Laboratory of Molecular Neurobiology and Immunology

Dr. Paraskevi Zisimopoulou | Department of Neurobiology

Head of the Laboratory

Contact:

+30 210-6478839 | .img@.img |  CV

ABOUT

Our group has a research and diagnosis history at the HPI of more than three decades. Our activities involve two arms: a. Neuroimmunology: understanding, diagnosis and treatment of neuroimmune diseases with emphasis on myasthenia gravis (MG) and recently also on neuromyelitis optica (NMO), and b. Structure-function relationships of nicotinic acetylcholine receptors (nAChRs).

Research Highlights

• Development of an antigen-specific therapy for myasthenia gravis (MG). Successful large-scale in vitro and in vivo experiments.
• Identification of LRP4 as a novel autoantigen in MG and coordination of a multinational study.
• Identification of AQP1 as a novel autoantigen in neuromyelitis optica (NMO).
• Elucidation of the crystal structure of the extracellular domain (ECD) of human neuronal α9 nAChR subunit in its free and ligand-bound states with resolutions up to 1.7 Å.
• Elucidation of the crystal structure of the human neuronal nAChR α2-ECD bound to the agonist epibatidine, in pentameric assembly.
• Revelation of important interactions for channel opening in α9- and α2-containing nAChRs by structure-guided mutations and electrophysiology.

UNITS

Neuroimmunology

i) Understanding and treatment of Myasthenia Gravis. Development of a model antigen-specific therapy based on autoAb apheresis.

Myasthenia gravis (MG) is a model antibody-mediated autoimmune disease caused by autoantibodies targeting the neuromuscular junction. About 85% of MG patients have autoantibodies against the acetylcholine receptor (AChR) and approximately 40% of the remaining MG patients have autoantibodies against the muscle specific kinase (MuSK), while antibodies to novel antigens are present in some of the remaining MG patients.
Current treatments for MG include anti-cholinesterases, immunosuppressive agents, thymectomy, plasmapheresis and intravenous immunoglobulins (IVIg). Plasmapheresis is very useful for MG patients when an immediate effect is needed. However, in addition to the autoantibodies, it also removes all other plasma components, the replacement of which increases the risk for allergic reactions and other side effects. The ideal aphaeresis should deplete only the specific autoantibodies, leaving all the other useful IgGs and plasma components unaltered. We are thus developing an antigen-specific therapy for MG, using sepharose columns with immobilized ECDs of nAChR or MuSK as specific immunoadsorbents. The proof of principle for such a promising method has been shown by our team in vitro: Sepharose-immobilized recombinant human AChR and MuSK domains successfully immunoadsorb the autoantibodies from patients’ sera.
Plasmapheresis is very useful for MG patients when an immediate effect is needed. However, in addition to the autoAbs, it also removes all other plasma components, the replacement of which increases the risk for allergic reactions and other side effects. The ideal aphaeresis should deplete only the specific autoAbs. We are developing an antigen-specific therapy for MG, using sepharose columns with immobilized ECDs of nAChR or MuSK as specific immunoadsorbents.
We have examined extensively all five human muscle nAChR ECDs and the MuSK ECD as immunoadsorbents. We generated mutants for large-scale expression in yeast systems with improved characteristics: i) high yields; ii) improved autoAb-binding efficiency and capacity; iii) high speed of adsorption and iv) ability of regeneration. Importantly, we demonstrated that whole sera and purified anti-AChR Abs (but not the Ab-depleted sera) could cause MG in rats, suggesting that immunoadsorption could be an efficient (tentative) therapy.
We developed and characterized in detail a novel rat model for experimental MG by active immunization with human nAChR ECDs, which results in high incidence of symptoms. We then used this model to perform immunoadsorptions in immunized rats, who had already developed MG symptoms. We found that our adsorbents could deplete the rat autoantibodies ex vivo rapidly and efficiently, alleviating or even completely eliminating the MG symptoms. Currently, the same approach is followed for MuSK MG, by developing a rat EAMG model based on immunization with the human MuSK ECD, and treating the immunized symptomatic animals with immunoadsorption. Similarly, the rats show a marked improvement upon treatment, while no signs of toxicity have been observed.
Development of an antigen-specific therapy for MG would provide the first tailor-made treatment for an autoimmune disease, with significant benefits for the patients’ quality of life.

Members involved
Konstantinos Lazaridis, Nikolaos Trakas, Nikolaos Tektonidis, Christalia Stavrou, Maria-Anna Maniou

Collaborators
E. Grapsa (Medical School, University of Athens), Glycorex (Sweden)

Relevant publications

• Lazaridis K, Baltatzidi V, Trakas N, Koutroumpi E, Karandreas N, Tzartos SJ. Characterization of a reproducible rat EAMG model induced with various human acetylcholine receptor domains. J Neuroimmunol. 2017 Feb 15;303:13-21. doi: 10.1016/j.jneuroim.2016.12.011.

• Lazaridis K, Evaggelakou P, Bendenidi E, Sideri A, Grapsa E and Tzartos S.J. 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.

• Lazaridis K, Zisimopoulou P, Giastas P, Bitzopoulou K, Evangelakou P; Sideri A, Tzartos SJ. Expression of human AChR extracellular domain mutants with improved characteristics. 2014 J Biol. Macromol;63:210-7. doi: 10.1016/j.ijbiomac.2013.11.003. Epub 2013 Nov 15

ii) Identification and characterization of novel MG subgroups with novel autoAbs.

The classical immunodiagnostic assays for MG involve radioimmunoassays (RIA) for AChR- and MuSK-Abs. “Seronegative” MG (without detectable AChR and MuSK Abs), accounting for ~15% of the MG patients, presents a serious gap in MG diagnosis, understanding and treatment. We are developing assays for the detection of yet undetectable Abs to novel or known MG autoantigens by which we have identified and partially characterized novel MG subgroups.
i. LRP4 as a novel MG autoantigen. With two American groups we detected LRP4 Abs in ~9% of “seronegative” MG [(1) one of the 3 papers which discovered the LRP4 Abs]. We then developed a cell-based assay (CBA) based on human LRP4-expressing HEK293 cells, for the efficient detection of LRP4 Abs. Using this assay we coordinated a large study (with clinics from 10 countries) in which we detected LRP4 Abs in 18% of 635 “seronegative” MG patients. Only 3.6% (4/110) of patients with other neuroimmune diseases were positive and none of the healthy controls. The clinical data showed that symptoms of LRP4-MG were mild, whereas the few double-positive patients (LRP4 and AChR or MuSK Abs) had more severe symptoms compared with any single-positive subgroup. LRP4 is also crucial in the development and function of motor neurons. Interestingly, we detected LRP4 Abs in 24/104 ALS patient sera; whether these Abs play any role in ALS requires further studies.
We will further investigate the pathogenic potential of LRP4 Abs by in vitro and in vivo experiments.

ii. Detection of novel Abs to known MG antigens: We have developed novel assays: improved CBA for MuSK Abs, RIA for titin Abs and a highly sensitive RIA (super-RIA) for AChR and MuSK Abs. With the assays for MuSK and titin we coordinated two large 13-country studies and identified earlier undetectable Abs in 13% and 13.4% of “seronegative” MG patients, respectively. The clinical characteristics of these novel MG subgroups were partially determined. Anti-titin Abs detected by an ELISA in routine diagnosis are a marker for the presence of thymoma in anti-AChR-positive MG patients. The detection of titin Abs in “seronegative” patients makes titin a novel MG biomarker. The “super-RIA” for AChR and MuSK Abs, has been now applied in a group of Chinese MG patients.

iii) Identification of a novel autoantigen in NMO.

NMO is a chronic inflammatory demyelinating disease of the CNS, related to multiple sclerosis (MS) and often misdiagnosed as MS. However, NMO requires very different treatments from MS, while its wrong diagnosis leads to ineffective treatment, often with detrimental outcome. Abs to aquaporin-4 (AQP4), a water channel in CNS astrocytes, are an invaluable biomarker for NMO diagnosis. Yet, AQP4 Abs are detected in only ~50-70% of NMO patients while a small NMO subgroup has Abs against myelin oligodendrocyte glycoprotein (MOG). Diagnosis of seronegative NMO remains challenging. We found that many “seronegative” NMO patients have Abs against aquaporin-1 (AQP1), another water channel of the astrocytes. We initially developed specific RIAs by which we detected AQP1- and AQP4-autoAbs in 16.7% and 12%, respectively, of 348 patients suspected for NMO but not in controls. Anti-AQP1 specificity was confirmed by competition, protein immunoblotting and ELISA assays, whereas epitope localization was studied by immunoadsorption on intact cells expressing AQP1 and peptide mapping experiments. Most AQP1-Abs were of the complement-activating IgG1 subclass and the majority bound to the ECD of AQP1, suggesting a possible pathogenic role. Overall, AQP1-Abs may prove a novel biomarker for NMO probably with milder symptoms. Interestingly, in collaboration with E. Tuzun and H. Lassmann, we observed AQP1 (but not AQP4) loss in the brain demyelinating lesions of an AQP1-NMO patient, strongly suggesting a possible pathogenic role of these Abs (submitted).
Subsequently, in collaboration with the diagnostic lab “Tzartos NeuroDiagnostics” and the Aeginition Hospital we will investigate the possible pathogenic role of these Abs while we are in the process of developing a commercial ELISA kit for the AQP1 Abs.

iv) Autoimmunity linked to neuronal nAChRs: Identification of neuronal nAChR Abs and their role in neurological diseases.

