Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis
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Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis. / Schroeter, Christina B; Nelke, Christopher; Stascheit, Frauke; Huntemann, Niklas; Preusse, Corinna; Dobelmann, Vera; Theissen, Lukas; Pawlitzki, Marc; Räuber, Saskia; Willison, Alice; Vogelsang, Anna; Marina, Adela Della; Hartung, Hans-Peter; Melzer, Nico; Konen, Felix F; Skripuletz, Thomas; Hentschel, Andreas; König, Simone; Schweizer, Michaela; Stühler, Kai; Poschmann, Gereon; Roos, Andreas; Stenzel, Werner; Meisel, Andreas; Meuth, Sven G; Ruck, Tobias.
In: ACTA NEUROPATHOL, Vol. 147, No. 102, 18.06.2024, p. 102.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis
AU - Schroeter, Christina B
AU - Nelke, Christopher
AU - Stascheit, Frauke
AU - Huntemann, Niklas
AU - Preusse, Corinna
AU - Dobelmann, Vera
AU - Theissen, Lukas
AU - Pawlitzki, Marc
AU - Räuber, Saskia
AU - Willison, Alice
AU - Vogelsang, Anna
AU - Marina, Adela Della
AU - Hartung, Hans-Peter
AU - Melzer, Nico
AU - Konen, Felix F
AU - Skripuletz, Thomas
AU - Hentschel, Andreas
AU - König, Simone
AU - Schweizer, Michaela
AU - Stühler, Kai
AU - Poschmann, Gereon
AU - Roos, Andreas
AU - Stenzel, Werner
AU - Meisel, Andreas
AU - Meuth, Sven G
AU - Ruck, Tobias
N1 - © 2024. The Author(s).
PY - 2024/6/18
Y1 - 2024/6/18
N2 - Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.
AB - Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.
KW - Humans
KW - Myasthenia Gravis/blood
KW - Biomarkers/blood
KW - Male
KW - Female
KW - Middle Aged
KW - Adult
KW - Aged
KW - Autoantibodies/blood
KW - Receptors, Cholinergic/immunology
KW - Proteomics/methods
KW - Cohort Studies
KW - Young Adult
KW - Proteinase Inhibitory Proteins, Secretory/blood
KW - Machine Learning
U2 - 10.1007/s00401-024-02754-6
DO - 10.1007/s00401-024-02754-6
M3 - SCORING: Journal article
C2 - 38888758
VL - 147
SP - 102
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 102
ER -