Chuang, Wen-Yu and Stroebel, Philipp and Bohlender-Willke, Anna-Lena and Rieckmann, Peter and Nix, Wilfred and Schalke, Berthold and Gold, Ralf and Opitz, Andreas and Klinker, Erdwine and Inoue, Masayoshi and Mueller-Hermelink, Hans Konrad and Saruhan-Direskeneli, Gueher and Bugert, Peter and Willcox, Nick and Marx, Alexander (2014) Late-onset myasthenia gravis-CTLA4(low) genotype association and low-for-age thymic output of naive T cells. JOURNAL OF AUTOIMMUNITY, 52. pp. 122-129. ISSN 0896-8411, 1095-9157
Full text not available from this repository. (Request a copy)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 CTLA4high/gain-offunction +49A/A genotype and with increased thymic export of na ve 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) CTLAew +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 na ve 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 60year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60. (C) 2013 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SYSTEMIC-LUPUS-ERYTHEMATOSUS; AUTOIMMUNE REGULATOR AIRE; SYNDROME TYPE-I; THYMOMA PATIENTS; PROTEIN 4; ACETYLCHOLINE-RECEPTOR; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; TITIN ANTIBODIES; EXCISION CIRCLES; Myasthenia gravis; CTLA4; AIRE; Myoid cells; TRECs; Thymus |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Sep 2019 13:22 |
| Last Modified: | 04 Sep 2019 13:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9816 |
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