Although small studies suggest the presence of Abs against neuronal nAChRs linked to autoimmune encephalitis, disautonomia, schizophrenia etc, no systematic search for such Abs has been performed yet, with the exception of α3 nAChR Abs. Furthermore, several MG patients have additional non-MG neurological symptoms, which could be due to cross-reaction of muscle nAChR Abs with neuronal nAChRs. We have now the tools to elucidate the involvement of these Abs in neurological diseases. We will develop assays (RIAs, ELISAs and CBAs) for several neuronal nAChRs and with these we will screen our large biobank of relevant sera and CSF. Then, in collaboration with clinicians we will study the subtype-specific clinical characteristics and response to therapies.

Members involved
Paraskevi Zisimopoulou, Maria Michael, Ioannis Tzartos, Christos Stergiou, Nikolaos Trakas

Relevant publications

Hong Y, Skeie GO, Zisimopoulou P, Karagiorgou K, Tzartos SJ, Gao X, Yue YX, Romi F, Zhang X, Li HF, Gilhus NE. Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms. J Neurol. 2017 Mar 31. doi: 10.1007/s00415-017-8478-z.

Kruger JM, Karussis D, Zisimopoulou P, Petrou P. Low-Density Lipoprotein Receptor-Related Protein 4-Positive Myasthenia Gravis in a Double-Seronegative, Electromyography-Negative Patient. J Neuroophthalmol. 2017 Mar 27. doi: 10.1097/WNO.0000000000000499.

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

Tzartos JS, Zisimopoulou P, Rentzos M, Karandreas N, Zouvelou V, Evangelakou P, Tsonis A, Thomaidis T, Lauria G, Andreetta F, Mantegazza R, Tzartos SJ. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-7

Tüzün E, Tzartos J, Ekizoğlu E, Stergiou C, Zisimopoulou P, Coban A, Shugaiv E, Türkoğlu R, Kürtüncü M, Baykan B, Tzartos S. Aquaporin-1 antibody in neuromyelitis optical patients. Eur Neurol. 2014;72(5-6):271-2

Zouvelou V, Zisimopoulou P, Psimenou E, Matsigkou E, Stamboulis E, Tzartos SJ. AChR-myasthenia gravis switching to double-seropositive several years after the onset. J Neuroimmunol. 2014 Feb 15;267(1-2):111-2

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

Tzartos JS, Stergiou C, Kilidireas K, Zisimopoulou P, Thomaidis T, Tzartos SJ. Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders. PLoS One. 2013 Sep 23;8(9):e74773

Zouvelou V, Zisimopoulou P, Rentzos M, Karandreas N, Evangelakou P, Stamboulis E, Tzartos SJ. Double seronegative myasthenia gravis with anti-LRP 4 antibodies. Neuromuscul Disord. 2013 Jul;23(7):568-70

Zouvelou V, Zisimopoulou P, Rentzos M, Karandreas N, Evangelakou P, Stamboulis E, Tzartos SJ. Double seronegative myasthenia gravis with anti-LRP 4 antibodies. Neuromuscul Disord. 2013 Jul;23(7):568-70

Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmun Rev. 2013 Jul;12(9):924-30

Trakas N, Zisimopoulou P, Tzartos SJ. Development of a highly sensitive diagnostic assay for muscle-specific tyrosine kinase (MuSK) autoantibodies in myasthenia gravis. J Neuroimmunol. 2011 Dec 15;240-241:79-86

Structure-function relationship studies of brain nAChRs

Introduction
nAChRs are the prototypic members of the pentameric ligand-gated ion channel (pLGIC) family, also including the serotonin 5-HT3, GABAA/C glycine (Gly) and some invertebrate receptors. They form cation-selective channels of homologous subunits, each comprising an N-terminal extracellular domain (ECD) of 210-250 amino acids, bearing the acetylcholine (ACh) or ligand-binding sites, a transmembrane domain (TM) of four α-helices and a large cytoplasmic loop (110–270 amino acids). Neuronal nAChRs are widely distributed in the peripheral and central nervous systems, regulating neuronal excitability and neurotransmitter release, and are also found in the immune system and in various peripheral tissues. Their dysfunction is related to various neurological and neuropsychiatric diseases. We have initiated studies on some of the most important subunits for understanding their structure, function and involvement in pathology with the ultimate aim to facilitate the design of effective and specific drugs targeting distinct subtypes associated with the above diseases. To this aim we express the ECDs of human neuronal nAChR subunits, as well as the intact and “truncated” nAChRs in higher eukaryotic expression systems, we produce monoclonal antibodies against them and we study their a) structural, b) pharmacological and c) electrophysiological properties.

We are conducting electrophysiology studies of nAChRs, wild type or mutants, expressed in either mammalian cell lines or Xenopus oocytes. Recently, we expressed the α9α10 and α2β2 nAChRs in Xenopus oocytes and performed two-electrode-voltage clamp recordings to assess the efficacy and potency of several ligands and the effect of structure-guided mutations on their functionality. We will perform similar electrophysiological studies for other nAChRs based on their anticipated crystal structures.

SERVICES

Specific Projects

i) α9 nAChR
The α9-ECD structurewas determined in its free state and in complexes with two antagonists at resolutions of 1.7 to 2.7 Å (Fig. 1). α9 forms either homopentameric α9 or heteropentameric α9α10 nAChRs, both found in the inner ear, sympathetic neurons and non-neuronal cells. The α9-containing nAChRs are potential targets for the therapy of ear disorders, chronic pain, pemphigus vulgaris and lung and breast cancers. Our structures revealed i) an important interaction, involving the unique in α9 Thr147 residue, essential for the initial rearrangements triggered upon agonist binding, leading to channel opening, ii) a hydration pocket linking residues important for signal transmission, iii) a membrane-facing network coordinated by Arg210, coupling agonist binding to channel opening and iv) the interactions of antagonists with α9 and the rearrangements occurring upon their binding. Furthermore, our biochemical characterization experiments validated the importance of the α9-ECD structure, despite its monomeric state.

Figure 1. Structures of the free and antagonist-bound human nAChR α9-ECD. Side-views of (a) the α9-ECD monomer, (b) the methyllycaconitine (MLA)-bound α9-ECD (MLA: displayed electron density in green mesh) and (c) the complex of α9-ECD (green) with α-bungarotoxin (magenta).

 

We are currently working on the elucidation of the structures of α9-ECD complexes with a number of ligands (e.g. nicotine, gallamine, α-conotoxin RgIA), which in conjunction with biochemical experiments will shed light on the pharmacological properties of the specific subunit. α-conotoxins (provided by Profs. V. Tsetlin, Russia and M. McIntosh, USA) are specific α9α10 nAChR antagonists and potential drugs for chronic pain. Moreover, functional studies are in progress in order to assess the contribution of the discovered interaction networks in transmitting the signal of agonist binding to the ion-channel pore.

Members involved
Marios Zouridakis, Petros Giastas, Eleftherios Zarkadas, Dafni Chroni-Tzartou

Collaborators
Prof.. V. Tsetlin (Russian Academy of Sciences, Moscow, Russia) and Prof. M. McIntosh (University of Utah, Salt Lake City, USA)

Relevant recent publications

• Zouridakis, M., Giastas, P., Zarkadas, E., Chroni-Tzartou, D., Bregestovski, P., Tzartos, S.J. Crystal structures of free and antagonist-bound states of human alpha 9 nicotinic receptor extracellular domain. Nature Struct. Mol. Biol., 21, 976-980, 2014
• Azam, L., Papakyriakou, A., Zouridakis, M., Giastas, P., Tzartos, S., McIntosh, M., Molecular interaction of α-conotoxin RgIA with rat α9α10 nAChR. Mol. Pharm.5, 855-64, 2015

ii) α2 nAChR
The α2-ECD structure was determined in its pentameric assembly induced by the bound agonist epibatidine (Fig. 2a,b), being the first reported pentameric structure for any neuronal nAChR domain. α2 assembles with the β2 subunit to form α2β2 nAChRs whose dysfunction has been associated with nicotine dependence, asthma, bipolar disorder, obesity, and other conditions. Two α2β2 subtypes exist with either low or high agonist sensitivity (LS or HS, respectively) presumed to have stoichiometries (α2)3(β2)2 and (α2)2(β2)3, respectively (Fig. 3a,b,c). The α2-ECD structure revealed i) an interacting network of binding-site residues shaping the binding cavity and ii) critical residues that stabilize the agonist binding. In addition, by structure-guided mutations and electrophysiology we a) proved the existence of the α2/α2 binding site in the LS subtype and b) showed the importance of specific intersubunit interactions in mediating the signal transduction processes, by influencing the activation sensitivity, and in the desensitization properties.

Figure 2. Structure of the pentameric assembly of human neuronal α2 nAChR-ECD in complex with epibatidine. (a) Side-view and (b) top-view of the structure. Each subunit is colored differently and the five epibatidine molecules bound to the five ligand-binding sites are shown in orange spheres.

 

 

Figure 3. Electrophysiological responses to 100 μM ACh (a) of the LS subtype and (b) of the HS subtype of α2β2 nAChR obtained in Xenopus oocytes. (c) Schematic representation of the two different subtypes. Their ligand-binding sites is shown with arrows. The additional binding site of the α2β2 LS subtype is shown in green.

We are currently working with mutated forms of the α2-ECD resembling other neuronal nAChR subunits (chimeric nAChRs) aiming at the structural elucidation of near-native ligand binding sites that are present in other nAChR subtypes. Moreover, we are exploiting the α2-ECD pentameric structure in order to identify allosteric binding sites, by implementing structural, biophysical and electrophysiological studies.

Members involved
Petros Giastas, Marios Zouridakis, Dafni Chroni-Tzartou, Giorgos Tsiafaras, Nikolaos Kouvatsos (former member).

