Titin antibodies in “seronegative” myasthenia gravis — A new role for an old antigen

Stergiou, Christos; Lazaridis, Konstantinos; Zouvelou, Vasiliki; Tzartos, John; Mantegazza, Renato; Antozzi, Carlo; Andreetta, Francesca; Evoli, Amelia; Deymeer, Feza; Saruhan‐Direskeneli, Güher; Durmuş, Hacer; Brenner, Talma; Vaknin, Adi; Berrih‐Aknin, Sonia; Béhin, Anthony; Sharshar, Tarek; Baets, Marc De; Losen, Mario; Martínez‐Martínez, Pilar; Kleopa, K. A.; Zamba‐Papanicolaou, Eleni; Kyriakides, Theodoros; Kostera‐Pruszczyk, Anna; Szczudlik, Piotr; Szyluk, Beata; Lavrnić, Dragana; Basta, Ivana; Perić, Stojan; Tallaksen, Chantal; Maniaol, Angelina; Gilhus, Nils Erik; Casasnovas, Carlos; Piťha, Jiří; Jakubíková, Michala; Hanisch, Frank; Bogomolovas, Julius; Labeit, D.; Labeit, Siegfried

doi:10.1016/j.jneuroim.2016.01.018

Cited by 64 publications

(71 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Autoantibodies against titin, a large intracellular protein of striated muscle, have been detected and well-studied in MG patients, mainly those who are positive for anti-AChR antibody with ~40 % of MG patients positive for both antibodies [87]. Double positivity between anti-MuSK and anti-titin, and anti-Lrp4 and anti-titin antibodies has been detected in 15 % of patients [87].…”

Section: Autoimmune Neuromuscular Junction Disordersmentioning

confidence: 99%

“…Double positivity between anti-MuSK and anti-titin, and anti-Lrp4 and anti-titin antibodies has been detected in 15 % of patients [87]. Stergiou et al have shown that 13 % of triple seronegative MG patients (without anti-AChR, anti-MusK, and anti-Lrp4 antibodies) had anti-titin antibodies [87]. The merit of anti-titin antibody as predictor of disease severity or thymoma in MG has been demonstrated by several investigators [88, 89].…”

Section: Autoimmune Neuromuscular Junction Disordersmentioning

confidence: 99%

“…This 30-kDa segment of titin, called MGT30, is considered the main immunogenic region of titin. MG thymoma patient sera reacted strongly with MGT30-expressing E. coli [87]. …”

Section: Autoimmune Neuromuscular Junction Disordersmentioning

confidence: 99%

See 2 more Smart Citations

Mapping autoantigen epitopes: molecular insights into autoantibody-associated disorders of the nervous system

Sinmaz

Nguyen

Charabati

et al. 2016

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundOur knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of extracellular and intracellular autoantigens have been identified, and there is no doubt that this field will continue to expand as more autoantigens are discovered as a result of improved clinical awareness and methodological practice. In recent years, interest has shifted to uncover the target epitopes of these autoantibodies.Main bodyThe purpose of this review is to discuss the mapping of the epitope targets of autoantibodies in CNS and PNS antibody-mediated disorders, such as N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), leucine-rich glioma-inactivated protein 1 (Lgi1), contactin-associated protein-like 2 (Caspr2), myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP4), 65 kDa glutamic acid decarboxylase (GAD65), acetylcholine receptor (AChR), muscle-specific kinase (MuSK), voltage-gated calcium channel (VGCC), neurofascin (NF), and contactin. We also address the methods used to analyze these epitopes, the relevance of their determination, and how this knowledge can inform studies on autoantibody pathogenicity. Furthermore, we discuss triggers of autoimmunity, such as molecular mimicry, ectopic antigen expression, epitope spreading, and potential mechanisms for the rising number of double autoantibody-positive patients.ConclusionsMolecular insights into specificity and role of autoantibodies will likely improve diagnosis and treatment of CNS and PNS neuroimmune diseases.

show abstract

Section: Autoimmune Neuromuscular Junction Disordersmentioning

confidence: 99%

Section: Autoimmune Neuromuscular Junction Disordersmentioning

confidence: 99%

See 1 more Smart Citation

Mapping autoantigen epitopes: molecular insights into autoantibody-associated disorders of the nervous system

Sinmaz

Nguyen

Charabati

et al. 2016

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…30,37 Antibodies against intracellular components of striated muscle viz titin and ryanodine receptor (RYR) also play a role in governing the disease severity. 8,39 Among the patients who died in the present cohort, two patients had titin antibody and one patient had RYR-antibody positivity. 8,39 Among the patients who died in the present cohort, two patients had titin antibody and one patient had RYR-antibody positivity.…”

Section: Discussionmentioning

confidence: 87%

Autoantibodies in acquired myasthenia gravis: Clinical phenotype and immunological correlation

