SAT0422 Indirect pathogenic roles of cerebrospinal fluid anti-u1rnp antibodies in the presence of anti-nr2 antibodies in patients with neuropsychiatric systemic lupus erythematosus
Authors: T. Fujii, S. Kondo-Ishikawa, N. Ishigooka, H. Yoshifuji, K. Ohmura, T. Mimori
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Autoantibodies (auto Abs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies indicated that anti-N-methyl <i>d</i>-aspartate receptor NR2 subunit (NR2) Abs have a pathogenic role in NPSLE by BBB abruption.<sup>Hirohata S, <i>et al, Arthritis Res Ther</i>, 2014</sup> We also reported the association between NPSLE and CSF-anti-U1RNP Abs (Sato, <i>et al, A and R</i>, 2010). <h3>Objectives</h3> In the present study, synergistic effects of these auto Abs, their associated IMs, and blood brain barrier (BBB) permeability are determined in NPSLE patients. <h3>Methods</h3> CSF samples were collected from 69 of NPSLE patients at their acute phase and 13 of non-NPSLE control after obtaining the written informed consent. CSF anti-NR2 and anti-U1RNP Abs were determined by ELISA. CSF IL-6, IL-8, and monokine induced by IFN-γ (MIG) were measured by quantitative multiplex cytokine analysis. BBB permeability was evaluated by albumin quotient (<i>Q</i>alb). <h3>Results</h3> 1) CSF IL-6 levels were higher in CSF anti-NR2 Ab +ve (70±178 pg/mL) than in -ve (11±32, p=0.02) patients and in controls (16±40, p=0.003) and positively correlated with anti-NR2 Ab titer (<i>r</i>=0.42, p=0.003). Anti-U1RNP Ab positivity was not associated with CSF IL6 elevation. 2) CSF IL-8 levels were higher in CSF anti-U1RNP Ab +ve than in –ve (270±862 vs. 52±177 pg/mL, p=0.04) patients. Anti-NR2 Ab positivity was not involved in CSF IL8 elevation. 3) CSF MIG levels were more elevated in both CSF anti-NR2 +ve (4483±11845 pg/mL, p=0.04) and anti-U1RNP Ab +ve (5519±13504, p=0.03) patients than in controls (115±125). 4) All the patients were divided into 4 groups: CSF anti-NR2 +ve/anti-U1RNP+ve (double positive [DP], n=9), anti-NR2 +ve/anti-U1RNP -ve (aNR2, n=15), anti-NR2 -ve/anti-U1RNP+ve (aU1RNP, n=9), and anti-NR2 -ve/anti-U1RNP -ve (double negative [DN], n=36). In comparison between DP and aNR2 groups, anti-U1RNP Abs had a synergistic effect on CSF IL-6 elevation (150±260 vs. 18±44 pg/mL, p=0.03) that is not directly associated with anti-U1RNP Ab positivity. In comparison with aNR2 group, both CSF IL-8 (543±1198 vs. 43±102 pg/mL, p=0.04) and MIG (10104±17 748 vs. 1111±2584 pg/mL, p=0.03) levels, which were positively correlated with CSF anti-U1RNP Ab titer, were more elevated in DP group. 5) <i>Q</i>alb was positively correlated with CSF IL-8 (<i>r</i>=0.51, p&lt;0.0001) and MIG (<i>r</i>=0.44, p=0.0003), suggesting that CSF anti-U1RNP Ab positivity is involved in the BBB abruption. Actually, <i>Q</i>alb (x10<sup>3</sup>) tended to be higher in DP than in aNR2 group (13±9 vs. 9±8, p=0.06) and CSF anti-NR2 Ab titer appeared to be more elevated in DP than in aNR2 group (81±47 vs. 57±21, p=0.06). <h3>Conclusions</h3> The present study suggested that anti-NR2 and U1RNP Abs have synergistic effects on CSF IL-6 elevation in patients with NPSLE. CSF IL-6 level was associated with anti-NR2 Ab titers, which depend on BBB permeability. CSF anti-U1RNP Ab-mediated IL-8 and MIG elevation may induce BBB abruption followed by anti-NR2 Ab penetration into CSF. <h3>References</h3> [1] Sato T, Fujii T, et al. Arthritis Rheum2010;62:3730. [2] Yokoyama T, Fujii T, et al. Lupus2014;23:635. <h3>Acknowledgements</h3> The present study is supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology. <h3>Disclosure of Interest</h3> None declared