Relevant publication

• Kouvatsos, N., Giastas, P., Chroni-Tzartou, D., Poulopoulou, C., Tzartos, J.S. Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer. Proc. Natl. Acad. Sci. USA 113(34):9635-40, 2016

iii) “Truncated” nAChRs
Despite the intense effort of several groups to obtain high resolution structures of intact nAChRs, this aim has not been achieved yet. This drawback is mainly ascribed to difficulties in obtaining sufficient expression yields of nAChRs, in crystallizing them due to their predicted partially unstructured large cytoplasmic loops and in obtaining heteromeric nAChR subtypes with single stoichiometries.
In order to increase the expression yield we have adopted the use of higher expression systems, such as insect and mammalian cells, which have proven suitable for the production of functional and properly assembled mammalian proteins due to their post-translational modification, targeting and membrane insertion machineries.
Moreover, to increase the crystallizability of our expressed proteins we replace their flexible cytoplasmic loops with short loops inspired by their prokaryotic homologues, producing by this way the “Truncated” nAChRs.
Recently, we coexpressed and purified wild type and truncated constructs of the human α4 and β2 nAChR subunits in Sf9 insect cells, using the baculovirus expression system. The truncated constructs presented increased expression yields compared to the wild type ones and we succeeded to the solubilize and purify pentameric α4β2 nAChR.
We are currently following the same strategy to express and purify α7 and α9α10 nAChRs in adequate quantities and of sufficient quality in order to proceed to structural studies.

Members involved
Eleftherios Zarkadas (former member), Marios Zouridakis, Petros Giastas, Nikolaos Kouvatsos (former member).

Relevant publication

Kouvatsos N, Niarchos A, Zisimopoulou P, Eliopoulos E, Poulas K, and Tzartos S. Purification and functional characterization of a truncated human α4β2 nicotinic acetylcholine receptor. Int. J Biol Macromol (14) 441-3, 2014.

iv) Expression of the wild-type and mutated forms of the ECDs of the neuronal α5 and β3 nAChRs and of the Zinc-activated protein (ZAC)
The α5 and β3 subunits of the neuronal nAChR have been long considered as auxiliary subunits of several nAChR subtypes. Recent data however have demonstrated their contribution to the formation of anorthodox orthosteric binding sites, while these are implicated in addiction to smoking or neurological disorders. Thus, elucidation of their 3D structures in the absence or presence of cholinergic ligands is gaining increased interest.
On the other hand, ZAC protein is the least studied member of the pentameric ligand gated ion channels, which is activated by zinc and other ions. The ultimate goal is elucidation of the 3D structure of the whole protein or at least of its soluble extracellular domain and the understanding of its functional mechanism by combination of structural studies with two-electrode voltage clamp recordings.

Members involved:
Marios Zouridakis, Petros Giastas, George Tsafaras (former member), Eleftherios Zarkadas (former member), Dafni Chroni-Tzartou

FUNDING

Current and past (recent) grants:

● Stavros Niarchos Foundation. Development of innovative biological products and services for infectious and neurodegenerative diseases: “Structural and functional studies of nAChRs” (2016-2019)
● Toleranzia. Treatment of experimental autoimmune MG (2016-2017)
● Hellenic Neuroimmunology Society. Antibodies to Aquaporin-1 in neuromyelitis optica (2016-2017)
● Muscular Dystrophy Association of America. Diagnosis and characterization of LRP4-MG, a novel myasthenia gravis subtype (2013-2016)
● GSRT Greek-Israeli bilateral Program: Development of tools for the understanding and diagnosis of neurological diseases (2013-2015)
● GSRT-Program Excellence: Myasthenia Gravis (2012-2015)
● Association Francaises des Myopathies (AFM) Diagnosis, prevalence and characterization of a novel myasthenia gravis subtype, LRP4-MG (2012-2014)
● FP7-Regpot “Neurosign”. Development of a center of excellence in Neurosignaling. With the labs of R. Matsas and L. Probert (coordinator: S. Tzartos) 2010-2014
● FP7 Fight-MG. Myasthenias, a group of immune mediated neurolog. diseases (2009-2014)
● Muscular Dystrophy Association of America (MDA). Antigen-specific therapeutic autoantibody depletion in myasthenia gravis (MDA158763) 2010-2012
● FP7 Fight-MG. Myasthenias, a group of immune mediated neurological diseases: from etiology to therapy (2009-2013)
● FP7-Neurocypres. Neurotransmitter Cys-loop receptors: structure, function and disease (2008-2012)
● Association Francaises des Myopathies (AFM), Pentameric AChR extracellular domain for efficient autoantibody depletion in myasthenia gravis (2009-2011)
● FP6-STREP-Myastaid. Development of models to improve management of myasthenia gravis: From basic knowledge to clinical application (2006-2010)
● FP6- Public Health. European Myasthenia Gravis Network (EuroMyasthenia) 2006-2009

COLLABORATORS (REGULATIONS)

Kostas Lazaridis, .img@.img
Christos Stergiou, .img@.img
John Tzartos, .img@.img

P.J. Corringer (Institut Pasteur Paris): Structural & Functional Biology
S. Berrih-Aknin (University P. and M. Curie, Paris): Neuroimmunology
P. Bregestovski (Universite de Marseille): Electrophysiology
M. DeBaets (Univ. Limburg, Maastricht, The Netherlands): Neuroimmunology
E. Touzun (Istanbul University) Neuroimmunology
M. McIntosh (Univ. Utah, USA): Protein structure-function
M. Skok (Palladin Institute. Biochemistry, Kiev, Ukraine): Physiology
V. Tsetlin (Shemyakin-Ovchinnikov Inst. of Bioorganic Chem., Moscow): Biophysics

FORMER MEMBERS (COURCES)

V. Avramopoulou, M. Belimezi, A. Bentenidi, K. Bitzopoulou, P. Evangelakou, E. Fostieri, I. Gavra, L. Jacobson, A. Karagiorgou, V. Katsemi, M. Kontou, K. Kostelidou, N. Kouvatsos, O. Lazos, A. Mamalaki, M. Marinou, E. Matsigkou, E. Papadaki, D. Papanastasiou, K. Poulas, E. Protopapadaki, L. Psaridi-Linardaki, M. Remoundos, L. Skriapa, A. Sotiriadis, P. Tsantili, A. Tsonis, Th. Tsouloufis, E. Zarkadas

LINKS

PUBLICATIONS

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Hong Y, Zisimopoulou P, Trakas N, Karagiorgou K, Stergiou C, Skeie GO, Hao HJ, Gao X, Owe JF, Zhang X, Yue YX, Romi F, Wang Q, Li HF, Gilhus NE, Tzartos SJ. Multiple antibody detection in 'seronegative' myasthenia gravis patients. Eur J Neurol. 2017 Jun;24(6):844-850. doi: 10.1111/ene.13300.

Giastas P, Zouridakis M, Tzartos SJ. Understanding structure-function relationships of the human neuronal acetylcholine receptor: insights from the first crystal structures of neuronal subunits. Br J Pharmacol. 2017 Apr 27. doi: 10.1111/bph.13838. [Epub ahead of print] Review.

Lazaridis K, Baltatzidi V, Trakas N, Koutroumpi E, Karandreas N, Tzartos SJ. Characterization of a reproducible rat EAMG model induced with various human acetylcholine receptor domains. J Neuroimmunol. 2017 Feb 15;303:13-21. doi: 10.1016/j.jneuroim.2016.12.011.

Koneczny I, Stevens JA, De Rosa A, Huda S, Huijbers MG, Saxena A, Maestri M, Lazaridis K, Zisimopoulou P, Tzartos S, Verschuuren J, van der Maarel SM, van Damme P, De Baets MH, Molenaar PC, Vincent A, Ricciardi R, Martinez-Martinez P, Losen M. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J Autoimmun. 2017 Feb;77:104-115. doi: 10.1016/j.jaut.2016.11.005.

Türkoğlu R, Lassmann H, Aker FV, Tzartos J, Tzartos S, Tüzün E. Recurrent tumefactive demyelinating lesions: a pathological study. Clin Neuropathol. 2017 Feb 17. doi: 10.5414/NP301005.

Hong Y, Skeie GO, Zisimopoulou P, Karagiorgou K, Tzartos SJ, Gao X, Yue YX, Romi F, Zhang X, Li HF, Gilhus NE. Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms. J Neurol. 2017 May;264(5):955-962. doi: 10.1007/s00415-017-8478-z.

2017
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Lykhmus O, Koval L, Pastuhova D, Zouridakis M, Tzartos S, Komisarenko S, Skok M. The role of carbohydrate component of recombinant α7 nicotinic acetylcholine receptor extracellular domain in its immunogenicity and functional effects of resulting antibodies. 2016 Immunobiology;221(12):1355-1361. doi: 10.1016/j.imbio.2016.07.012.

Kouvatsos N, Giastas P, Chroni-Tzartou D, Poulopoulou C, TzartosSJ. Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9635-40. doi: 10.1073/pnas.1602619113.

Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimoupoulou P, and Tzartos S. Myasthenia gravis-autoantibody characteristics and their implications for therapy. Nat. Rev. Neurol. 2016; 12(5):259-68. doi: 10.1038/nrneurol.2016.44. Epub 2016 Apr 22. Review

Küçükerden M, Huda R, Tüzün E, Yılmaz A, Skriapa L, Trakas N, T. Strait R, Finkelman FD, Kabadayı S, Zisimopoulou P, TzartosS, Christadoss P. MuSK induced experimental autoimmune myasthenia gravis does not require IgG1 antibody to MuSK. J. Neuroimmunol. 2016. Jun 15;295-296:84-92. doi: 10.1016/j.jneuroim.2016.04.003.

