Introduction
Neuropsychiatric SLE (NPSLE) is one of the recalcitrant complications of the disease, leading to substantial impairment of quality of life as well as disability.1 Among a variety of manifestations in NPSLE, acute confusional state (ACS) in diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE) is the most serious one, requiring extensive immunosuppressive therapy and sometimes resulting in poor prognosis.1 2
N-Methyl-d-aspartate (NMDA) receptors are one of the glutamate receptor families.3 Recently, it has been disclosed that autoantibodies to NMDA receptor subunit NR2 (anti-NR2) play an important role in the development of brain damages in mouse.4 More importantly, it was shown that such neuronal damage requires the influx of anti-NR2 into the central nervous system (CNS) through a breakdown of the blood–brain barrier (BBB).5
In human, it was also found that cerebrospinal fluid (CSF) anti-NR2, but not serum anti-NR2, were significantly higher in diffuse NPSLE than in focal NPSLE.6 Furthermore, CSF anti-NR2 were shown to be elevated in patients with ACS compared with those in non-ACS diffuse NPSLE or in focal NPSLE.7 More importantly, the elevation of CSF anti-NR2 in patients with ACS has been shown to result from the damage of BBB, but not from the increased intrathecal production thereof.7 Thus, it has been demonstrated that BBB damages play a crucial role in the pathogenesis of diffuse NPSLE, especially ACS. However, the mechanism of the BBB breakdown in NPSLE remained unclear.
Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disorder of the CNS.8 Previous studies discovered that serum IgG from patients with NMOSD contained autoantibodies specific for aquaporin-4 (anti-AQP4), the brain’s main water channel protein, primarily expressed on CNS astrocytes.9 Thus, detection of anti-AQP4 in sera from patients facilitates clinical diagnosis of NMOSD.10 However, it remained unclear how anti-AQP4 penetrates BBB to access astrocytes.
Glucose-regulated protein 78 (GRP78) is a stress protein belonging to the Hsp70 multigene family.11 Previous studies demonstrated that GRP78 is expressed on the surface of cell membrane and is released on activation.11 Moreover, it was found that small amounts of free GRP78 as well as naturally occurring anti-GRP78 autoantibodies were detected in the peripheral blood of normal healthy individuals.11 Of note, it was demonstrated that high titres of autoantibodies to GRP78 were induced in mice immunised with recombinant Ro52.12 Thus, it was suggested that the association of immunogenic proteins with GRP78 might promote autoimmune responses, including those to GRP78 itself.12
Cell surface expression of GRP78 in human lung microvascular endothelial cells or human umbilical vascular endothelial cells has been described, but no consistent relationship to endothelial integrity has been reported.13 14 Recently, Shimizu et al have demonstrated that GRP78 is localised on the cell surface of brain microvascular endothelial cells.15 Thus, they have identified antibodies from a panel of monoclonal recombinant antibodies established from CSF plasmablasts of patients with NMOSD that strongly bound to brain microvascular endothelial cells and decreased their expression of claudin5.15 Unbiased membrane proteomics identified GRP78 as the target of these recombinant autoantibodies.15 Accordingly, repeated administration of anti-GRP78 caused extravasation of serum albumin, IgG and fibrinogen in mice.15 Thus, it has been suggested that anti-GRP78 antibodies might facilitate the entry of anti-AQP4 into the CNS, allowing the access of these antibodies to astrocytes and resulting in NMO attacks.15
The expression of a variety of autoantibodies is a hallmark of SLE.16 It is thus possible that anti-GRP78 might be expressed in patients with SLE. The current studies were therefore designed in order to examine whether anti-GRP78 might be involved in the development of NPSLE.