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

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 -