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, TzartosSJ.Titin antibodies in “seronegative” myasthenia gravis – A new role for an old antigen, J. Neuroimmunology, 2016. 292: 108-115. doi: 10.1016/j.jneuroim.2016.01.018.

2016
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Lykhmus O, Voytenko L, Koval L, Mykhalskiy S, Cholin V, Peschana K, Zouridakis M, Tzartos S, Komisarenko S and Skok M. α7 Nicotinic Acetylcholine Receptor-Specific Antibody Induces Inflammation And Amyloid β42 Accumulation In The Mouse Brain To Impair Memory. Plos-1, 2015 Mar 27;10(3):e0122706. doi: 10.1371/journal.pone.0122706.

Maurer M, Bougoin S, Feferman T, Frenkian M, Bismuth J, Mouly V, Clairac G, Tzartos S, Fadel E, Eymard B, Fuchs S, Souroujon MC, Berrih-Aknin S. IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis. Acta Neuropathol Commun. 2015 Jan 15;3(1):1. doi: 10.1186/s40478-014-0179-6.

Azam L, Papakyriakou A, Zouridakis M, Giastas P, Tzartos SJ, McIntosh JM. Molecular Interaction of α-Conotoxin RgIA with the Rat α9α10 Nicotinic Acetylcholine Receptor.Mol Pharmacol. 2015 May;87(5):855-64. doi: 10.1124/mol.114.096511. Epub 2015 Mar 4. PMID:25740413

Arnaouteli S, Giastas P, Andreou A, Tzanodaskalaki M, Aldridge C, Tzartos SJ, Vollmer W, Eliopoulos E, Bouriotis V. Two putative polysaccharide deacetylases are required for osmotic stability and cell shape maintenance in Bacillus anthracis. J Biol Chem. 2015 Mar 30.pii: jbc.M115.640029. [Epub ahead of print] PMID:25825488

Yilmaz V, Oflazer P, Aysa F, Durmus H, Poulas K, Parman Y, Tzartos S, Tuzun E, Deymeer F, Saruhan-Direskeneli G. Differential cytokine changes in patients with myasthenia gravis with antibodies against AChR and MuSK. PLOS-1. 2015; 10(4):e0123546. doi: 10.1371/journal.pone.0123546

Özkök E, Durmus H, Yetimler B, Taslı H, Trakas N, Ulusoy C, Lagoumintzis G, Tzartos S, and Tüzün E: Reduced muscle mitochondrial enzyme activity in MuSK-immunized mice. Clinical Neuropathology. 2015 Nov-Dec;34(6):359-63. doi: 10.5414/NP300875.

Ulusoy C, Zibandeh N, Yıldırım S, Trakas N, Zisimopoulou P, Küçükerden M, Tașlı H, TzartosS, Göker K, Tüzün E, Akkoç T. Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. J Neuroinflammation. 2015 Dec 9;12(1):231. doi: 10.1186/s12974-015-0451-0.

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, TzartosSJ. MuSK autoantibodies in myastheniagravis detected by cell based assay-A multinational study. J Neuroimmunol. 2015 Jul 15;284:10-7. doi: 10.1016/j.jneuroim.2015.04.015.

Lykhmus O, Gergalova G, Zouridakis M, Tzartos S, Komisarenko S, Skok M. Inflammation decreases the level of alpha7 nicotinic acetylcholine receptors in the brain mitochondria and makes them more susceptible to apoptosis induction. Int Immunopharmacol. 2015 Nov;29(1):148-51. doi: 10.1016/j.intimp.2015.04.007.

Tuzun E, Berrih-Aknin S, Brenner T, Kusner LL, Le Panse R, Yang H, Tzartos S, Christadoss P. Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization. Exp Neurol. 2015 Feb 16. pii: S0014-4886(15)00032-1. doi: 10.1016/j.expneurol.2015.02.009.

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 Mar 3.pii: S0014-4886(15)00055-2. doi: 10.1016/j.expneurol.2015.02.025.

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 Mar 18.pii: S0014-4886(15)00078-3. doi: 10.1016/j.expneurol.2015.03.010.

2015
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Zouvelou V, Zisimopoulou P, Psimenou E, Matsigkou E, Stamboulis E, Tzartos SJ. AChR-myasthenia gravis switching to double-seropositive several years after the onset.J. Neuroimmunol. 2014 Feb 15;267(1-2):111-2. doi: 10.1016/j.jneuroim.2013.12.012.

Tsivgoulis G, Dervenoulas G, Tzartos SJ, Zompola C, Papageorgiou SG, Voumvourakis K. Double seropositive myasthenia gravis with acetylocholine receptor and lipoprotein receptor-related protein 4 antibodies. Muscle and Nerve.2014 Jan 7.doi: 10.1002/mus.24166.

Zis P, Argiriadou V, Temperikidis PP, Zikou L, Tzartos SJ, Tavernarakis A. Parkinson’s disease associated with myasthenia gravis and rheumatoid arthritis. Neurol. Sci.(Letter to the Editor). Published on line 2-7-2014. DOI 10.1007/s10072-014-1660-5

Marino M, Maiuri MT, Di Sante G, Scuderi F, La Carpia F, Trakas N, Provenzano C, Zisimopoulou P, Ria F, Tzartos SJ, Evoli A, Bartoccioni E. T cell repertoire in DQ5-positive MuSK-positive myasthenia gravis patients. J Autoimmun. 2014 Jan 4.pii: S0896-8411(13)00154-6. doi: 10.1016/j.jaut.2013.12.007.

Avidan N, Le Panse R; Harbo H, Bernasconi P, Poulas K, Ginzburg E; Cavalcante P, Colleoni L; Baggi F, Antozzi C, Truffault F, Horn-Saban S, Pöschel S, Zagoriti Z, Maniaol A, Lie B; Bernard I, Saoudi A, Illes Z, Casasnovas C, Melms A, Tzartos S; Willcox N, Kostera-Pruszczyk A, Tallaksen C, Mantegazza R, Berrih-Aknin S, Miller A. VAV1 and BAFF, via NFκB pathway, are genetic risk factors for Myasthenia Gravis. 2014 Annals of Clinical and Translational Neurology,1(5):329-39. doi: 10.1002/acn3.51

Ulusoy C, Kim E, Tüzün E, Huda R, Yılmaz V, Poulas K, Trakas N, Skriapa L, Niarchos A, Strait RT, Finkelman FD, Turan S, Zisimopoulou P, Tzartos S, Saruhan-Direskeneli G, Christadoss P. Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice. Clin Immunol. 2014 Feb 28.pii: S1521-6616(14)00049-7. doi: 10.1016/j.clim.2014.02.012.

Tuzun E., Tzartos J., Ekizoglu E., Stergiou C., Zisimopoulou P., Çoban A., Shugaiv E., Türkoglu R., Kürtüncü M., Baykan B., Tzartos S. Title: Aquaporin-1 Antibody in Neuromyelitis Optica Patients. European Neurology, 2014. Eur Neurol. 2014 Sep 27;72(5-6):271-272.

Kouvatsos N, Niarchos A, Zisimopoulou P, Eliopoulos E, Poulas K, and Tzartos S. Purification and functional characterization of a truncated human α4β2 nicotinic acetylcholine receptor. Int. J Biol Macromol, 2014 Jul 8. pii: S0141-8130(14)00441-3. doi: 10.1016/j.ijbiomac.2014.06.058.

Boltsis I, Lagoumintzis G, Chatzileontiadou DSM, Giastas P, Tzartos SJ, Leonidas DD, and Poulas K. Non-contact Current Transfer Induces the Formation and Improves the X-ray Diffraction Quality of Protein Crystals. 2014 Cryst.Growth Des. DOI: 10.1021/cg5004098

Zouridakis M, Giastas P, Zarkadas E, Chroni-Tzartou D, Bregestovski P and Tzartos SJ. Crystal structures of the free and antagonist-bound states of the extracellular domain of human α9 nicotinic receptor. 2014. Nat. Struct & Mol. Biol. doi:10.1038/nsmb.2900.

Tsivgoulis G, Dervenoulas G, Kokotis P, Zompola C, Tzartos J, Tzartos SJ, Voumvourakis KI. Double seronegative myasthenia gravis with low density lipoprotein-4 (LRP4) antibodies presenting with isolated ocular symptoms. 2014. J. Neurol. Sci. doi: 10.1016/j.jns.2014.09.013.

Kordas G, Lagoumintzis G, Sideris S, Poulas K and Tzartos SJ.Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients.PLOS-1.2014. Sep 26;9(9):e108327. doi: 10.1371/journal.pone.0108327.

Skriapa L, Zisimopoulou P, Trakas N, Grapsa E, Tzartos SJ. Expression of extracellular domains of Muscle Spesific Kinase (MuSK) and use as immunoadsorbents for the development of an antigen specific therapy. 2014. J. Neuroimmunol. DOI: 10.1016/j.jneuroim.2014.09.013

Lazaridis K, Evaggelakou P, Bendenidi E, Sideri A, Grapsa E and Tzartos S.J. 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. Kouvatsos N, Niarchos A, Zisimopoulou P, Eliopoulos E, Poulas K, and Tzartos S. Purification and functional characterization of a truncated human α4β2 nicotinic acetylcholine receptor. Int. J Biol Macromol, 2014 Jul 8. pii: S0141-8130(14)00441-3. doi: 10.1016/j.ijbiomac.2014.06.058.

Boltsis I, Lagoumintzis G, Chatzileontiadou DSM, Giastas P, Tzartos SJ, Leonidas DD, and Poulas K. Non-contact Current Transfer Induces the Formation and Improves the X-ray Diffraction Quality of Protein Crystals. 2014 Cryst.Growth Des. DOI: 10.1021/cg5004098

Zouridakis M, Giastas P, Zarkadas E, Chroni-Tzartou D, Bregestovski P and Tzartos SJ. Crystal structures of the free and antagonist-bound states of the extracellular domain of human α9 nicotinic receptor. 2014. Nat. Struct & Mol. Biol. doi:10.1038/nsmb.2900.

