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Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia¹

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8162, Institut Paris-Sud Cytokines, Université Paris XI, Hôpital Marie Lannelongue, Le Plessis-Robinson, France

Myasthenia gravis (MG) is an autoimmune disease mainly caused by antiacetylcholine receptor autoantibodies (seropositive (SP) disease) or by Abs against unknown autoantigenic target(s) (seronegative (SN) disease). Thymectomy is usually beneficial although thymic hyperplasia with ectopic germinal centers is mainly observed in SP MG. To understand the role of thymus in the disease process, we compared the thymic transcriptome of non-MG adults to those of SP patients with a low or high degree of hyperplasia or SN patients. Surprisingly, an overexpression of MHC class II, Ig, and B cell marker genes is observed in SP but also SN MG patients. Moreover, we demonstrate an overexpression of CXCL13 in all MG thymuses leading probably to the generalized B cell infiltration. However, we find different chemotactic properties for MG subgroups and, especially, a specific overexpression of CCL21 in hyperplastic thymuses triggering most likely ectopic germinal center development. Besides, SN patients present a peculiar signature with an abnormal expression of genes involved in muscle development and synaptic transmission, but also genes implicated in host response, suggesting that viral infection might be related to SN MG. Altogether, these results underline differential pathogenic mechanisms in the thymus of SP and SN MG and propose new research areas.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (NS 39869), the European Community (QLG1-CT 2001-01918 and QLK3-CT 2001-00225), and the Association Française contre les Myopathies.

² R.L.P. and G.C.-C. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Sonia Berrih-Aknin, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8162, Hôpital Marie Lannelongue, 133, avenue de la résistance, 92350 Le Plessis-Robinson, France. E-mail address: sonia.berrih{at}ccml.u-psud.fr

⁴ Abbreviations used in this paper: MG, myasthenia gravis; SP, seropositive; AChR, acetylcholine receptor; TEC, thymic epithelial cell; SN, seronegative; MuSK, muscle-specific tyrosine kinase; GC, germinal center; ML, SP MG patients with low thymic hyperplasia; MH, SP MG patients with high thymic hyperplasia; FC, fold change; ISG, IFN-stimulated gene; DAP12, DNAX-activating protein of 12 kDa.

⁵ The online version of this article contains supplemental material.

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				R. LE PANSE, G. CIZERON-CLAIRAC, M. CUVELIER, F. TRUFFAULT, J. BISMUTH, P. NANCY, N. K. DE ROSBO, and S. BERRIH-AKNIN Regulatory and Pathogenic Mechanisms in Human Autoimmune Myasthenia Gravis Ann. N.Y. Acad. Sci., June 1, 2008; 1132(1): 135 - 142. [Abstract] [Full Text] [PDF]