Circulating microRNA in Myasthenia gravis (MG)
Keywords:circulating microRNA, Myasthenia gravis, miR-150-5p, miR-21-5p, miR-30e-5p, biomarker
One of the main difficulties in predicting the clinical course of Myasthenia Gravis (MG) is the heterogeneity of the disease, where disease progression differs greatly depending on the patient's subgroup. MG subgroups are classified according to the age of onset [early onset MG (EOMG; onset ≤ 50 years) versus late-onset MG (LOMG; onset >50 years]; the presence of a thymoma (thymoma associated MG), antibody subtype [acetylcholine receptor antibody seropositive (AChR+), muscle-specific tyrosine kinase antibody seropositive (MuSK+)], or presence of antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) or agrin as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue scores, do not necessarily reflect disease progression. Hence, there is a great need for reliable, objective biomarkers in MG to follow the disease course and the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patient sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decreased by the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.
A. R. Punga, P. Maddison, J. M. Heckmann, J. T. Guptill, A. Evoli, Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol 21, 176-188 (2022).
M. H. Rivner, M. Pasnoor, M. M. Dimachkie, R. J. Barohn, L. Mei, Muscle-Specific Tyrosine Kinase and Myasthenia Gravis Owing to Other Antibodies. Neurol Clin 36, 293-310 (2018).
E. Cortes-Vicente et al., Clinical and therapeutic features of myasthenia gravis in adults based on age at onset. Neurology 94, e1171-e1180 (2020).
R. H. P. de Meel, M. R. Tannemaat, J. Verschuuren, Heterogeneity and shifts in distribution of muscle weakness in myasthenia gravis. Neuromuscul Disord 29, 664-670 (2019).
A. Meisel et al., Role of autoantibody levels as biomarkers in the management of patients with myasthenia gravis: A systematic review and expert appraisal. Eur J Neurol, (2022).
H. Wang, R. Peng, J. Wang, Z. Qin, L. Xue, Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin Epigenetics 10, 59 (2018).
A. R. Punga, T. Punga, Circulating microRNAs as potential biomarkers in myasthenia gravis patients. Ann N Y Acad Sci 1412, 33-40 (2018).
L. Sabre, T. Punga, A. R. Punga, Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine. Front Immunol 11, 213 (2020).
L. F. R. Gebert, I. J. MacRae, Regulation of microRNA function in animals. Nat Rev Mol Cell Biol 20, 21-37 (2019).
J. Q. Chen, G. Papp, P. Szodoray, M. Zeher, The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev 15, 1171-1180 (2016).
A. Hata, J. Lieberman, Dysregulation of microRNA biogenesis and gene silencing in cancer. Science signaling 8, re3 (2015).
L. Maegdefessel, The emerging role of microRNAs in cardiovascular disease. Journal of internal medicine 276, 633-644 (2014).
O. Bryzgunova, M. Konoshenko, I. Zaporozhchenko, A. Yakovlev, P. Laktionov, Isolation of Cell-Free miRNA from Biological Fluids: Influencing Factors and Methods. Diagnostics (Basel) 11, (2021).
L. M. Doyle, M. Z. Wang, Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 8, (2019).
P. D. Stahl, G. Raposo, Extracellular Vesicles: Exosomes and Microvesicles, Integrators of Homeostasis. Physiology (Bethesda) 34, 169-177 (2019).
C. Bar, T. Thum, D. de Gonzalo-Calvo, Circulating miRNAs as mediators in cell-to-cell communication. Epigenomics 11, 111-113 (2019).
S. M. El-Daly, S. A. Gouhar, Z. Y. Abd Elmageed, Circulating microRNAs as Reliable Tumor Biomarkers: Opportunities and Challenges Facing Clinical Application. J Pharmacol Exp Ther 384, 35-51 (2023).
S. Donati, S. Ciuffi, M. L. Brandi, Human Circulating miRNAs Real-time qRT-PCR-based Analysis: An Overview of Endogenous Reference Genes Used for Data Normalization. Int J Mol Sci 20, (2019).
F. Beretta, Y. F. Huang, A. R. Punga, Towards Personalized Medicine in Myasthenia Gravis: Role of Circulating microRNAs miR-30e-5p, miR-150-5p and miR-21-5p. Cells 11, (2022).
L. Sabre et al., Circulating microRNA plasma profile in MuSK+ myasthenia gravis. J Neuroimmunol 325, 87-91 (2018).
L. Sabre et al., miR-30e-5p as predictor of generalization in ocular myasthenia gravis. Ann Clin Transl Neurol 6, 243-251 (2019).
T. Punga et al., Circulating miRNAs in myasthenia gravis: miR-150-5p as a new potential biomarker. Ann Clin Transl Neurol 1, 49-58 (2014).
A. R. Punga, M. Andersson, M. Alimohammadi, T. Punga, Disease specific signature of circulating miR-150-5p and miR-21-5p in myasthenia gravis patients. J Neurol Sci 356, 90-96 (2015).
C. J. Molin, L. Sabre, C. A. Weis, T. Punga, A. R. Punga, Thymectomy lowers the myasthenia gravis biomarker miR-150-5p. Neurol Neuroimmunol Neuroinflamm 5, e450 (2018).
H. Zhong et al., Low-dose rituximab lowers serum Exosomal miR-150-5p in AChR-positive refractory myasthenia gravis patients. J Neuroimmunol 348, 577383 (2020).
E. Westerberg, C. J. Molin, I. Lindblad, M. Emtner, A. R. Punga, Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance-based measures: A pilot study. Muscle Nerve 56, 207-214 (2017).