Tsivgoulis G, Dervenoulas G, Kokotis P, Zompola C, Tzartos J, Tzartos SJ, Voumvourakis KI. Double seronegative myasthenia gravis with low density lipoprotein-4 (LRP4) antibodies presenting with isolated ocular symptoms. 2014. J. Neurol. Sci. doi: 10.1016/j.jns.2014.09.013.

Kordas G, Lagoumintzis G, Sideris S, Poulas K and Tzartos SJ.Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients.PLOS-1.2014. Sep 26;9(9):e108327. doi: 10.1371/journal.pone.0108327.

Skriapa L, Zisimopoulou P, Trakas N, Grapsa E, Tzartos SJ. Expression of extracellular domains of Muscle Spesific Kinase (MuSK) and use as immunoadsorbents for the development of an antigen specific therapy. 2014. J. Neuroimmunol. DOI: 10.1016/j.jneuroim.2014.09.013

Lazaridis K, Evaggelakou P, Bendenidi E, Sideri A, Grapsa E and Tzartos S.J. 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.

2014
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Zouvelou V, Stamboulis E, Skriapa L, Tzartos SJ. MuSK-Ab positive myasthenia: Not always grave. J Neurol Sci. 2013, 15;331(1-2):150-1.

Zouvelou V, Kyriazi S, Rentzos M, Belimezi M, Micheli MA, Tzartos SJ, Stamboulis E. Double-seropositive myasthenia gravis. Muscle Nerve. 2013, 47(3):465-6.

Zouvelou V, Zisimopoulou P, Rentzos M, Karandreas N, Evangelakou P, Stamboulis E, Tzartos SJ. Double seronegative myasthenia gravis with anti-LRP 4 antibodies.Neuromuscul Disord. 2013 Jul;23(7):568-70.

Tzartos JS, Stergiou Ch, Kilidireas K, Zisimopoulou P, Thomaidis T, and Tzartos SJ, Aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders. PLOS-1, 2013.doi: 10.1371/journal.pone.0074773.

Lagoumintzis G, Zisimopoulou P, Trakas N, Grapsas E, Poulas K and Tzartos SJ (2013). Scale up and safety parameters of antigen specific immunoadsorption of human anti-acetylcholine receptor antibodies. J. Neuroimmunol. 2014; 267(1-2):1-6. doi: 10.1016/j.jneuroim. 2013.11.001. Epub 2013 Nov 10.

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. Autoimmunity. 2013. Epub ahead of print. http://dx.doi.org/10.1016/j.jaut.2013.12.004

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. Autoimmunity. 2014. doi: 10.1016/j.jaut.2013.12.008.

Lazaridis K, Zisimopoulou P, Giastas P, Bitzopoulou K, Evangelakou P; Sideri A, Tzartos SJ. Expression of human AChR extracellular domain mutants with improved characteristics. 2014 J Biol. Macromol;63:210-7. doi: 10.1016/j.ijbiomac.2013.11.003. Epub 2013 Nov 15

Niarchos A, Zouridakis M, Douris V, Georgostathi A, Kalamida D, Sotiriadis A, Poulas K, Iatrou K.. Tzartos SJ. Expression of a highly antigenic and native-like folded extracellular domain of the human α1 subunit of muscle nicotinic acetylcholine receptor, suitable for use in antigen specific therapies for Myasthenia Gravis. 2013 PLOS-1; 8(12):e84791. doi: 10.1371/journal.pone.0084791

Tzartos JS, Zisimopoulou P, Rentzos M, Karandreas N, Zouvelou V, Evangelakou P, Tsonis A, Thomaidis T, Lauria G, Andreetta F, Mantegazza R, Tzartos SJ. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann. Clin Transl Neurol. Dec. 2013. doi: 10.1002/acn3.26.

Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmun Rev. 2013 Jul;12(9):924-30.

Zagoriti Z, Kambouris M, Patrinos GP, Tzartos S, and Poulas K. (2013). Recent advances in genetic predisposition of myasthenia gravis. BioMed Res Int. Epub 2013 Nov 5.

2013
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Zagoriti Z, Georgitsi M, Giannakopoulou O, Ntellos F, Tzartos SJ, Patrinos GP, Poulas K. Genetics of myasthenia gravis: a case-control association study in the Hellenic population. Clin Dev Immunol. 2012;2012:484919. doi:10.1155/2012/484919. Epub 2012 Sep 25.

Poulas K, Koutsouraki E, Kordas G, Kokla A, Tzartos SJ. Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by d-penicillamine. J Neuroimmunol. 2012 Sep 15;250(1-2):94-8. doi: 10.1016/j.jneuroim.2012.05.011.

Tzartos, J., C. Stergiou, H. Alexopoulos, P. Zisimopoulou, C. Karageorgiou, K. Kilintireas, M. Dalakas, and S. Tzartos, (2012) Highly Sensitive Radioimmunoassay Identifies Anti-Aquaporin-4 Autoantibodies in Several “Seronegative” Patients Suspected for Neuromyelitis Optica-Spectrum Disorders (NMO). Neurology, 78, P02133.

Zhang, B., J.S. Tzartos, M. Belimezi, S. Ragheb, B. Bealmear, R.A. Lewis, W.C. Xiong, R.P. Lisak, S.J. Tzartos, and L. Mei, (2012) Autoantibodies to Lipoprotein-Related Protein 4 in Patients With Double-Seronegative Myasthenia Gravis. Archives of Neurology. 69(4): p. 445-451.

2012
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Trakas, N., P. Zisimopoulou, and S.J. Tzartos, Development of a highly sensitive diagnostic assay for muscle-specific tyrosine kinase (MuSK) autoantibodies in myasthenia gravis. 2011 Journal of Neuroimmunology. 240: p. 79-86.

Koval, L., O. Lykhmus, O. Kalashnyk, N. Bachinskaya, G. Kravtsova, M. Soldatkina, M. Zouridakis, C. Stergiou, S. Tzartos, V. Tsetlin, S. Komisarenko, and M. Skok, (2011) The Presence and Origin of Autoantibodies Against alpha 4 and alpha 7 Nicotinic Acetylcholine Receptors in the Human Blood: Possible Relevance to Alzheimer’s Pathology. Journal of Alzheimers Disease. 25(4): p. 747-761.

Lykhmus, O., L. Koval, M. Skok, M. Zouridakis, P. Zisimopoulou, S. Tzartos, V. Tsetlin, S. Granon, J.P. Changeux, S. Komisarenko, and I. Cloez-Tayarani, (2011) Antibodies against Extracellular Domains of alpha4 and alpha7 Subunits Alter the Levels of Nicotinic Receptors in the Mouse Brain and Affect Memory: Possible Relevance to Alzheimer’s Pathology. Journal of Alzheimers Disease. 24(4): p. 693-704.

Pavlakis, P.P., H. Alexopoulos, M.L. Kosmidis, E. Stamboulis, J.G. Routsias, S.J. Tzartos, A.G. Tzioufas, H.M. Moutsopoulos, and M.C. Dalakas, (2011) Peripheral neuropathies in Sjogren syndrome: a new reappraisal. Journal of Neurology Neurosurgery and Psychiatry. 82(7): p. 798-802.

Stergiou, C., P. Zisimopoulou, and S.J. Tzartos, (2011) Expression of Water-soluble, Ligand-binding Concatameric Extracellular Domains of the Human Neuronal Nicotinic Receptor alpha 4 and beta 2 Subunits in the Yeast Pichia pastoris; glycosylation is not required for ligand binding. Journal of Biological Chemistry. 286(11): p. 8884-8892.

2011
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Keefe, D., C. Parng, D. Lundberg, S. Ray, J. Martineau-Bosco, C. Leng, S. Tzartos, J. Powell, M. Concino, M. Heartlein, J. Lamsa, and S. Josiah, (2010) In vitro characterization of an acetylcholine receptor-transferrin fusion protein for the treatment of myasthenia gravis. Autoimmunity. 43(8): p. 628-639.

Lagoumintzis, G., P. Zisimopoulou, G. Kordas, K. Lazaridis, K. Poulas, and S.J. Tzartos, (2010) Recent approaches to the development of antigen-specific immunotherapies for myasthenia gravis. Autoimmunity. 43(5-6): p. 436-445.

Gattenlohner, S., H. Jorissen, M. Huhn, A. Vincent, D. Beeson, S. Tzartos, A. Mamalaki, B. Etschmann, H.K. Muller-Hermelink, E. Koscielniak, S. Barth, and A. Marx, A Human Recombinant Autoantibody-Based Immunotoxin Specific for the Fetal Acetylcholine Receptor Inhibits Rhabdomyosarcoma Growth In Vitro and in a Murine Transplantation Model. Journal of Biomedicine and Biotechnology Art. No. 187621.

2010
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Keefe, D., Hess, D., Dosco, J., Tzartos, S., Powell, J., Lamsa. J., and Josiah, S. (2009) A rapid, fluorescence based assay for detecting antigenic modulation of the acetylcholine receptor on human cell lines. Cytometry B Clin Cytom. 76(3):206-12.

Zouridakis M, Zisimopoulou P, Eliopoulos E, Poulas K, and Tzartos SJ (2009) Design and expression of human α7 nicotinic acetylcholine receptor extracellular domain mutants with enhanced solubility and ligand-binding properties. Bioch. Bioph. Acta. 1794: 355-66.

