title: Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells.
abstract: Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany; Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: chuang.taiwan@gmail.com.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chuang
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany. Electronic address: philipp.stroebel@med.uni-goettingen.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany. Electronic address: anna-lena.bohlender@medma.uni-heidelberg.de.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Bohlender-Willke
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany. Electronic address: neurologie@sozialstiftung-bamberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.affiliation: Department of Neurology, University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany. Electronic address: nix@arztkolleg.de.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Nix
authors.affiliation: Department of Neurology, University of Regensburg, Bezirkskrankenhaus, D-93042 Regensburg, Germany. Electronic address: berthold.schalke@medbo.de.
authors.forename: Berthold
authors.initials: B
authors.lastname: Schalke
authors.affiliation: Department of Neurology, University of Bochum, Bochum, Germany. Electronic address: ralf.gold@rub.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Transfusion Medicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. Electronic address: a.opitz@blutspende.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Opitz
authors.affiliation: Department of Transfusion Medicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. Electronic address: klinker_e@klinik.uni-wuerzburg.de.
authors.forename: Erdwine
authors.initials: E
authors.lastname: Klinker
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany. Electronic address: mi@thoracic.med.osaka-u.ac.jp.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany. Electronic address: konrad.mh@mail.uni-wuerzburg.de.
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.affiliation: Department of Physiology, University of Istanbul, Istanbul Tip Fakultesi, Temel Bilimler, 34093 CAPA-Istanbul, Turkey. Electronic address: gsaruhan@istanbul.edu.tr.
authors.forename: Güher
authors.initials: G
authors.lastname: Saruhan-Direskeneli
authors.affiliation: Department of Transfusion Medicine and Immunology, University Medical Centre Mannheim, University of Heidelberg, Germany. Electronic address: p.bugert@blutspende.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.affiliation: Department of Clinical Neurology, Weatherall Institute for Molecular Medicine, University of Oxford, WIMM, Headington OX3 9DS, UK. Electronic address: nick.willcox@imm.ox.ac.uk.
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany. Electronic address: alexander.marx@umm.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology*; D013945:Thymoma / Q000150:complications / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D013953:Thymus Neoplasms / Q000150:complications / Q000235:genetics / Q000276:immunology*; D044465:White People
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human
keywords: AIRE; CTLA4; Myasthenia gravis; Myoid cells; TRECs; Thymus