Ομαδα Κωνσταντίνου Λαζαρίδη

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease affecting the neuromuscular junction, causing muscle weakness and fatigability. In the majority of patients (85-90%) it is caused by autoantibodies targeting the muscle acetylcholine receptor (AChR), thus impeding neuromuscular signal transmission. Although the B cell-produced autoantibodies are the pathogenic agents in MG, T cells play a central and indispensable role in disease development, promoting the activity of autoreactive B cells.

The major MG autoantigen, the muscle AChR, is a pentameric transmembrane protein composed of four homologous subunits with the stoichiometry 2α₁-β₁-ε-δ (or 2α₁-β₁-γ-δ for embryonic receptors). Interestingly, most of the MG autoantibodies target the α1 subunit. Furthermore, a number of T cell epitopes have been identified within the α1 subunit.

We have developed and characterized in detail an experimental autoimmune MG (EAMG) model in rats, induced by immunization with domains of the human AChR and MuSK subunits, which results in highly reproducible symptom emergence and progression. Due to the use of human proteins for disease induction, this model is ideal for the study of antigen-specific MG immunotherapies. 

We are working on the development of antigen-specific therapies for MG. One of the main targets is a therapeutic strategy aiming to restore the lost tolerance towards the muscle AChR. The treatment rational is based on administration of the autoantigen or its domains under specific tolerance-inducing conditions. Recent findings in in vivo studies have shown a significant reduction of symptoms in treated compared to mock-treated animals. Our main efforts are currently focused on elucidating the precise immunological mechanisms involved in this response, which will not only increase our understanding and facilitate progression towards clinical application, but also allow the development of next generation approaches.