Tsiamalos, P., Kordas, G., Kokla, A., Poulas, K., and Tzartos, S.J. (2009). Epidemiological and immunological profile of MuSK myasthenia gravis in Greece. Eur. J. Neurol. 16: 925-30.

Lykhmus, O , Koval, L., Pavlovych, S., Zouridakis, M., Zisimopoulou, P., Tzartos, S., Tsetlin, V., Volpina, O., Cloëz-Tayarani, I., Komisarenko, S., and Skok, M. (2009) Functional effects of antibodies against non-neuronal nicotinic acetylcholine receptors. Immunol. Lett. 128(1):68-73.

Gattenlohner, S, Jörißen, H., Huhn, M., Vincent, A., Beeson, D., Tzartos, S., Mamalaki, A., Etschmann, B., Müller-Hermelink, H.K., Koscielniak, E., Barth S.and Marx, A. (2009). A human recombinant autoantibody-based immunotoxin specific for the fetal acetylcholine receptor inhibits rhabdomyosarcoma growth in vitro and in a murine transplantation model. J. Biomed. Biotech. 2010:187621. doi: 10.1155/2010/187621

Keefe, D., Parng , C., Lundberg, D., Ray, S., Martineau-Bosc, J., Leng, C., Tzartos, S., Powell , J., Concino, M., Michael Heartlein, M., Lamsa. J., and Josiah, S. (2010). In vitro characterization of an acetylcholine receptor-transferrin fusion protein for the treatment of Myasthenia Gravis. Autoimmunity, 43(8):628-39

2009
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Konstantakaki, M, Tzartos, S.J., Poulas, K. and Eliopoulos, E. (2008). Μodel of the extracellular domain of the human α7 nAChR based on the crystal structure of the mouse α1 nAChR extracellular domain. J. Mol. Graph Modelling. 26: 1333-7.

Bitzopoulou, K., ,Kostelidou, K., Poulas, K and Tzartos, S.J. (2008) Expression and characterization of mutant forms of the extracellular domain of the human AChR gamma-subunit with improved solubility and enhanced antigenicity. Biochem. Biophys. Acta. 1784: 1226-33.

Zisimopoulou, P., Lagoumintzis, G., Poulas, K. and Tzartos, S.J. (2008). Antigen-specific apheresis of human anti-acetylcholine receptor autoantibodies from myasthenia gravis patients’ sera using Escherichia coli-expressed receptor domains. J. Neuroimmmunol. 200: 133-141.

Yi, H.J., Chae, C.S., So, J.S., Tzartos, S.J. Souroujon MC, Fuchs, S., Im, SH (2008) Suppression of experimental myasthenia gravis by a B-cell epitope-free recombinant acetylcholine receptor. Mol. Immunol. 461:192-201.

2008
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Konstantakaki, M., Tzartos, S.J., Poulas, K., and Eliopoulos, E. (2007) Molecular modeling of the complex between Torpedo acetylcholine receptor and anti-MIR Fab198. Biochem. Biophys. Res. Commun. 356:569-75.

Sideris, S., Lagoumintzis, G., Kordas, G., Kostelidou, K., Sotiriadis, A, Poulas, K. and Tzartos, S.J. (2007) Isolation and functional characterization of anti-acetylcholine receptor subunit-specific autoantibodies from myasthenic patients: receptor loss in cell culture. J. Neuroimmunol. 189:111-7.

Zouridakis, M., Kostelidou, K., Sotiriadis, A., Stergiou, Ch. Eliopoulos, E., Poulas, K., and Tzartos, S. (2007) Circular Dichroism Studies of Recombinant Extracellular Domains of Human Muscle and Neuronal Nicotinic Acetylcholine Receptors Provide an Insight into their structure. Intl. J. Biol. Macromol. 41:423-9.

Kostelidou, K., Trakas,N. and Tzartos, S.J. (2007) Extracellular domains of the β, γ and ε subunits of the human acetylcholine receptor as immunoadsorbents for myasthenic autoantibodies: a combination of immunoadsorbents results in increased efficiency. J. Neuroimmmunol. 190:44-52

2007
Picture

Kostelidou, K., Trakas,N., Zouridakis, M., Bitzopoulou, K., Sotiriadis,A., Gavra, H., and Tzartos, S.J. (2006). Expression and characterization of soluble forms of the extracellular domains of the β, γ and ε subunits of the human muscle acetylcholine receptor. FEBS J. 273: 3557-3568

Fostieri, E., Tzartos, S.J., Berrih-Aknin, S., Beeson, D. and Mamalaki A. (2005) Isolation of potent human Fab fragments against a novel highly immunogenic region on human muscle acetylcholine receptor, which protect the receptor from myasthenic autoantibodies. Eur. J. Immunol. 35:632-643.

2006
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Protopapadakis, E., Kokla, A., Tzartos, S.J. and Mamalaki, A (2005) Isolation and characterization of human anti-acetylcholine receptor monoclonal antibodies from transgenic mice expressing human immunoglobulin loci. Eur. J. Immunol. 35:1960-68.

Guyon, S., Christadoss, P., Lepanse, R, Guyon, T, DePoea Baets, M., Wakkach, A., Bidault, J., Tzartos, S., and Berrih-Aknin, S. (2005) Effects of cytokines on AChR expression. Implications for myasthenia gravis. J. Immunol. 174: 5941-49.

Psaridi-Linardaki, L., Mamalaki, A., Trakas, N. and Tzartos, S.J. (2005) Specific immunoadsorption of the autoantibodies from myasthenic patients using the extracellular domain of the human muscle acetylcholine receptor α-subunit. Development of an antigen-specific therapeutic strategy. J. Neuroimmunol. 159:183-91.

Avramopoulou, V., Mamalaki, A., Tzartos, S.J. (2004) Soluble, oligomeric and ligand-binding extracellular domain of human alpha7 acetylcholine receptor expressed in yeast. Replacement of the hydrophobic cys-loop by the hydrophilic loop of ACh-binding protein enhances protein solubility. J. Biol. Chem. 279: 38287-93.

Marinou, M. and Tzartos, S.J. (2003). Identification of regions involved in the binding of α-Bungarotoxin to the human α7 neuronal nicotinic acetylcholine receptor using synthetic peptides. Biochem. J. 372, 543-554.

Phan-Chan-Du, A., Hemmerlin, C., Krikorian, D., Sakarellos-Daitsiotis, M., Tsikaris, V., Sakarellos, C., Marinou. M.,Thureau, A., Cung, M.T. and Tzartos, S.J. (2003). Solution conformation of the antibody-bound tyrosine phosphorylation site of the nicotinic acetylcholine -subunit in its phosphorylated and nonphosphorylated states. Biochemistry, 42:7371-7380.

Campos, E.C., Schiavi, C., Bolognesi, A., Bellusci, C., Lubelli, C., Duca, A., Polito, L., Vismara, S., Poulas, K., Tzartos, S.I., and Stirpe, F. (2002). Selective lesions of rabbit extraocular muscles injected with the anti-AChR immunotoxin saporin-mAb 73. Curr. Eye Res. 24: 58-65.

Psaridi-Linardaki, L.,Mamalaki, A., Remoundos, M. and Tzartos, S.J. (2002). Expression of soluble ligand- and antibody-binding extracellular subunit in yeast Pichiadomain of human muscle acetylcholine receptor α- pastoris. Role of glycosylation in α-bungarotoxin binding. J. Biol. Chem. 277: 26980-6.

Μetaxas, A., Tzartos, S., Liakopoulou-Kyriakide, M. (2002). The production of anti-hexapeptide antibodies which recognize the S7, L6 and L13 ribosomal proteins of Escherichia coli. J Pept Sci. 8:118-24.

Tataridis, D., Kolocouris, A., Fytas, G., Kolocouris, N., Foscolos, G.B., Poulas, K. and Tzartos, S.J. (2002).Mounting the nicotinic pharmacophoric structural elements in an homoadamantane scaffold: synthesis, molecular modeling and binding affinities to α7 nicotinic acetylcholine receptors. IL Farmaco. 57:979-984.

Poulas, K. and Tzartos, S.J (2001). The gender gap in autoimmune disease. Letter to Lancet, 357, 234.

Poulas, K., Eliopoulos, E., Vatzaki, E., Navaza, J., Kontou, M., Oikonomakos, N., Acharya, K.R., and Tzartos, S. J. (2001). Crystal structure of Fab198, an efficient protector of acetylcholine receptor against myasthenogenic antibodies. Eur. J. Biochem. 268: 3685-3693.

Poulas, K., Tsibri, E., Papanastasiou, D., Tsouloufis, T., Marinou, M., Tsantili, P., Papapetropoulos, T., and Tzartos, S.J. (2001). Epidemiology of seropositive myasthenia gravis in Greece. J. Neurol. Neurosur. Psych. 71:352-6.

Theodorou, V.,Tsikaris, V., Sakarellos-Daitsiotis, M, Avramopoulou, V., Kostelidou, K., Tzartos, S.J. and Sakarellos, C. (2001). Design, synthesis and conformational study of biologically active photolabeled analogues of the Main Immunogenic Region of the acetylcholine receptor. Biopolymers. 56: 37-46.

Trakas, N. and Tzartos, S.J. (2001) Conjugation of acetylcholine receptor-protecting Fab fragments with polyethylene glycol results in a prolonged half-life in the circulation and reduced immunogenicity. J. Neuroimmunol. 120:42-49.

Skok, M., Lykhmus, E., Bobrovnik, S., Tzartos, S.I., Tsouloufis, T., Vanderesse, R. , Coutrot, F., Cung, M.T., Marraud, M., Krikorian, D., and Sakarellos-Daitsiotis, M. (2001). Structure of epitopes recognized by the antibodies to alpha (181-192) peptides of neuronal nicotinic acetylcholine receptors: extrapolation to the structure of acetylcholine-binding domain. J. Neuroimmunol. 121: 59-66.

