Background/Purpose: Autoantibodies (auto Abs) in cerebrospinal fluid (CSF) and inflammatory mediators (IMs) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies revealed that auto Abs such as anti-NMDA(N-methyl D-aspartate) receptor NR2 subunit (NR2) Abs are linked to a certain kind of NPSLE. We reported the association between NPSLE and CSF-anti-U1RNP Abs. What kinds of IMs in the central nervous system are stimulated by these Abs, however, remains unknown. The aim of the present study is to determine the association of both Abs with neurotoxic IMs.

Methods: Serum and CSF samples were obtained from NPSLE patients with diffuse NPSLE (n=39) or focal NPSLE (n=35), and non-NPSLE patients (control, n=13). Serum- and CSF-anti-NR2 Abs were determined by ELISA. Serum- and CSF-anti-U1RNP Ab positivity and titer were determined by RNA-immunoprecipitation assay and ELISA, respectively. CSF-IL-6, IL-8, and monokine induced by IFN-γ(MIG), which were reported to be neurotoxic, were measured by quantitative multiplex cytokine analysis. To elucidate the possibility that these IMs pass through blood-brain barrier (BBB), the permeability of BBB was evaluated by albumin quotient (Qalb).

Results: 1) IL-6 (67.4 vs. 17.5 pg/mL, p=0.02) and MIG (4307 vs. 109 pg/mL, p=0.03) levels, but not IL-8, were higher in CSF-anti-NR2 Ab-positive patients than controls. IL-6 level was higher in serum-anti-NR2 Ab-positive patients than in controls (50.0 vs. 17.4 pg/mL, p=0.03). There was no association of CSF-IMs with serum- and CSF-anti-NR2 Ab titer. CSF-anti-NR2 Ab positivity and titers were correlated with an increased permeability of BBB, as previously reported. 2) MIG level, but not IL-6 or IL-8, was higher in CSF-anti-U1RNP Ab-positive patients than in controls (2142 vs. 109 pg/mL, p=0.04). CSF-IMs were not correlated with serum-anti-U1RNP Ab titer. MIG level tended to positively correlated with CSF-anti-U1RNP Ab titer (r=0.49, p=0.07). 3) All the NPSLE patients were divided into 4 groups: CSF-anti-NR2 Ab +/U1RNP+ (double positive [DP], n=7), anti-NR2 Ab+/U1RNP- (NR2, n=18), anti-NR2-/U1RNP+ (U1RNP, n=9), anti-NR2 Ab-/U1RNP- (double negative [DN], n=40). In CSF-DP group, IL-6 and MIG levels, but not IL-8, were higher than in NR2 and U1RNP groups. 4) Qalb was positively correlated with IL-8 (r=0.45, p<0.0001) and MIG (r=0.56, p<0.0001) levels. Elevated CSF-IL-6 level, however, was not associated with an increased permeability of BBB. 5) The frequency of diffuse NPSLE in CSF-DP group (71%) tended to be higher than in the other groups. Auto Ab positivity was not associated with the brain MRI abnormalities.

Conclusion: CSF-IL-6 level was closely associated with the presence of CSF-anti-NR2 Abs, but not correlated with the BBB permeability. CSF-MIG level was associated with the presence of CSF-auto Abs and the BBB permeability. CSF-IL-8 level might be dependent of the BBB permeability alone. Thus, the involvements of auto Abs in CSF and BBB permeability in neurotoxic IM activation of NPSLE patients are different one another. The present study also suggests that NPSLE with both anti-NR2 and U1RNP Abs in CSF may have more severe manifestations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-anti-nr2-and-u1rnp-antibodies-with-neurotoxic-inflammatory-mediators-in-cerebrospinal-fluid-from-patients-with-neuropsychiatric-systemic-lupus-erythematosus/