1. Koral G, Ulusoy C, Cossins J, Lazaridis K, Türkoğlu R, Dong YY, Tüzün E, Yılmaz V. Silencing of FCRLB by shRNA ameliorates MuSK-induced EAMG in mice. J Neuroimmunol. 2023 Oct 15;383:578195. doi: 10.1016/j.jneuroim.2023.578195. 
2. Sarrigeorgiou I, Moschandreou D, Dimitriadis A, Tsinti G, Sotiropoulou E, Ntoukaki E, Eliadis P, Backovic M, Labropoulou S, Escriou N, Pouliakis A, Giannopoulou G, Gaitanarou E, Lazaridis K, Mentis A, Mamalaki A, Grouzi E, Lymberi P. Combined monitoring of IgG and IgA anti-Spike and anti-Receptor binding domain long term responses following BNT162b2 mRNA vaccination in Greek healthcare workers. PLoS One. 2022;17(11):e0277827. doi: 10.1371/journal.pone.0277827.
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4. Koneczny I, Tzartos J, Mané-Damas M, Yilmaz V, Huijbers MG, Lazaridis K, Höftberger R, Tüzün E, Martinez-Martinez P, Tzartos S, Leypoldt F.  IgG4 Autoantibodies in Organ-Specific Autoimmunopathies: Reviewing Class Switching, Antibody-Producing Cells, and Specific Immunotherapies. Front Immunol. 2022;13:834342. doi: 10.3389/fimmu.2022.834342. 
5. Yilmaz V, Ulusoy C, Hajtovic S, Turkoglu R, Kurtuncu M, Tzartos J, Lazaridis K, Tuzun E. Effects of Teriflunomide on B Cell Subsets in MuSK-Induced Experimental Autoimmune Myasthenia Gravis and Multiple Sclerosis. Immunol Invest. 2020 Jun 29;:1-14. doi: 10.1080/08820139.2020.1785491.
6. Koneczny I, Yilmaz V, Lazaridis K, Tzartos J, Lenz TL, Tzartos S, Tüzün E, Leypoldt F. Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common? Front Immunol. 2020;11:605214. doi: 10.3389/fimmu.2020.605214.
7. Lazaridis K*, Tzartos SJ. Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management. Front Neurol. 2020;11:596981. doi: 10.3389/fneur.2020.596981.
8. Lazaridis K*, Baltatzidi V, Tzartos S. Immunoadsorption of MuSK autoantibodies as a specific treatment of MuSK-induced experimental autoimmune myasthenia gravis. J Neuroimmunol, 2020 Feb 15;339:577136. doi: 10.1016/j.jneuroim.2019.577136.
9. Lazaridis K*, Tzartos SJ. Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics. Front Immunol. 2020;11:212. doi: 10.3389/fimmu.2020.00212.
10. Hahtapornsawan S, Lazaridis K, Criado FJ, Torsello GF,  Bisdas T, Austermann M, Donas KP. CTA Assessment of Midterm Morphological Changes to Chimney Grafts Used in the Treatment of Juxtarenal Aortic Aneurysms. J Endovasc Ther, 2019 Jul 8. doi: 10.1177/1526602819861747.
11. Koneczny I, Rennspiess D, Marcuse F, Dankerlui N, Abdul Hamid M, Mané-Damas M, Maessen J, Van Schil P, Saxena A, Zisimopoulou P, Lazaridis K, Woodhall M, Karagiorgou K, Tzartos J, Tzartos S, De Baets MH, Molenaar PC, Marx A, Zur Hausen A, Losen M, Martinez-Martinez P. Characterization of the thymus in Lrp4 myasthenia gravis: Four cases. Autoimmun Rev. 2019 Jan;18(1):50-55. doi: 10.1016/j.autrev.2018.07.011.
12. Saxena A, Stevens J, Cetin H, Koneczny I, Webster R, Lazaridis K, Tzartos S, Vrolix K, Nogales-Gadea G, Machiels B, Molenaar PC, Damoiseaux J, De Baets MH, Simon-Keller K, Marx A, Vincent A, Losen M, Martinez-Martinez P. Characterization of an anti-fetal AChR monoclonal antibody isolated from a myasthenia gravis patient. Sci Rep. 2017 Oct 31;7(1):14426. doi: 10.1038/s41598-017-14350-8
13. Lazaridis K*, DalianoudisI, Baltatzidi V, RougkouV, Tzartos S.J. Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis. Journal of Neuroimmun. 2017 Nov 15;312:24-30.. doi:10.1016/j.jneuroim.2017.09.001.
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15. Koneczny I, Stevens J, de Rosa A, Huda S, Huijbers M, Saxena A, Maestri M, Lazaridis K, Zisimopoulou P, Tzartos S, Verschuuren J, van der Maarel S, van Damme P, Vincent A, de Baets M, Molenaar P, Ricciardi R, Martinez-Martinez P , Losen M. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J. Autoimm. 2016 Dec 10. pii: S0896-8411(16)30160-3. doi: 10.1016/j.jaut.2016.11.005. [Epub ahead of print]
16. Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis - autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016 May;12(5):259-68. doi: 10.1038/nrneurol.2016.44. Epub 2016 Apr 22.
17. Stergiou C, Lazaridis K, Zouvelou V, Tzartos J, Mantegazza R, Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, Brenner T, Vaknin A, Berrih-Aknin S, Behin A, Sharshar T, De Baets M, Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, Maniaol A, Gilhus NE, Casasnovas Pons C, Pitha J, Jakubíkova M, Hanisch F, Bogomolovas J, Labeit D, Labeit S, Tzartos SJ. Titin antibodies in "seronegative" myasthenia gravis - A new role for an old antigen. J Neuroimmunol. 2016 Mar 15;292:108-15. doi: 10.1016/j.jneuroim.2016.01.018.
18. Losen M, Martinez-Martinez P, Molenaar PC, Lazaridis K, Tzartos S, Brenner T, Duan RS, Luo J, Lindstrom J, Kusner L. Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors--Recommendations for methods and experimental designs. Exp Neurol. 2015 Aug;270:18-28. doi: 10.1016/j.expneurol.2015.03.010.