Kleinjung, J., Petit, M-C., Orlewski, P., Mamalaki, A., Tzartos, S.J., Tsikaris, V., Sakarellos-Daitsiotis, M., Sakarellos, C., Marraud, M. and Cung. M.-T. (2000). The 3D structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: A combined 2D-NMR, homology and molecular modeling approach. Biopolymers. 53: 113-128

Sevin-Landais, A., Rigler, P., Tzartos, S., Hucho, F., Hovius, R. and Vogel, H. (2000). Immobilisation of the nicotinic acetylcholine receptor in tethered lipid membranes. Biophys. Chem. 85:141-52.

Poulas, K., Tsouloufis, Th., and Tzartos S.J. (2000) Treatment of passively transferred experimental autoimmune myasthenia gravis using papain. Clin. Expl. Immunol. 120:363-368.

Tsouloufis, T., Mamalaki, A., Remoundos, M. and Tzartos, S.J. (2000). Reconstitution of conformationally-dependent epitopes on the N-terminal extracellular domain of the human muscle acetylcholine receptor α-subunit expressed in E. coli. Implications for Myasthenia Gravis therapeutic approaches. Int. Immunol. 12: 1255-65.

Papanastasiou, D., Poulas, K., Kokla, A and Tzartos, S. J. (2000). Prevention of passively transferred experimental autoimmune myasthenia gravis by Fab fragments of monoclonal antibodies directed against the main immunogenic region of the acetylcholine receptor. J. Neuroimmunol. 104:124-132.

Kontou, M., Leonidas, D., Vatzaki, E.H., Tsantili, P., Mamalaki, A., Oikonomakos, N.G., Acharya, K.R, and Tzartos, S. J. (2000).The crystal structure of the Fab fragment of a rat monoclonal antibody against the main immunogenic region of the human muscle acetylcholine receptor. Eur. J. Biochem. 267:2389-2397

Michalet, S., Teixeira, F., Gilquin, B., Mourier, G., Servent, S., Drevet, P., Binder, P., Tzartos, S., Ménez, A., and Kessler, P. (2000). Relative spatial position of a snake neurotoxin and the reduced disulfide bond αCys192-Cys193) at the αγ interface of the nicotinic acetylcholine receptor. J. Biol. Chem. 275: 25608-25615.

Sieb, J.P., Kraner, S., Schrank, B., Reitter, B., Goebel, H.H., Tzartos, S. J. and Steinlein, O.K. (2000). Severe congenital myasthenic syndrome due to homozygosity of the 1293insG ε-AChR subunit mutation. Ann. Neurol. 48:379-83

Fostieri, E., Beeson, D. and Tzartos, S.J. (2000). The conformation of the main immunogenic region on the α-subunit of muscle acetylcholine receptor is affected by neighboring receptor subunits. FEBS Lett. 481: 127-130.

Poulas, K., Tsibri, E., Papanastasiou, D., Tsouloufis, T., Marinou, M., Tsantili, P., Papapetropoulos, T., and Tzartos, S.J. (2000). Equal male and female incidence of myasthenia gravis. Neurology, 54, 1202-1203.

2000-2005
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Nenninger, R., Schultz, A., Helmreich, M., Wilisch, A., Vandekerckhove, B., Hunig, T., Schalke, B., Tzartos, S.J., Kahlbacher, H., Muller-Hermelink, H. and Marx, A. (1998). Abnormal thymocyte development – Generation of autoaggressive T-cells in mixed and cortical thymomas. Lab. Invest. 78:743-753.

Tsantili, P., Tzartos, S.J. and Mamalaki, A. (1999) High affinity scFv antibody fragments protecting the human nicotinic acetylcholine receptor. J. Neuroimmunol. 94: 15-27.

Papanastasiou, D., Mamalaki, A., Eliopoulos, E., Poulas, K., Liolitsas Ch. and Tzartos, S.J. (1999). Construction and characterization of a humanized single chain Fv antibody fragment against the main immunogenic region of the acetylcholine receptor. J. Neuroimmunol. 94: 182-195.

Tzartos, S.J. and Remoundos, M. (1999). Detection of antibodies directed against the cytoplasmic region of the human acetylcholine receptor in sera from myasthenia gravis patients. Clin. Expl. Immunol. 116: 146-152.

Skok, M.V., Voitenko, L. P., Voitenko, S. V., Lykhmus, E. Yu., Kalashnik, E. N., Litvin, T. I., Tzartos S. J. and Skok, V. I. (1999). Alpha subunit composition of nicotinic acetylcholine receptors in the rat autonomic ganglia neurons as determined with subunit-specific anti-α(181-192) peptide antibodies. Neuroscience. .93: 1436-1447.

Wilisch, A., Gutsche, S., Hoffacker, V., Schultz, A., Tzartos, S., Nix, W., Schalke, B., Schneider, C., Muller-Hermelink, H. K. and Marx A. (1999). Association of acetylcholine receptor α-subunit expression in mixed thymoma with myasthenia gravis. Neurology. 52: 1460-1466.

Schultz, A., Hoffacker, V.,Wilisch, A., Nix, W., Schalke, B., Nix, W., Tzartos, S., Muller-Hermelink, H. K. and Marx A. (1999). Neurofilament is an autoantigenic determinant in myasthenia gravis. Ann. Neurology. 46: 167-75.

Martin-Ruiz, C.M., Court, J.A., Molnar, Ε., Lee, Μ., Gotti, C., Mamalaki, A., Tsouloufis, T., Tzartos, S., Ballard, C., Perry, R.H. and Perry, E.K. (1999) Alpha 4 but not alpha 3 and 7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer’s disease. J. Neurochem. 73: 1635-1640.

Jacobson, L., Beeson, D., Tzartos, S. and Vincent, A. (1999). Monoclonal antibodies raised against human acetylcholine receptor bind to all five subunits of the fetal isoform. J. Neuroimmunol. 98: 112-120.

Wakkach, A., Poea, S., Chastre, E., Gespach, C., Lecerf, F., De la Porte, S., Tzartos, S., Coulombe, A., and Berrih-Aknin, S. (1999). Establishment of a thymic myoid cell line: phenotypic and functional characteristics. Am. J. Pathol. 155:1229-1240

Sieb, J.P., Dorfler, P., Tzartos, S., Wewer, U., Ruegg, M.,Meyer, D., Baumann, I., Lindemuth, R., Jakschik, J. and Ries, F. (1998). Congenital myasthenic syndromes in two kinships with endplate acetylcholine receptor and utrophin deficiency. Neurology, 50: 54-61.

De la Porte, S., Chaubourt, E., Fabre, F., Poulas, K., Chapron, J., Eymard, B., Tzartos, S.J., and Koenig, J. (1998). Accumulation of acetylcholine receptors is a necessary condition for normal accumulation of acetylcholinesterase during in vivo neuromuscular synaptogenesis. Eur. J. Neurosci., 10: 1631-1643.

Barchan, D., Asher, O., Tzartos, S.J., Fuchs, S. and Souroujon, M. (1998). Modulation of the anti-acetylcholine receptor and experimental autoimmune myasthenia gravis by recombinant fragments of the acetylcholine receptor. Eur. J. Immunol. 28:616-624.

Gattenloehner, S., Vincent, A., Leuschner, I., Tzartos, S., Kirchner, T., Muller-Hermelink, H.-K., Marx, A. (1998) Investigation of the acetylcholine receptor in rhabdomyosarcomas as compared with other childhood tumors. Am. J. Pathol. 152: 437-444.

Guyon, T., Wakkach, A., Klingel-Schmitt, I., Levasseur, P., Beeson, D., Asher, O., Tzartos, S.J. and Berrih-Aknin, S. (1998). Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidence for a compensatory mechanism triggered by receptor loss. J. Clin. Invest. 102: 249-263.

Orlewski, P., Marraud, M., Cung, M.T, Tsikaris, V., Sakarellos-Daitsiotis, M., Sakarellos, K., Vatzaki, E. and Tzartos, S.J. (1996). Compared structures of the free AChR MIR decapeptide and the antibody-bound [A76]MIR analogue. A molecular dynamics simulation from 2D-NMR data. Biopolymers (Peptide Science). 40: 419-432.

Gotti, C., Balestra, B., Mantegazza, R., Tzartos, S., Moretti, M. & Clementi, F. (1997) Detection of antibody subpopulations in myasthenia gravis using a non radioactive new enzyme immunoassay. Muscle & Nerve, 20: 800-808.

Loutrari, H., Kokla, A., N. Trakas and Tzartos, S.J. (1997). Expression of human-Torpedo hybrid acetylcholine receptors for analyzing the antigenic specificities in myasthenic antisera. Clin. Expl. Immunol. 109, 538-546.

Andre, F., Marraud, M., Tsouloufis, T., Tzartos, S.J., Boussard, G. (1997) Triphosgene: An efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide. J. Pep. Science . 3: 429-441

Voltz, R., Kamm, C., Padberg, F., Malotka, J., Kerschensteiner, M., Spuler, S., Tzartos, S., and Dornmair, K. (1997) Highly purified oligo-His tagged human recombinant alpha(1)-AChR is immunogenic in vivo and suitable for T cell stimulation in vitro in experimental and human myasthenia gravis. J.Neuroimmunol. 80:131-136.

