Objective: Myasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplification of chronic inflammatory disorders and autoimmune diseases. We sought to investigate the role of RAGE and its ligands in the pathophysiology of MG. Methods: In this cross-sectional study we enrolled 42 patients with MG and 36 volunteers. we employed enzyme-linked immunosorbent assays to determine the concentration of soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1) in serum of patients and volunteers. In a subpopulation of patients we measured the serum levels of endogenous secretory (es) RAGE and various RAGE ligands, such as S100B, S100A8 and advanced glycation endproducts (AGE-CML). Reported are means and standard error mean. Results: We found significantly reduced levels of the soluble receptors sRAGE and esRAGE in patients with MG compared to volunteers without MG (sRAGE [pg/ml] 927.2 +/- 80.8 vs. 1400.1 +/- 92.4; p < 0.001 esRAGE [pg/ml] 273.5 +/- 24.6 vs. 449.0 +/- 22.4; p < 0.001). Further categorization of patients with MG according to the distribution of muscle involvement revealed the following sRAGE concentrations: generalized MG 999.4 +/- 90.8 and ocular MG 696.1 +/- 161.8 (vs. control; One-way ANOVA: p < 0.001: Post hoc analysis: generalized vs. ocular MG: p = 0.264, generalized MG vs. control: p = 0.008, ocular MG vs. control: p =0.001). In patients with detectable antibodies specific for acetylcholine receptors (Anti-AChR positive) the sRAGE concentration was 970.0 +/- 90.2 compared to those without (seronegative) 670.6 +/- 133.1 (vs. control; One-way ANOVA: p < 0.001; Post hoc analysis: Pos vs. Neg.: p = 0.418, Pos vs. control: p = 0.003, Neg. vs. control: p = 0.008). We next investigated the role of RAGE ligands in MG. The concentrations of RAGE ligands in patients with MG and controls were as follows: (HMGB1 [ng/ml] 1.7 +/- 0.1 vs. 2.1 +/- 0.2; p = 0.058; S100B [pg/ml] 22.5 +/- 22.5 vs. 14.4 +/- 9.2; p = 0.698; S100A8 [pg/ml] 107.0 +/- 59.3 vs. 242.5 +/- 103.6; p = 0.347; and AGE-CML [ng/ml] 1100.8 +/- 175.1 vs. 1399.8 +/- 132.8; p = 0.179). Conclusions: Our data suggest a role for the RAGE pathway in the pathophysiology of MG. Further studies are warranted to elucidate more about this immunological axis in patients with MG. (C) 2012 Elsevier Inc. All rights reserved.