Serum and Cerebrospinal Fluid Autoantibodies in Patients with Neuropsychiatric Lupus Erythematosus. Implications for Diagnosis and Pathogenesis

Abstract

BackgroundDespite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE).Methodology/Principal FindingsForty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-β2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased.ConclusionIn NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity

“…Mice immunized with a multimerized configuration of DWEYS produce antidsDNA/NMDAR antibodies, display glomerular Ig deposition, and exhibit neuronal damage after a breach of the blood-brain barrier (BBB) that allows transit of these antibodies into the CNS (17). In humans, elevated titers of cross-reactive anti-dsDNA/ NMDAR antibodies are present in the serum of 40% of lupus patients and their presence in CSF of lupus patients correlates with CNS manifestations of neuropsychiatric lupus (NPSLE), which afflicts up to 80% of lupus patients (15,(18)(19)(20)(21)(22). Moreover, human anti-dsDNA/NMDAR antibodies have been eluted from postmortem brain tissue, and such antibodies isolated from lupus patient sera can cause brain damage (e.g., cognitive or behavioral dysfunction) in mice (23,24).…”

Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: a systematic review

“…Three further publications [57][58][59] were obtained from review of the reference lists of included articles.…”

“…Three further publications were obtained from review of the reference lists of included articles [57][58][59] . While one of those 59 showed and association between serum anti-NR2…”

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

“…However, these mechanisms do not account for the majority of symptom complexes associated with NPSLE-in particular, the insidious cognitive decline manifested by up to 80% of lupus patients and the common mood disorders. Recent studies have demonstrated direct neurotoxic effects of lupus autoantibodies; antibodies to n-methyl-D-aspartate receptor (NMDAR), ribosomal P (anti-P), α-tubulin and phospholipid have been shown to bind neurons ex vivo with harmful effects (1)(2)(3)(4)(5) and all have been identified in the cerebrospinal fluid of SLE patients with CNS symptoms attributable to SLE (6)(7)(8)(9). In murine studies, circulating antibrain antibodies can cause neuronal dysfunction and apoptosis after breach of the BBB (5,(10)(11)(12), resulting in functional impairment on cognitive and behavioral tasks, as can antibodies directly injected intraventric- …”