SAT0422 Indirect pathogenic roles of cerebrospinal fluid anti-u1rnp antibodies in the presence of anti-nr2 antibodies in patients with neuropsychiatric systemic lupus erythematosus

Background 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 d -aspartate receptor NR2 subunit (NR2) Abs have a pathogenic role in NPSLE by BBB abruption. Hirohata S, et al, Arthritis Res Ther , 2014 We also reported the association between NPSLE and CSF-anti-U1RNP Abs (Sato, et al, A and R , 2010). Objectives In the present study, synergistic effects of these auto Abs, their associated IMs, and blood brain barrier (BBB) permeability are determined in NPSLE patients. Methods 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 ( Q alb). Results 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 ( r =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) Q alb was positively correlated with CSF IL-8 ( r =0.51, p r =0.44, p=0.0003), suggesting that CSF anti-U1RNP Ab positivity is involved in the BBB abruption. Actually, Q alb (x10 3 ) 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). Conclusions 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. References [1] Sato T, Fujii T, et al. Arthritis Rheum2010;62:3730. [2] Yokoyama T, Fujii T, et al. Lupus2014;23:635. Acknowledgements The present study is supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology. Disclosure of Interest None declared