelial cells (BMECs), inducing nuclear translocation of NF-κB that facilitates ICAM-1 transcription and promotes binding of activated immune cells that enhance the diameter of cerebral blood vessels in [ 58 ]. Similar mechanisms have been observed with anti-GRP78 antibodies in AMOGAD [ 56 ] and LEMS [ 8 ] that induce brain endothelial cells to open the BBB, thereby allowing access to other pathogenic antibodies in the CNS. A compromised BBB and antiendothelial cell antibodies have been found in patients with SLE [ 68 ], suggesting that csGRP78 in brain endothelial cells may also be a target of antiGRP78 antibodies in SLE [ 69 ].…”

“…GRP78 autoantibodies have been identified in MS [ 54 ], NPSLE [ 55 ], AMOGAD [ 56 ], LEMS [ 8 ], and NMO [ 57 ]. MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by the presence of focal demyelinated plaques within the white matter [ 58 ].…”

“…AMOGAD was recently recognized as a new pathology in the spectrum of inflammatory diseases, which differs from either MS or NMO. The serum levels of anti-GRP78 antibodies in patients with AMOGAD are significantly higher than those of MS patients or healthy controls [ 56 ]. LEMS is an autoimmune disease of the neuromuscular junction commonly defined as a paraneoplastic neurological syndrome, involving muscle weakness, areflexia and autonomic dysfunction [ 62 ].…”

Pathomechanisms in demyelination and astrocytopathy: autoantibodies to AQP4, MOG, GFAP, GRP78 and beyond

“…Similar as for the detection of AQP4-IgG or MOG-IgG and GFAP antibodies, the establishment of a high throughput cell-based assay that allows detection of GRP78 antibodies on the cell surface of mammalian cells will be required to understand the presence of this antibody in a large set of patients and controls. In NMOSD, the presence of GRP78 antibodies was associated with LETM phenotype [91], whereas in MOGAD the rate of GRP78 antibody positivity was higher in the acute MOGAD group compared to patients with a stable MOGAD disease [90 ▪ ].…”

Autoimmune diseases and cancers overlapping with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): A systematic review

“…MOGAD was perceived primarily as a monophasic CNS inflammatory disease, but further observations showed that a relapsing course occur in 28–60% of patients, and in up to 83% of cases with long-term observation, especially those with persistent positive MOG-IgG status. 99,143 Some evidence of subclinical disease activity and progression has been shown to be present in some of the patients with MOGAD. 2 Patients with anti-NMDAR-EN tend to have more severe neurologic presentations, and poor long-term functional outcomes, and the mortality rate has been reported between 5% and 7%.…”