Bufler, J., Kahlert, S., Tzartos, S.J., Toyka, C. and Franke, C. (1996). Activation and blockage of nicotinic channels by antibodies directed against the binding site of the acetylcholine receptor. J. Physiol. 492: 107-114

Kontou, M., Vatzaki, E.H., Kokla, A., Acharya, K.R., Oikonomakos, N.G. and Tzartos, S.J. (1996). Characterisation, crystallisation and preliminary X-ray diffraction analysis of a Fab fragment of a rat monoclonal antibody with very high affinity for the human muscle acetylcholine receptor. FEBS Lett. 389: 195-198.

Wakkach, A., Guyon, T., Bruand, C., Tzartos, S., Cohen-Kaminsky, S. and Berrih-Aknin, S. (1996) Expression of acetylcholine receptor genes in human thymic epithelial cells. Implication for myasthenia gravis. J. Immunol. 157: 3752-3760.

Pappas, I.S., Sophianos, D., Tzartos, S.J. and Tsiftsoglou, A.S. (1996). Expression of memory, differentiation and repression of c-myc and p53 genes in human RD/TE-671 cells induced by a uveido-derivative of pyridine (UDP-4). Cell Growth and Differentiation. 7: 797-809.

Tsikaris, V., Sakarellos, C., Sakarellos-Daitsiotis, M., Orlewski, P., Marraud, M. Cung, M.T., Vatzaki, E., and Tzartos, S.J. (1996). Construction and application of a new class of sequential oligopeptide carriers for multiple anchoring of antigenic peptides. Application to the AChR main immunogenic region. Intern. J. Biol. Macromol. 19: 195-205.

Tzartos, S.J., Kouvatsou, R. and Tzartos E. (1995) Monoclonal antibodies as site-specific probes for the acetylcholine receptor δ-subunit tyrosine and serine phosphorylation sites. Eur. J. Biochem. 228, 463-472.

Mapouras, D., Philippou, G., Charalabous, S., Tzartos, S.J. Balafas, A., Souvatzoglou, A. and Lymberi, P. (1995). Antibodies to acetylcholinesterase cross-reacting with thyroglobulin in myasthenia gravis and graves disease. Clin. Exp. Immunol 100: 336-343.

Tzartos, S.J., Tzartos, E., and Tzartos, J.S. (1995) Monoclonal antibodies against the acetylcholine receptor γ-subunit as site specific probes for receptor tyrosine phosphorylation. FEBS Letters. 363: 195-198.

Mamalaki, A., Boutou, E., Hurel, C., Patsavoudi, E., Tzartos, S.J. and Matsas, R. (1995). The BM88 antigen, a novel neuron-specific molecule, promotes the differentiation of mouse neuroblastoma cells. J. Biol. Chem. 270: 14201-14208.

Asher, O., Kues, W.A., Witzemann, V.,Tzartos, S.J., Fuchs, S. and Souroujon, M.C. (1993) Increased gene expression of acetylcholine receptor and myogenic factors in passively transferred experimental autoimmune myasthenia gravis. J. Immunol. 151, 6442-6450.

Schmutz, M., Kling, D., Tzartos, S.J. and Brisson, A. (1994). A mixed ELISA-immunoelectron microscopy approach for studying epitope topology of membrane proteins: application to the acetylcholine receptor. J. Histochem. Cytochem. 42, 315-327 (1994).

Tzartos, S.J., Valcana, C., Kouvatsou, R., and Kokla, A. (1993) The tyrosine phosphorylation site of the acetylcholine receptor β-subunit is located in a highly immunogenic epitope implicated in channel function. Antibody-probes for β subunit phosphorylation and function. EMBO J. 12, 5141-5149.

Papadouli, I., Sakarellos, C.,and Tzartos, S.T. (1993). High resolution epitope mapping and fine antigenic characterization of the main immunogenic region of the acetylcholine receptor. Improving the binding activity of synthetic analogues of the region. Eur. J. Biochem. 211, 227-234.

Eleftheriou, C.S., Trakas, N., Kokla, A. and Tzartos, S.J. (1993). A group of three fibroblast secreted polypeptides suppressed by cellular ageing and interferon-γ. Bioch. Bioph. Acta. 1180, 304-312.

Detsikas, E., Tsikaris, V., Sakarellos-Daitsiotis, M., Sakarellos, C., Cung, M.T., Marraud, M., Vatzaki, E. and Tzartos, S.J. (1993). Cyclic lactam analogues containing the main immunogenic region of Torpedo acetylcholine receptor. Peptide Research 6, 17-23.

Tsikaris, V., Detsikas, E., Sakarellos-Daitsiotis, M., Sakarellos, C., Vatzaki, E., Tzartos, S.J., Marraud, M. and Cung, M.T., (1993). Conformational requirements for molecular recognition of ACh receptor MIR analogues by monoclonal anti-MIR antibody: A 2D-NMR and molecular dynamics approach. Biopolymers. 33, 1123-1134.

Mamalaki, A., Trakas, N., and Tzartos, S.J. (1993). Bacterial expression of a single-chain Fv fragment which efficiently protects the acetylcholine receptor against antigenic modulation caused by myasthenic antibodies. Eur. J. Immunol. 23, 1839-1845.

Melms, A., Weissert, R., Klinkert, W.E.F., Schalke, B.C.G., Tzartos, S. and Wekerle, H. (1993). Specific immune complexes augment in vitro acetylcholine receptor-specific T-cell proliferation. Neurology 43, 583-588.

Vatzaki, E. H., Acharya, K.R., Oikonomakos, N. G. and Tzartos, S.J. (1993). Crystallization and preliminary crystallographic study of an Fab fragment of a pathogenic rat monoclonal antibody against the nicotinic acetylcholine receptor. Protein Science. 2: 1770-1772.

Loutrari, H., Tzartos, S.J. and Claudio, T. (1992). Use of Torpedo-mouse hybrid acetylcholine receptors reveals immunodominance of the α-subunit in myasthenia gravis antisera. Eur. J. Immunol. 22, 2949-2956.

Loutrari, H., Kokla, A. and Tzartos, S.J. (1992). Passive transfer of experimental myasthenia gravis via antigenic modulation of acetylcholine receptor. Eur. J. Immunol. 22, 2449-2452.

Zhang, Y., and Tzartos, S.J. (1992). B-T lymphocyte interactions in experimental autoimmune myasthenia gravis. Autoantibody mediated up-regulation of the response of AChR-specific T-lymphocytes. Immunology 77, 571-576.

Marx, A., Osborn, M., Tzartos, S., Geuder, K.I., Schalke, B., Nix, W., Kirchner, T., and Muller-Hermelink, H.K. (1992). A striational muscle antigen and myasthenia gravis-associated thymomas share an acetylcholine receptor epitope. Develop. Immunol. 2, 77-84.

Cung, M.T., Demange, P., Marraud, M., Tsikaris, V., Sakarellos, C., Papadouli, I., Kokla, A., Tzartos, S.J. (1991). Two-dimentional 1H-NMR study of antigen-antibody interactions: binding of synthetic decapeptides to an anti-acetylcholine receptor monoclonal antibody. Biopolymers. 31, 769-776.

Verschuuren, J.J.G.M., Graus Y.M.F., Bos N.A., Tzartos S.J., Van Breda Vriesman P.J.C., and De Baets M.H. (1991). Paratope and framework related idiotopes on acetylcholine receptor antibodies. J. Immunol. 146, 941-948.

Verschuuren, J.J.G.M., Graus Y.M.F., Van Breda Vriesman P.J.C., Tzartos S.J., and De Baets M.H. (1991). In vivo effects of neonatal administration of anti-idiotype antibodies on experimental autoimmune myasthenia gravis Autoimmunity. 10:173-179.

Tzartos, S. J., Loutrari, H., Tang, F., Kokla, A., Walgrave, S., Milius, R. P. and Conti-Tronconi, B. (1990). Main immunogenic region of Torpedo electroplax and human muscle acetylcholine receptor. Localization and micro-heterogeneity reveiled by the use of synthetic peptides. J. Neurochem. 54, 51-61.

Plinkert, P.K., Gitter, A.H., Zimmermann, U., Kirchner, T., Tzartos, S. and Zenner, H.P. (1990). Visualization and functional testing of acetylcholine receptor-like molecules in cochlear outer hair cells. Hearing Res. 44, 25-34.

Marx, A., O’ Connor, R., Geuder, K.I., Hoppe, F., Schalke, B., Tzartos, S., Kalies, I., Kirchner, T., and Muller-Hermelink, H. K. (1990). Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas. Lab. Invest.. 62, 279-286.

Tzartos, S.J., Efthimiadis, A., Morel, E. and Bach, J.F. (1990) Neonatal myasthenia gravis: antigenic specificities of antibodies in sera from mothers and their infants. Clin. Exp. Immunol. 80, 376-380.

Papadouli, I., Potamianos, S., Hadjidakis, I., Bairaktari, H., Tsikaris, V., Sakarellos, C., Cung, M.T., Marraud, M. and Tzartos, S.J. (1990). Antigenic role of single residues within the main immunogenic region of the nicotinic acetylcholine receptor. Biochem. J. 269, 239-245.

Tzartos, S.J and Remoundos, M.S. (1990). Fine localization of the major α-bungarotoxin binding site to residues α189-195 of the Torpedo acetylcholine receptor. Residues 189, 190 and 195 are indispensable for binding. J. Biol. Chem. 265, 21462-21467.

1990-1999

MEMBERS

Dr. Paraskevi Zisimopoulou

Principal Investigator
Head of Laboratory of Molecular Neurobiology and Immunology
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Dr. Socrates Tzartos

Emeritus Researcher
Research Director
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Dafni Chroni

Post-doctoral Fellow
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Petros Giastas

Post-doctoral Fellow
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Anna Haroniti

Post-doctoral Fellow

Marios Zouridakis

Post-doctoral Fellow
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Maria Michael

PhD Student
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Vasiliki Baltatzidi

MSc student
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