Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy
Lauren Elizabeth Walker, Federica Frigerio, Teresa Ravizza, Emanuele Ricci, Karen Tse, Rosalind E. Jenkins, Graeme John Sills, Andrea Jorgensen, Luca Porcu, Thimmasettappa Thippeswamy, Tiina Alapirtti, Jukka Peltola, Martin J. Brodie, Brian Kevin Park, Anthony Guy Marson, Daniel James Antoine, Annamaria Vezzani, and Munir Pirmohamed
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First published April 8, 2019 - More info
© 2019 American Society for Clinical Investigation
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Abstract
Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.
Authors
Lauren Elizabeth Walker, Federica Frigerio, Teresa Ravizza, Emanuele Ricci, Karen Tse, Rosalind E. Jenkins, Graeme John Sills, Andrea Jorgensen, Luca Porcu, Thimmasettappa Thippeswamy, Tiina Alapirtti, Jukka Peltola, Martin J. Brodie, Brian Kevin Park, Anthony Guy Marson, Daniel James Antoine, Annamaria Vezzani, Munir Pirmohamed
Original citation: J Clin Invest. 2017;127(6):2118–2132. https://doi.org/10.1172/JCI92001
Citation for this retraction: J Clin Invest. https://doi.org/10.1172/JCI129285
Following an inquiry at the University of Liverpool, the Editorial Board was recently informed that the mass spectrometry data provided by Daniel J. Antoine is unreliable and likely to be fraudulent. Specifically, data relating to HMGB1 isoforms presented in Figures 1B, 2, 4A, and 5A and Supplemental Figure 3 are not reliable. Due to this finding, the JCI is retracting this article. No issues have been raised with regard to any of the other data in the paper. The corresponding author has stated that data presented in Figure 1A and data related to total HMGB1 blood levels measured by ELISA, which include that in Figure 1B, Figure 2, and Figure 4A as well as data reported in Figure 3 and Figure 4B, are reliable. The corresponding author has also stated that all supplemental figures, except those depicting HMGB1 isoforms, are reliable.
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)