Features of self-tolerance loss in patients with different clinical phenotypes of myasthenia


Keywords: clinical myasthenia phenotypes; autoantibody spectrum; regulatory T lymphocytes; co-stimulating molecules; acute phase proteins

Abstract

The incidence of myasthenia gravis which is characterized by progressive muscular weakness on the background of structural disorders of the thymus, has increased. Myasthenia gravis is a multifactorial autoimmune disease, it has a pronounced clinical heterogeneity, and therefore the standard diagnostic and treatment protocol is not always effective. To substantiate an individual approach to the treatment of various clinical forms of myasthenia, we conducted a study of mechanisms and markers of loss of central and peripheral self-tolerance in thymus-independent myasthenia (M) and thymus-dependent myasthenia gravis with thymus hyperplasia (MH) and thymoma (MT), involving a total of 427 patients examined. In patients with different phenotypes of myasthenia, we used the methods of spectrophotometry, flow cytometry, enzyme immunoassay. In patients with MH on the background of lymphofollicular thymus hyperplasia we revealed a pronounced humoral sensitization in comparison with the reference values: the concentration of C4 complement, C-reactive protein, circulating immune complexes and the initiation of an indirect autoimmune reaction a reliable increase in autoantibodies (AAbs) to the α1 and α7 subunit of subunit of nicotinic receptors (nAChR). In M and MT groups a high similar titer of AAbs to other epitopes was revealed: DNA, β2-glycoprotein I, membranes of intestinal and stomach cells, lung, liver, kidney cells. A pronounced blast-transforming response to the presence of the mitogen PHA was revealed in the MT group. In the MT group, a decrease in the content of CD4+ CD28+ co-stimulatory molecules and in the MH group, a decrease in СD4+ CD25+ Treg lymphocytes was revealed. Individual methods for correcting the loss of self-tolerance in patients with different clinical phenotypes of myasthenia were justified taking into account the use of immunosuppression, specific viral-neutralizing immunoglobulins and massive IgG immunoglobulin therapy, and the application of anti-inflammatory recombinant interleukins.

References

Aricha, R., Reuveni, D., Fuchs, S., & Souroujon, M. C. (2016). Suppression of experimental autoimmune myasthenia gravis by autologous T regulatory cells. Journal of Autoimmunity, 67, 57–64.


Bach, J. F. (2012). The etiology of autoimmune diseases: The case of myasthenia gravis. Annals of the New York Academy of Sciences, 1274, 33–39.


Barzago, C., Lum, J., Cavalcante, P., Srinivasan, K. G., Faggiani, E., Camera, G., Bonanno, S., Andreetta, F., Antozzi, C., Baggi, F., Calogero, R. A., Bernasconi, P., Mantegazza, R., Mori, L., & Zolezzi, F. (2016). A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients. Immunology, 221(11), 1227–1236.


Berrih-Aknin, S, Frenkian-Cuvelier, М., & Eymard, В. (2014). Diagnostic and clinical classification of autoimmune myasthenia gravis. Journal of Autoimmunity, 48/49, 143–148.


Berrih-Aknin, S. (2014). Myasthenia gravis: Paradox versus paradigm in autoimmunity. Journal of Autoimmunity, 52, 1–28.


Burden, S. J., Yumoto, N., & Zhang, W. (2013). The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harbor Perspect in Biology, 5(5), a009167.


Carr, A. S., Cardwell, C. R., McCarron, P. O., & McConville, J. A. (2010). A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurology, 18(10), 46.


Cavalcante, P., Bernasconi, P., & Mantegazza, R. (2012). Autoimmune mechanisms in myasthenia gravis. Current Opinion in Neurology, 25(5), 621–629.


Curnow, J., Corlett, L., Willcox, N., & Vincent, A. (2001). Presentation by myoblasts of an epitope from endogenous acetylcholine receptor indicates a potential role in the spreading of immune response. Journal of Neuroimmunology, 115, 127–134.


Dalakas, M. C. (2012). Biologics and other novel approaches as new therapeutic options in myasthenia gravis: A view to the future. Annals of the New York Academy of Sciences, 1274, 1–8.


Danikowski, K. M., Jayaraman, S., & Prabhakar, B. S. (2017). Regulatory T cells in multiple sclerosis and myasthenia gravis. Journal of Neuroinflammation, 14(1), 117.


Darabid, H., Perez-Gonzales, A. P., & Robitaille, R. (2014). Neuromuscular synaptogenesis: Coordinating patherns with multiple function. Nature Reviews Neuroscience, 15, 703–718.


Dedaev, S. I. (2014). Antibodies to autoantigenic targets in myasthenia gravis and their importance in clinical practice. Neuromuscular Diseases, 2, 6–15.


