Abstract
Objectives
Neuroinflammation represents one of the two major pathological components of multiple sclerosis (MS). The aim of our study was to find the role of the late pro-inflammatory cytokine HMGB1 (high mobility group box) in MS pathogenesis.
Subjects and methods
A total of 165 patients from three MS centers in Slovakia were enrolled in the study. Patients underwent a complex clinical investigation and their plasma levels of HMGB1 were analyzed by a sandwich ELISA test.
Results
MS patients had 4.5 times higher plasma level of HMGB1 (median, 13.529 ng/mL; IQR = 2.330-113.45) than healthy controls (median, 2.999 ng/mL; IQR = 1.686-9.844; P < 0.0001). The concentrations of HMGB1 were significantly associated with increased number of affected areas diagnosed by MRI (P < 0.0001) (the median for one affected area, 4.205 ng/mL; median for five affected areas, 17.843 ng/mL; P < 0.05). Patients with at least one active lesion in any of the affected areas in the brain had significantly higher plasma levels of HMGB1 (median, 20.118 ng/mL; IQR, 3.693–100.12) than those without any active lesion (median, 16.695 ng/mL; IQR, 3.255–113.45; P < 0.0235). We found also a very highly significant association of HMGB1 plasma levels with clinical condition expressed as EDSS (expanded disability status scale) (P < 0.0001); patients with higher EDSS had higher levels of HMGB1 (EDSS ≤ 2.5, 11.648 ng/mL vs. EDSS ≥ 3, 17.549 ng/mL; P = 0.0115).
Conclusion
Our results suggest chronic low-grade inflammation in MS patients that correlates with clinical conditions of MS patients, and for HMGB1 as a possible target molecule in future therapy.
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References
Koch-Henriksen N, Sørensen PS (2010) The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 9:520–532
Kurtzke JF (2000) Epidemiology of multiple sclerosis. Does this really point toward an etiology? Lectio doctoralis. Neurol Sci 21:383–403
Torbus-Paluszczak M, Bartman W, Adamczyk-Sowa M (2018) Klotho protein in neurodegenerative disorders. Neurol Sci 39(10):1677–1682
Lassmann H, Brück W, Lucchinetti C (2007) The immuno-pathology of multiple sclerosis: an overview. Brain Pathol 17:210–218
Lucchinetti CF, Popescu BF, Bunyan RF et al (2011) Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 365:2188–2197
Pierrot-Deseilligny C, Souberbielle JC (2017) Vitamin D and multiple sclerosis: an update. Mult Scler Relat Disord 14:35–45
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517
Hughes AJ, Dunn KM, Chaffee T (2018) Sleep disturbance and cognitive dysfunction in multiple sclerosis: a systematic review. Curr Neurol Neurosci Rep 18(1):2
Hughes J, Jokubaitis V, Lugaresi A, Hupperts R, Izquierdo G, Prat A, Girard M, Duquette P, Grand'Maison F, Grammond P, Sola P, Ferraro D, Ramo-Tello C, Trojano M, Slee M, Shaygannejad V, Boz C, Lechner-Scott J, van Pesch V, Pucci E, Solaro C, Verheul F, Terzi M, Granella F, Spitaleri D, Alroughani R, Jun JK, Fambiatos A, van der Walt A, Butzkueven H, Kalincik T, MSBase Study Group (2018) Association of inflammation and disability accrual in patients with progressive-onset multiple sclerosis. JAMA Neurol 75:1407–1415
Sadeghi Bahmani D, Kesselring J, Papadimitriou M et al (2019) In patients with multiple sclerosis, both objective and subjective sleep, depression, fatigue, and paresthesia improved after 3 weeks of regular exercise. Front Psychiatry 10:265
Razazian N, Yavari Z, Farnia V, Azizi A, Kordavani L, Bahmani DS, Holsboer-Trachsler E, Brand S (2016) Exercising impacts on fatigue, depression, and paresthesia in female patients with multiple sclerosis. Med Sci Sports Exerc 48:796–803
Buc M (2013) Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis. Mediat Inflamm 963748
Jadidi-Niaragh F, Mirshafiey A (2012) The deviated balance between regulatory T cell and Th17 in autoimmunity. Immunopharmacol Immunotoxicol 34:727–739
Mohiuddin IH, Pillai V, Baughman EJ et al (2016) Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis. Clin Immunol 166-167:12–18
Muls N, Jnaoui K, Dang HA, Wauters A, van Snick J, Sindic CJ, van Pesch V (2012) Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network. J Neuroimmunol 243:73–80
