Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis.

Autor: Schroeter CB; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Nelke C; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Stascheit F; Department of Neurology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany., Huntemann N; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Preusse C; Department of Neuropathology, Charité - Universitätsmedizin Berlin, Bonhoefferweg 3, 10117, Berlin, Germany., Dobelmann V; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Theissen L; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Pawlitzki M; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Räuber S; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Willison A; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Vogelsang A; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Marina AD; Department of Neuropaediatrics, Neuromuscular Centre, Universitätsmedizin Essen, Hufelandstr. 55, 45122, Essen, Germany., Hartung HP; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.; Brain and Mind Center, University of Sydney, 94 Mallett St, Sydney, Australia.; Department of Neurology, Palacky University Olomouc, Nová Ulice, 779 00, Olomouc, Czech Republic., Melzer N; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Konen FF; Department of Neurology, Hannover Medical School, 30625, Hannover, Germany., Skripuletz T; Department of Neurology, Hannover Medical School, 30625, Hannover, Germany., Hentschel A; Leibniz-Institut Für Analytische Wissenschaften - ISAS - E.V, 44227, Dortmund, Germany., König S; Core Unit Proteomics, Interdisciplinary Center for Clinical Research, Medical Faculty, University of Münster, 48149, Münster, Germany., Schweizer M; Electron Microscopy Unit, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany., Stühler K; Institute for Molecular Medicine, Proteome Research, University Hospital and Medical Faculty, Heinrich Heine University, 40225, Duesseldorf, Germany.; Molecular Proteomics Laboratory, Biological Medical Research Center, Heinrich Heine University, Universitätsstr 1, 40225, Duesseldorf, Germany., Poschmann G; Institute for Molecular Medicine, Proteome Research, University Hospital and Medical Faculty, Heinrich Heine University, 40225, Duesseldorf, Germany., Roos A; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.; Department of Neuropaediatrics, Neuromuscular Centre, Universitätsmedizin Essen, Hufelandstr. 55, 45122, Essen, Germany., Stenzel W; Department of Neuropathology, Charité - Universitätsmedizin Berlin, Bonhoefferweg 3, 10117, Berlin, Germany., Meisel A; Department of Neurology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany., Meuth SG; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany., Ruck T; Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany. Tobias.ruck@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 Jun 18; Vol. 147 (1), pp. 102. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1007/s00401-024-02754-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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