Blood-brain barrier damages and intrathecal synthesis of anti-N-methyl-D-aspartate receptor NR2 antibodies in diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

INTRODUCTION Although neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the recalcitrant complications of the disease, its pathogenesis still remains unclear. Previous studies revealed that antibodies reactive with NMDA (N-methyl-D-aspartate) receptor NR2 (anti-NR2) are elevated in cerebrospinal fluid (CSF) of patients with diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE), which is usually more recalcitrant than neurologic syndromes of NPSLE (focal NPSLE). Two mechanisms have been implicated for the elevation of CSF IgG, including intrathecal synthesis and transudation through the damaged blood-brain barrier (BBB). The present study was designed in order to elucidate the roles of BBB function and intrathecal synthesis of anti-NR2 in the elevation of CSF anti-NR2 with regard to the severity in NPSLE. METHODS Paired serum and CSF samples were obtained from 81 systemic lupus erythematosus (SLE) patients when they presented active neuropsychiatric manifestations, and from 22 non-SLE control patients with non-inflammatory neurological diseases. The 81 SLE patients consisted of 55 patients with diffuse NPSLE, including 23 patients with acute confusional state (ACS), the severest form of diffuse NPSLE, and 26 patients with neurologic syndromes or peripheral nervous system involvement (focal NPSLE). IgG anti-NR2 and albumin were measured by ELISA. BBB function and intrathecal synthesis of anti-NR2 were evaluated by Q albumin and by CSF anti-NR2 index, respectively. RESULTS CSF anti-NR2 levels, Q albumin and CSF anti-NR2 index were significantly higher in NPSLE than in non-SLE control. CSF anti-NR2 levels and Q albumin were significantly higher in ACS than in non-ACS diffuse NPSLE (anxiety disorder, cognitive dysfunction, mood disorder and psychosis) or in focal NPSLE, whereas there was no significant difference in CSF anti-NR2 index among the 3 groups. CSF anti-NR2 levels were significantly correlated with Q albumin in diffuse NPSLE (r = 0.3754, P = 0.0053). CONCLUSIONS These results demonstrate that the severity of BBB damages plays a crucial role in the development of ACS, the severest form of diffuse NPSLE, through the accelerated entry of larger amounts of anti-NR2 into the central nervous system.