Devic, P., Petiot, P., Simonet, T., Stojkovic, D., Delmont, E., Franques, J., Magot, A., Vial, C., Lagrange, E., Nicot, A. S., Risson, V., Eymard, B., & Schaeffer, L. (2014). Antibodies to clustered acetylcholine receptor: Expanding the phenotype. European Journal of Neurology, 21(1), 130–134.


Dyachenko, A. G., Dyachenko, P. A., Gorobchenko, E. N., & Miroshnichenko, E. A. (2014). Preodolenie immunologicheskoj tolerantnosti novoe napravlenie v lechenii solidnyh opuholej [Overcoming immunological tolerance is a new direction in the treatment of solid tumors]. Clinical Immunology, Alergology, Infectology, 73(4), 5–10 (in Russian).


Evoli, A., & Padua, L. (2013). Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase. Autoimmunity Reviews, 12(9), 931–935.


Galassi, G., Mazzoli, M., Ariatti, A., Kaleci, S., Valzania, F., & Nichelli, P. F. (2018). Antibody profile may predict outcome in ocular myasthenia gravis. Acta Neurologica Belgica, 118(3), 435–443.


Gergalova, G. L., Lehmus, O. J., & Skok, M. V. (2011). Possible effect of activation of α7-nicotinic acetylcholine receptors in the mitochondrial membrane on the development of apoptosis. Neurophysiology, 43(3), 195–197.


Ha, J. C., & Richman, D. P. (2015). Myasthenia gravis and related disorders: Pathology and molecular pathogenesis. Biochimica et Biophysica Acta, 1852, 651–657.


Hall, B. M., Tran, G. T., Robinson, C. M., & Hodgkinson, S. J. (2015). Induction of antigen specific CD4(+)CD25(+)Foxp3(+)T regulatory cells from naive natural thymic derived T regulatory cells. International Immunopharmacology, 28, 875–886.


Huijbers, M. G., Zhang, W., Klooster, R., Niks, E. H., Friese, M. B., Straasheijm, K. R., Thijssen, P. E., Vrolijk, H., Plomp, J. J., Vogels, P., Losen, M., Van der Maarel, S. M., Burden, S. J., & Verschuuren, J. J. (2013). MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proceedings of the National Academy of Sciences, 110(51), 20783–20788.


Jiang, C., Liu, P., Liang, Y., Qiu, S., Bao, W., & Zhang, J. (2013). Clinical treatment of myasthenia gravis with deficiency of spleen and kidney based on combination of disease with syndrome theory. Journal of Traditional Chinese Medicine, 33(4), 444–448.


Kamyshnikov, V. S. (2004). Spravochnik po kliniko-biohimicheskim issledovanijam i laboratornoj diagnostike [Reference book on clinical and biochemical research and laboratory diagnostics]. MEDpress-inform, Moscow (in Russian).


Khaitov, R. M., & Ilina, N. I. (2009). Allergologija i immunologija: Nacional'noe rukovodstvo [Allergology and immunology: National leadership]. Geotar-Media, Moscow (in Russian).


Klimova, E. M., & Kalashnikova, J. V. (2016). The role of acute phase proteins in induction of tension of nonspecific resistance system in various clinical phenotypes of myasthenia. Journal of Clinical and Experimental Pathology, 6(6), 5–11.


Klimova, E. M., Bozhkov, A. I., Boyko, V. V., Drozdova, L. A., Lavinskaya, Е. V., & Skok, M. V. (2016). Endogenic cytotoxic compounds and formation of the clinic forms of myasthenia. Translational Biomedicine, 7(3), 84.


Koneczny, I., Cossins, J., Waters, P., Beeson, D., & Vincent, A. (2013). MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. PLoS One, 8(11), e80695.


Kusner, L. L., Halperin, J. A., & Kaminski, H. J. (2013). Cell surface complement regulators moderate experimental myasthenia gravis pathology. Muscle Nerve, 47(1), 33–40.


Levinson, A. I. (2013). Modeling the intrathymic pathogenesis of myasthenia gravis. Journal of the Neurological Science, 333, 60–67.


Lopomo, A., & Berrih-Aknin, S. (2017). Autoimmune thyroiditis and myasthenia gravis. Frontiers in Endocrinology, 8, 169.


Makino, T., Nakamura, R., Terekawa, M., Muneoka, S., Nagahira, K., Nagane, Y., Yamate, J., Motomura, M., & Utsigisawa, K. (2017). Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools. PLoS One, 12(10), e0185976.


Masuda, T., Motomura, M., Utsugisawa, K., Nagane, K., Nakata, R., Toluda, M., Fukuda, T., Yoshimura, T., Tsujihata, M., & Kawakami, A. (2012). Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. Journal of Neurology, Neurosurgery and Psychiatry, 83, 935–940.


