Association of cerebrospinal fluid anti-Sm antibodies with acute confusional state in systemic lupus erythematosus

Abstract

IntroductionNeuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. Previous studies revealed the strong association between serum anti-Sm and organic brain syndrome, consisting mainly of acute confusional state (ACS) of diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE). However, the precise mechanism by which anti-Sm causes diffuse NPSLE remains unclear. Of note, recent studies demonstrated that anti-U1 RNP antibodies (anti-RNP) in cerebrospinal fluid (CSF) are associated with NPSLE. The present study was designed to explore the association of anti-Sm antibodies in CSF with NPSLE.MethodsPaired serum and CSF specimens were obtained from 72 patients with NPSLE (49 with diffuse NPSLE, 23 with neurological syndromes or peripheral neuropathy (focal NPSLE) and from 22 control patients with non-SLE neurological diseases. Sera were also obtained from 41 patients with active SLE without neuropsychiatric manifestations (non-NPSLE). Anti-Sm and anti-RNP were measured by enzyme-linked immunosorbent assay (ELISA). Blood-brain barrier (BBB) function and intrathecal anti-Sm production were evaluated by Q albumin and CSF anti-Sm index, respectively. Binding of anti-Sm to neuroblastoma cell lines SK-N-MC and Neuro2a was examined by flow cytometry and by cell ELISA.ResultsAnti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control. CSF anti-Sm, but not CSF anti-RNP, was significantly elevated in ACS compared with non-ACS diffuse NPSLE or with focal NPSLE. By contrast, there were no significant differences in serum anti-Sm or anti-RNP among subsets of NPSLE and non-NPSLE. Whereas there were no significant differences in CSF anti-Sm index, Q albumin was elevated in ACS compared with non-ACS or with focal NPSLE. Notably, CSF anti-Sm was correlated with Q albumin (r = 0.2373, P = 0.0447) or with serum anti-Sm (r = 0.7185, P <0.0001) in 72 patients with NPSLE. Finally, monoclonal anti-Sm and purified human anti-Sm bound to the surface of SK-N-MC and Neuro2a.ConclusionsThese results demonstrate that the elevation of CSF anti-Sm through transudation from systemic circulation due to damaged BBB plays a critical role in the pathogenesis of ACS. More importantly, the data indicate that anti-Sm is yet another autoantibody with presumed neural toxicity, but might not be the last.

Differential activation mechanisms of serum C5a in lupus nephritis and neuropsychiatric systemic lupus erythematosus

“…As is consistent with previous studies [5], Q albumin values were significantly elevated in diffuse NPSLE (8.87 ± 6.96) compared with in focal NPSLE (4.74 ± 2.81) (p ¼ 0.033) (Figure 3, left). There were no significant differences in CSF C5a or in serum C5a between diffuse NPSLE and focal NPSLE (Figure 3, middle and right).…”

“…It is therefore suggested that C5a might be involved in BBB damages in human SLE. Of note, we have recently disclosed that anti-Sm antibodies and anti-NR2 antibodies play important roles in acute confusional state (ACS), the severest form of diffuse NPSLE [4,5]. More importantly, the elevation of these antibodies in CSF was shown to result mainly from BBB damages rather than the increased production in CNS [4,28].…”

“…Previous studies showed that antibodies to NMDA receptor NR2 subunit (anti-NR2) in CSF, but not those in sera, were closely associated with diffuse psychiatric/neuropsychological manifestation in SLE (diffuse NPSLE) [4]. We have recently demonstrated that anti-Sm antibodies as well as anti-NR2 were elevated in CSF from patients with acute confusional state of NPSLE through the damage of blood-brain barriers (BBB) [5]. However, the mechanism of the BBB breakdown in SLE remained unclear.…”

Neuropsychiatric Lupus in clinical practice

“…It has been associated with the presence of anti-NR2 antibodies and anti-Sm antibodies in the CSF 10,28 . The pathogenic mechanism behind this diffuse neuropsychiatric manifestation seems to be primarily inflammatory with increased production of inflammatory mediators, BBB disruption, and intrathecal immune complex formation 6 .…”

“…Potential pathogenic mechanisms in primary NPSLE are direct action of intrathecal inflammatory cytokines, blood-brain barrier (BBB) disruption, accelerated atherosclerosis and thrombotic vasculopathy caused by aPL antibodies 4 . Autoantibodies may also bind to neurons leading to neuronal dysfunction and apoptosis 7,10 (Table 2).…”