et al. 2019

View full text Add to dashboard Cite

Background: Data on antibody profile in myasthenia gravis (MG) from India are limited. Objectives: To investigate antibody profile in patients with MG and their clinical correlates. Patients and Methods: Patients of MG (n = 85, M:F::1.1:1, mean age: 39.29 ± 17.3 years, mean symptom duration: 72.94 ± 91.8 months) were evaluated for clinical features, MG foundation of America (MGFA) score, response to treatment, and outcome at last follow-up. Antibodies to acetylcholine receptor (AChR), muscle-specific kinase (MUSK), titin and ryanodine receptor (RYR) were analysed using ELISA.Results: Based on the regional distribution of weakness, the cohort could be categorized as: generalized: 60, ocular: 16 and oculo-bulbar: 9. Sixty patients were followed up for a mean duration of 26.74 ± 13.8 months. Outcome at last follow-up was as follows: remission-22, no remission-33 and dead-5. AChR and MUSK antibodies were detected in 58 and 8 patients, respectively. Frequency of generalized MG, worse MGFA score during the disease course and thymomatous histology significantly correlated with presence of AChR-antibodies, though outcome at last followup was comparable between AChR-antibody positive and negative groups. Patients with MUSK antibodies had oculo-bulbar or generalized MG and frequent respiratory crisis, but majority improved or remitted with treatment. Titin antibodies were detected in 31.8% and RYR antibodies in 32.9%. Their presence did not correlate with age at onset of MG, severity or presence of thymoma. Conclusion: This report highlights the spectrum of antibodies in MG in an Indian cohort. AChR-antibody positivity correlated with clinical severity. Outcome was good in majority of MUSK antibody-positive MG. The role of other antibodies, complementary vs epiphenomenon, remains open. K E Y W O R D S acetylcholine receptor, muscle-specific kinase, myasthenia gravis, ryanodine receptor, titin | 429 NAGAPPA et Al.

show abstract

“…Ces dernières années, il a été possible d'affiner les techniques de détection des anticorps anti-titine et de remplacer le test ELISA par la RIPA, technique plus sensible. Ce test a permis d'identifier les patients myasthé-niques triple-séronégatifs (sans anticorps anti-RACh, anti-MuSK ni anti-LRP4) mais porteurs d'anticorps anti-titine [3,21]. Ces patients présentent une myasthénie cliniquement bénigne (n'excédant pas le stade III selon la classification MGFA) qui se manifeste le plus souvent par une fatigabilité modérée des quatre ments habituels.…”

Section: Anticorps Anti-titineunclassified

Myasthénie auto-immune séronégative

Catar¹,

Aubé-Nathier²,

Nadaj‐Pakleza³

2017

Med Sci (Paris)

View full text Add to dashboard Cite

> La myasthénie est une maladie auto-immune avec, dans 80 % des cas, des anticorps dirigés contre le récepteur de l'acétylcholine (anti-RACh) positifs et deux formes cliniques distinctes, oculaire et généralisée. Les formes séronégatives sont relativement rares et cliniquement hétérogènes. Le diagnostic de la myasthénie séronégative reste souvent difficile, notamment pour les formes oculaires et est essentiellement basé sur une symptomatologie fluctuante caractéristique. La décou-verte des anticorps anti-RACh à faible affinité et des nouveaux anticorps comme les antiMuSK (dirigés contre le récepteur spécifique de la tyrosine kinase), les anti-LRP4 (dirigés contre la protéine 4 reliée au récepteur des lipoprotéines de faible densité), les antiagrine ou les anti-cortactine constitue un avancement considérable dans la compréhen-sion de la physiopathologie de la myasthénie. Selon le profil sérologique, il est possible de prévoir la gravité potentielle de la maladie, la réponse aux traitements et le risque de pathologie thymique associée. < Myasthénie auto-immune séronégativeOana Catar, Anne-Catherine Aubé-Nathier, Aleksandra Nadaj-Pakleza Diagnostic de la myasthénie séronégative En l'absence d'anticorps spécifiques (anti-RACh ou anti-MuSK), le diagnostic de la myasthénie séro-négative repose avant tout sur le tableau clinique caractéristique qui se manifeste essentiellement par une fatigabilité musculaire excessive à l'effort. La fluctuation des symptômes cliniques, le déficit moteur réversible et non systématisé constituent des éléments essentiels dans le diagnostic de la myasthénie ; diagnostic qui devrait encore être confirmé : -par la présence d'un défaut de transmission neuromusculaire mise en évidence par une étude électroneuromyographique (décré-ment significatif sur plusieurs couples nerf-muscles supérieur à 10 % ou allongement du « jitter » lors de l'étude en fibre unique) ; -et/ou par la réponse positive au traitement anticholinestéras-ique (test pharmacologique à l'édrophonium par voie intraveineuse ou traitement oral avec la pyridostigmine ou l'ambénonium) [1]. Il existe un intérêt à refaire le dosage des anticorps anti-RACh à distance du diagnostic de la myasthénie, notamment à 6-12 mois si le premier dosage a été négatif [2]. Par ailleurs, il est nécessaire de rechercher des arguments en faveur d'une coexistence avec une autre pathologie auto-immune ; la plus fréquente étant la dysthyroïdie [1,3]. Dans le diagnostic différentiel, il est essentiel de prendre en compte le syndrome myasthénique congénital à début tardif dont les manifestations cliniques peuvent être quasi identiques à celles observées dans la myasthénie auto-immune séronégative [4]. L'ensemble des éléments cliniques et paracliniques doit être analysé attentivement (Tableau I). Par conséquent, l'existence d'un ou de plusieurs éléments parmi les suivants doit faire penser au syndrome myasthénique congénital : -une amyotrophie et/ou un déficit musculaire permanent ; -des rétractions tendineuses ; -des antécédents familiaux de maladie neurom...

show abstract

Titin antibodies in “seronegative” myasthenia gravis — A new role for an old antigen

Cited by 64 publications

References 35 publications

Mapping autoantigen epitopes: molecular insights into autoantibody-associated disorders of the nervous system

Mapping autoantigen epitopes: molecular insights into autoantibody-associated disorders of the nervous system

Autoantibodies in acquired myasthenia gravis: Clinical phenotype and immunological correlation

Myasthénie auto-immune séronégative

Contact Info

Product

Resources

About