Melzer, N., Ruck, T., Fuhr, P., Gold, R., Hohlfeld, R., Marx, A., Melms, A., Tackenberg, B., Schalke, B., Schneider-Gold, C., Zimprich, F., Meuth, S. G., & Wiendl, H. (2016). Clinical features, pathogenesis, and treatment of myasthenia gravis: A supplement to the guidelines of the German Neurological Society. Journal of Neurology, 263, 1473–1494.


Muniz-Junqueira, M. I., Peçanha, L. M., Silva-Filho, V. L., Cardoso, M. C. A., & Tosta, C. E. (2003). Novel microtechnique for assessment of postnatal maturation of the phagocytic function of neutrophils and monocytes. Clinical and Vaccine Immunology, 10, 1096–1102.


Nakamura, R., Makino, T., Hanada, T., Terakawa, M., Nagahira, K., Yamate, J., Shiraishi, H., & Motomura, M. (2018). Heterogeneity of auto-antibodies against nAChR in myasthenic serum and their pathogenic roles in experimental autoimmune myasthenia gravis. Journal of Neuroimmunology, 320, 64–75.


Nilsson, B., & Nilsson, E. K. (2012). Complement diagnostics: Concepts, indications, and practical guidelines. Clinical and Developmental Immunology, 2012, e962702.


Oger, J., & Frykman, Н. (2015). An update on laboratory diagnosis in myasthenia gravis. Clinica Chimica Acta, 444, 126–131.


Otsuka, K., Ito, M., Ohkawara, B., Masuda, A., Kawakami, Y., Sahashi, K., Nishida, H., Mabuchi, N., Takano, A., Engel, A. G., & Ohno, K. (2015). Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/ MuSK signaling. Scientific Reports, 10(5), 13928.


Park, B. H., Fikrig, S. M., & Smithwick, E. M. (1968). Infection and nitroblue-tetrazolium reduction by neutrophils: A diagnostic acid. Lancet, 2, 532–534.


Pevzner, A., Schoser, B., Peters, K., Cosma, N. C., Karakatsani, A., Schalke, B., Melms, A., & Kröger, S. (2012). Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. Journal of Neurolology, 259(3), 427–435.


Phillips, W. D., & Vincent, A. (2016). Pathogenesis of myasthenia gravis: Update on disease types, models, and mechanisms. F1000Research, 5. pii: F1000 Faculty Rev-1513.


Poletaev, A. B., Stepanyuk, V. L., & Gershwin, M. E. (2008). Integrating immunity: The immunculus and self-reactivity. Journal of Autoimmunity, 30, 68–73.


Richard, J., & Howard, J. F. (2017). Seronegative myasthenia gravis associated with malignant thymoma. Neuromuscular Disorders, 27(5), 417–418.


Sakaguchi, S. (2005). Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and nonself. Nature Immunology, 6, 345–352.


Sergeeva, N. A. (1999). Klinicheskaja laboratornaja diagnostika [Clinical laboratory diagnostics], 2, 25–32 (in Russian).


Shen, C., Lu, Y., Zhang, B., Fiqueiredo, D., Bean, J., Jung, J., Wu, H., Barik, A., Yin, D. M., Xiong, W. C., & Mei, L. (2013). Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. Journal of Clinical Investigations, 123(12), 5190–5202.


Skok, M. V. (2013). Nicotinic acetylcholine receptors: Specific antibodies and functions in humoral immunity. Biochemistry and biotechnology Everyday medicine. FOP Moskalenko, Kiev. Pp. 271–286.


Sprent, J., & Kishimoto, H. (2002). The thymus and negative selection. Immunology Reviews, 185, 126–135.


Tovazhnyanskaya, O. L., & Samoylova, A. P. (2016). Clinical and neurophysiological features in patients with myasthenia gravis depending on the structural changes of the thymus. International Neurological Journal, 82, 49–53.


Vincent, A., Huda, S., Caj, M., Cetin, H., Koneczny, I., Rodriguez-Cruz, P., Jacobson, L., Viegas, S., Jacob, S., Woodhall, M., Nagaishi, A., Maniaol, A., Damato, V., Leite, M. I., Cossins, J., Webster, R., Palace, J., & Beeson, D. (2018). Serological and experimental studies in different forms of myasthenia gravis. Annals of the New York Academy of Sciences, 1413(1), 143–153.

Published
2018-07-11
How to Cite
Klimova, E. M., Minuchin, D. V., Drozdova, L. A., Lavinskaya, E. V., Kordon, T. I., & Kalashnykova, Y. V. (2018). Features of self-tolerance loss in patients with different clinical phenotypes of myasthenia. Regulatory Mechanisms in Biosystems, 9(4), 561-567. https://doi.org/https://doi.org/10.15421/021884

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