Kleinewietfeld M, Hafler DA (2014) Regulatory T cells in autoimmune neuroinflammation. Immunol Rev 259:231–244
Kürtüncü M, Tüzün E, Türkoğlu R, Petek-Balcı B, Içöz S, Pehlivan M, Birişik Ö, Ulusoy C, Shugaiv E, Akman-Demir G, Eraksoy M (2012) Effect of short-term interferon-β treatment on cytokines in multiple sclerosis: significant modulation of IL-17 and IL-23. Cytokine 59:400–402
Skundric DS, Cruikshank WW, Montgomery PC, Lisak RP, Tse HY (2015) Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis. Cytokine S1043-4666(15):00009–00005
Waisman A, Hauptmann J, Regen T (2015) The role of IL-17 in CNS diseases. Acta Neuropathol 129:625–637
Pérez-Cerdá F, Sánchez-Gómez MV, Matute C (2016) The link of inflammation and neurodegeneration in progressive multiple sclerosis. Mult Scler Demyel Disord 1:1–9
Lubetzki C, Stankoff B (2014) Demyelination in multiple sclerosis. Handb Clin Neurol 122:89–99
Lazibat I, Rubinić Majdak M, Županić S (2018) Multiple sclerosis: new aspects of immunopathogenesis. Acta Clin Croat 57:352–361
Naglova H, Bucova M (2012) HMGB1 and its physiological and pathological roles. Bratisl Lek Listy 113:163–171
He SJ, Cheng J, Feng X, Yu Y, Tian L, Huang Q (2017) The dual role and therapeutic potential of high-mobility group box 1 in cancer.Oncotarget 8:64534-64550
Goodwin GH, Sanders C, Johns EW (1973) A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 38:14–19
Landsman D, Bustin M (1993) A signature for the HMG-1 box DNA-binding proteins. Bioessays 15:539–546
Tsuda K, Kikuchi M, Mori K, Waga S, Yoshida M (1988) Primary structure of non-histone protein HMG1 revealed by the nucleotide sequence. Biochemistry 27:6159–6163
Pellegrini L, Foglio E, Pontemezzo E, Germani A, Russo MA, Limana F (2019) HMGB1 and repair: focus on the heart. Pharmacol Ther 196:160–182
Deng M, Scott MJ, Fan J, Billiar TR (2019) Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation. J Leukoc Biol 106:161–169
Yang H, Tracey KJ (2010) Targeting HMGB1 in inflammation. Biochim Biophys Acta 1799:149–156
Polman C, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452
Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell G, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sørensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sá M, Salemi G, Savettieri G, Hillert J, Compston DA (2005) Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 64:1144–1151
Cendrowski WS (1985) Progression index and disability status in multiple sclerosis: a resurvey of 207 patients in central Poland. Swiss Arch Neurol Psychiatry Psychother 137:5–13
Bjelobababa I, Savic D, Lavrnja I (2017) Multiple sclerosis and neuroinflammation: the overview of current and prospective therapies. Curr Pharm Des 23:693–730
Kuhlmann T, Ludwin S, Prat A, Antel J, Bruck W, Lassmann H (2017) An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol 133:13–24
Zindler E, Zipp F (2010) Neuronal injury in chronic CNS inflammation. Best Pract Res Clin Anaesthesiol 24:551–562
Zhu S, Li W, Ward MF, Sama AE, Wang H (2010) High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation. Inflamm Allergy Drug Targets 9:60–72
Zhen C, Wang Y, Li D, Zhang W, Zhang H, Yu X, Wang X (2019) Relationship of High-mobility group box 1 levels and multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord 31:87–92
Zhu B, Zhu Q, Li N, Wu T, Liu S, Liu S (2018) Association of serum/plasma high mobility group box 1 with autoimmune diseases: a systematic review and meta-analysis. Medicine (Baltimore) 97(29):e11531
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Our acknowledgments go to all patients contributing to this study.
Funding
This work was supported by grant Vega 1/0833/13.
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The study was approved by a local Ethic Committee of Faculty of Medicine, Comenius University, in Bratislava and each patient has signed informed consent.
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Bucova, M., Majernikova, B., Durmanova, V. et al. HMGB1 as a potential new marker of disease activity in patients with multiple sclerosis. Neurol Sci 41, 599–604 (2020). https://doi.org/10.1007/s10072-019-04136-3
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DOI: https://doi.org/10.1007/s10072-019-04136-3