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.
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.
Authors: Bernhard Moser; Stefan Janik; Ana-Iris Schiefer; Leonhard Müllauer; Christine Bekos; Anke Scharrer; Michael Mildner; Ferenc Rényi-Vámos; Walter Klepetko; Hendrik Jan Ankersmit Journal: PLoS One Date: 2014-04-04 Impact factor: 3.240
Authors: S Janik; A I Schiefer; C Bekos; P Hacker; T Haider; J Moser; W Klepetko; L Müllauer; H J Ankersmit; B Moser Journal: Sci Rep Date: 2016-04-21 Impact factor: 4.379