19. Kusner LL, Losen M, Vincent A, Lindstrom J, Tzartos S, Lazaridis K, Martinez-Martinez P. Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model-Recommendations for methods and experimental designs. Exp Neurol. 2015 Aug;270:3-10. doi:10.1016/j.expneurol.2015.02.025.
20. Tsonis AI, Zisimopoulou P, Lazaridis K, Tzartos J, Matsigkou E, Zouvelou V, Mantegazza R, Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, Brenner T, Vaknin A, Berrih-Aknin S, Behin A, Sharshar T, De Baets M, Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, Maniaol A, Casasnovas Pons C, Pitha J, Jakubíkova M, Hanisch F, Tzartos SJ. MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study. J Neuroimmunol. 2015 Jul 15;284:10-7. doi:10.1016/j.jneuroim.2015.04.015.
21. Lazaridis K, Evaggelakou P, Bentenidi E, Sideri A, Grapsa E, Tzartos SJ. Specific adsorbents for myasthenia gravis autoantibodies using mutants of the muscle nicotinic acetylcholine receptor extracellular domains. J Neuroimmunol. 2015 Jan 15;278:19-25. doi: 10.1016/j.jneuroim.2014.12.001.
22. Vrolix K, Fraussen J, Losen M, Stevens J, Lazaridis K, Molenaar PC, Somers V, Bracho MA, Le Panse R, Stinissen P, Berrih-Aknin S, Maessen JG, Van Garsse L, Buurman WA, Tzartos SJ, De Baets MH, Martinez-Martinez P. Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor. J Autoimmun. 2014 Aug;52:101-12. doi:10.1016/j.jaut.2013.12.008.
23. Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R, Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, Brenner T, Vaknin A, Berrih-Aknin S, Frenkian Cuvelier M, Stojkovic T, DeBaets M, Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, Maniaol A, Tzartos SJ. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2014 Aug;52:139-45. doi: 10.1016/j.jaut.2013.12.004. Epub 2013 Dec 24. PubMed PMID:24373505.
24. Lazaridis K, Zisimopoulou P, Giastas P, Bitzopoulou K, Evangelakou P, Sideri A, Tzartos SJ. Expression of human AChR extracellular domain mutants with improved characteristics. Int J Biol Macromol. 2014 Feb;63:210-7. doi: 10.1016/j.ijbiomac.2013.11.003.
25. Austermann M, Bisdas T, Torsello G, Bosiers MJ, Lazaridis K, Donas KP. Outcomes of a novel technique of endovascular repair of aneurysmal internal iliac arteries using iliac branch devices. J Vasc Surg. 2013 Nov;58(5):1186-91. doi:10.1016/j.jvs.2013.04.054.
26. Leivonen SK^co, Lazaridis K^co, Decock J, Chantry A, Edwards DR, Kähäri VM. TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2. PLoS One. 2013;8(2):e57474. doi: 10.1371/journal.pone.0057474.
27. Lazaridis K, Zisimopoulou P, Lagoumintzis G, Skriapa L, Trakas N, Evangelakou P, Kanelopoulos I, Grapsa E, Poulas K, Tzartos S. Antigen-specific apheresis of autoantibodies in myasthenia gravis. Ann N Y Acad Sci. 2012 Dec;1275:7-12. doi: 10.1111/j.1749-6632.2012.06788.x.
28. Donas KP, Torsello G, Lazaridis K. Current status of hybrid procedures for thoracoabdominal and pararenal aortic aneurysm repair: techniques and considerations. J Endovasc Ther. 2010 Oct;17(5):602-8. doi: 10.1583/10-3051.1.
29. Lagoumintzis G, Zisimopoulou P, Kordas G, Lazaridis K, Poulas K, Tzartos SJ. Recent approaches to the development of antigen-specific immunotherapies for myasthenia gravis. Autoimmunity. 2010 Aug;43(5-6):436-45. doi: 10.3109/08916930903518099.
30. Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G, Lazaridis K, Sideri A, Zouridakis M, Tzartos SJ. Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J. 2007 Aug;274(15):3799-845. doi: 10.1111/j.1742-4658.2007.05935.x.
31. Denton CP, Lindahl GE, Khan K, Shiwen X, Ong VH, Gaspar NJ, Lazaridis K, Edwards DR, Leask A, Eastwood M, Leoni P, Renzoni EA, Bou Gharios G, Abraham DJ, Black CM. Activation of key profibrotic mechanisms in transgenic fibroblasts expressing kinase-deficient type II Transforming growth factor-β receptor (TβRIIΔk). J Biol Chem. 2005 Apr 22;280(16):16053-65. doi: 10.1074/jbc.M413134200.
32. Wormstone IM, Tamiya S, Eldred JA, Lazaridis K, Chantry A, Reddan JR, Anderson I, Duncan G. Characterisation of TGF-beta2 signalling and function in a human lens cell line. Exp Eye Res. 2004 Mar;78(3):705-14. doi: 10.1016/j.exer.2003.08.006
33. Denton CP, Zheng B, Evans LA, Shi-wen X, Ong VH, Fisher I, Lazaridis K, Abraham DJ, Black CM, de Crombrugghe B. Fibroblast-specific expression of a kinase-deficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J Biol Chem. 2003 Jul 4;278(27):25109-19. doi: 10.1074/jbc.M300636200.
34. Woolaway KE, Lazaridis K, Belsham GJ, Carter MJ, Roberts LO. The 5' untranslated region of Rhopalosiphum padi virus contains an internal ribosome entry site which functions efficiently in mammalian, plant, and insect translation systems. J Virol. 2001 Nov;75(21):10244-9. doi: 10.1128/JVI.75.21.10244-10249.2001.