Myasthenia gravis: a pathologic approach
DOI:
https://doi.org/10.26481/marble.2014.v2.324Abstract
Our immune system protects us from all kinds of pathogens our body faces every day. However, the immune system can also initiate an immune response against our own proteins. This is called autoimmunity. Myasthenia gravis (MG) is a rare autoimmune disease in which patients show severe muscle weakness, due to antibody production against proteins of the neuromuscular junction, which is the connection between nerve and muscle. At this moment, three different forms of myasthenia gravis are identified. Muscle-specific tyrosine kinase (MuSK)-MG is a form of MG in which patients produce antibodies, predominantly immunoglobulin (Ig)G4, against MuSK. This paper is a summary of a B cell immortalization project, in which antibodies produced by MuSK-MG patients are investigated. The aim of this study was to sequence and generate antibodies produced by these patients in vitro to learn more about the pathological mechanism of MuSK-MG. Blood-derived B cells of MuSK-MG patients were immortalized by the Epstein Bar Virus and stimulated to grow and produce antibodies in culture. Genes of these antibodies were amplified and analyzed. These amplification products were cloned in vectors and will be transfected in a human embryonic kidney (HEK)-cell line. This study showed that the B cell immortalization method worked and that MuSK-MG patients predominantly produce IgM antibodies against MuSK. This is very striking as literature states that these patients predominantly produce IgG4 against MuSK. It is suggested that this high production of IgM is due to the absence of the heavy chain isotype switch from IgM to IgG. Moreover, as the pathologic mechanism of MuSK-MG is still unknown, IgM may play an important pathological role.References
Abbas A, Lichtman A. Basic Immunology: Functions and Disorders of the Immune System. Updated 3rd ed. Philadelphia Saunders Elsevier; 2011.
Ngo S, Steyn F, McCombe P. Gender differences in autoimmune disease. Frontiers in neuroendocrinology. 2014.
Alberts B, Johnson A. Molecular Biology of the Cell. 4th ed. New York: Garland Science 2002.
Avidan N, Le Panse R, Berrih-Aknin S, Miller A. Genetic basis of myasthenia gravis–a comprehensive review. J Autoimmun. 2013.
Motomura M. Pathogenic antibodies in myasthenia gravis. Brain and nerve. 2010;62(4):411-8.
Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R, et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2013.
Huijbers MG, Lipka A, Plomp J, Niks E, Maarel S, Verschuuren J. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody-binding epitopes in myasthenia gravis. Journal of internal medicine. 2014;275(1):12-26.
Lavrnic D, Losen M, Vujic A, De Baets M, Hajdukovic L, Stojanovic V, et al. The features of myasthenia gravis with autoantibodies to MuSK. Journal of Neurology, Neurosurgery & Psychiatry. 2005;76(8):1099-102.
Gomez AM, Van Den Broeck J, Vrolix K, Janssen SP, Lemmens MA, Van Der Esch E, et al. Antibody effector mechanisms in myasthenia gravis-pathogenesis at the neuromuscular junction. Autoimmunity. 2010;43(5- 6):353-70.
Sieb JP. Myasthenia gravis: an update for the clinician. Clinical & Experimental Immunology. 2014;175(3):408-18.
Vrolix K, Fraussen J, Losen M, Stevens J, Lazaridis K, Molenaar PC, et al. Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor. J Autoimmun. 2014.
Williams DG, Taylor PC. Clonal analysis of immunoglobulin mRNA in rheumatoid arthritis synovium: characterization of expanded IgG3 populations. European journal of immunology. 1997;27(2):476-85.
Kawasaki K, Minoshima S, Schooler K, Kudoh J, Asakawa S, de Jong PJ, et al. The organization of the human immunoglobulin lambda gene locus. Genome Research. 1995;5(2):125-35.
Querol L, Illa I. Myasthenia gravis and the neuromuscular junction. Current opinion in neurology. 2013;26(5):459- 65.
Heilmann C, Barington T. Distribution of kappa and lambda light chain isotypes among human blood immunoglobulin-secreting cells after vaccination with pneumococcal polysaccharides. Scand J Immunol 1989;29(2):159-64.
Molé CM, Béné MC, Montagne PM, Seilles E, Faure GC. Light chains of immunoglobulins in human secretions. Clinica chimica acta. 1994;224(2):191-7.
Yamamoto T, Vincent A, Ciulla TA, Lang B, Johnston I, Newsom-Davis J. Seronegative myasthenia gravis: A plasma factor inhibiting agonist-induced acetylcholine receptor function copurifies with IgM. Annals of neurology. 1991;30(4):550-7.
Hofstad H, Ulvestad E, Gilhus N, Matre R, Aarli J. Myasthenia gravis muscle antibodies examined by ELISA: IgG and IgM antibodies characterize different patient subgroups. Acta neurologica scandinavica. 1992;85(4):233-8.
Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets. The Lancet Neurology. 2003;2(2):99-106.
Duarte-Rey C, Bogdanos DP, Leung PS, Anaya J-M, Gershwin ME. IgM predominance in autoimmune disease: genetics and gender. Autoimmun Rev. 2012;11(6):A404-A12.