G. Nogales-Gadea et al., Analysis of serum miRNA profiles of myasthenia gravis patients. PloS one 9, e91927 (2014).
N. Chunjie, N. Huijuan, Y. Zhao, W. Jianzhao, Z. Xiaojian, Disease-specific signature of serum miR-20b and its targets IL-8 and IL-25, in myasthenia gravis patients. Eur Cytokine Netw 26, 61-66 (2015).
Y. Xin et al., miR-20b Inhibits T Cell Proliferation and Activation via NFAT Signaling Pathway in Thymoma-Associated Myasthenia Gravis. Biomed Res Int 2016, 9595718 (2016).
C. A. Weis, B. Schalke, P. Strobel, A. Marx, Challenging the current model of early-onset myasthenia gravis pathogenesis in the light of the MGTX trial and histological heterogeneity of thymectomy specimens. Annals of the New York Academy of Sciences 1413, 82-91 (2018).
L. Sabre, P. Maddison, G. Sadalage, P. A. Ambrose, A. R. Punga, Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis. Journal of neuroimmunology, (2018).
S. H. Wong, A. Petrie, G. T. Plant, Ocular Myasthenia Gravis: Toward a Risk of Generalization Score and Sample Size Calculation for a Randomized Controlled Trial of Disease Modification. J Neuroophthalmol 36, 252-258 (2016).
L. M. Sabre, P; Wong, SH; Sadalage, G; Ambrose, P; Plant, GP; Punga, AR., miR‐30e‐5p as predictor of generalization in ocular myasthenia gravis. Ann Clin Transl Neurol, (2019).
M. J. Kupersmith, Does early immunotherapy reduce the conversion of ocular myasthenia gravis to generalized myasthenia gravis? J Neuroophthalmol 23, 249-250 (2003).
M. J. Kupersmith, Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. Journal of neurology 256, 1314-1320 (2009).
A. Evoli et al., Myasthenia gravis with antibodies to MuSK: an update. Annals of the New York Academy of Sciences 1412, 82-89 (2018).
T. Punga et al., Disease specific enrichment of circulating let-7 family microRNA in MuSK+ myasthenia gravis. J Neuroimmunol 292, 21-26 (2016).
K. Wang et al., Comparing the MicroRNA spectrum between serum and plasma. PloS one 7, e41561 (2012).
B. J. Kroesen et al., Immuno-miRs: critical regulators of T-cell development, function and ageing. Immunology 144, 1-10 (2015).
E. Corsiero, A. Nerviani, M. Bombardieri, C. Pitzalis, Ectopic Lymphoid Structures: Powerhouse of Autoimmunity. Front Immunol 7, 430 (2016).
M. A. Cron et al., Thymus involvement in early-onset myasthenia gravis. Annals of the New York Academy of Sciences 1412, 137-145 (2018).
B. Zhou, S. Wang, C. Mayr, D. P. Bartel, H. F. Lodish, miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proceedings of the National Academy of Sciences of the United States of America 104, 7080-7085 (2007).
L. Zhou, J. J. Park, Q. Zheng, Z. Dong, Q. Mi, MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cellular & molecular immunology 8, 380-387 (2011).
P. de Candia et al., Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation. PloS one 8, e75348 (2013).
M. A. Cron et al., Causes and Consequences of miR-150-5p Dysregulation in Myasthenia Gravis. Front Immunol 10, 539 (2019).
B. Stamatopoulos et al., Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia. Mol Med 21, 123-133 (2015).
R. Hu, R. M. O'Connell, MicroRNA control in the development of systemic autoimmunity. Arthritis research & therapy 15, 202 (2013).
Z. Xue et al., miR-21 promotes NLRP3 inflammasome activation to mediate pyroptosis and endotoxic shock. Cell Death Dis 10, 461 (2019).
L. Barnabei, E. Laplantine, W. Mbongo, F. Rieux-Laucat, R. Weil, NF-kappaB: At the Borders of Autoimmunity and Inflammation. Front Immunol 12, 716469 (2021).
J. Wang et al., miR-30e reciprocally regulates the differentiation of adipocytes and osteoblasts by directly targeting low-density lipoprotein receptor-related protein 6. Cell Death Dis 4, e845 (2013).
A. M. Gurtan et al., Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts. Genes & development 27, 941-954 (2013).
M. Patterson et al., let-7 miRNAs can act through notch to regulate human gliogenesis. Stem Cell Reports 3, 758-773 (2014).
S. Wang et al., Let-7/miR-98 regulate Fas and Fas-mediated apoptosis. Genes Immun 12, 149-154 (2011).
M. Dominguez-Villar, A. S. Gautron, M. de Marcken, M. J. Keller, D. A. Hafler, TLR7 induces anergy in human CD4(+) T cells. Nature immunology 16, 118-128 (2015).
J. Li et al., Altered expression of miR-125a-5p in thymoma-associated myasthenia gravis and its down-regulation of foxp3 expression in Jurkat cells. Immunol Lett 172, 47-55 (2016).
M. A. Cron et al., Analysis of microRNA expression in the thymus of Myasthenia Gravis patients opens new research avenues. Autoimmunity reviews 17, 588-600 (2018).
R. Mantegazza, P. Bernasconi, P. Cavalcante, Myasthenia gravis: from autoantibodies to therapy. Curr Opin Neurol 31, 517-525 (2018).
A. Bavelloni et al., MiRNA-210: A Current Overview. Anticancer Res 37, 6511-6521 (2017).
X. Feichtinger et al., Bone-related Circulating MicroRNAs miR-29b-3p, miR-550a-3p, and miR-324-3p and their Association to Bone Microstructure and Histomorphometry. Sci Rep 8, 4867 (2018).
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