Published online before print August 3, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070240

Accepted for publication May 22, 2007.

Article

Myasthenia Gravis Thymus. Complement Vulnerability of Epithelial and Myoid Cells, Complement Attack on Them, and Correlations with Autoantibody Status

Maria I. Leite^*, Margaret Jones, Philipp Ströbel, Alexander Marx, Ralf Gold, Erik Niks, Jan J.G.M. Verschuuren, Sonia Berrih-Aknin^¶, Francesco Scaravilli^||, Aurea Canelhas^**, Paul B. Morgan, Angela Vincent^*, and Nick Willcox^*@

From the Department of Clinical Neurology,* Neuroscience Group, Weatherall Institute for Molecular Medicine, and Nuffield Department of Clinical and Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; the Departments of Pathology and Neurology, University of Würzburg, Würzburg, Germany; the Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands; Centre National de Recherche Scientifique Unité Mixte de Recherche 8078,^¶ Université Paris-Sud, IPSC, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; the Division of Neuropathology,^|| the National Hospital for Neurology and Neurosurgery, London, United Kingdom; and the Department of Pathology,** Hospital Santo Antonio, Porto University, Porto, Portugal; the Department of Medical Biochemistry and Immunology, School of Medicine, University of Cardiff, Cardiff, United Kingdom

^@ To whom correspondence should be addressed. E-mail: nick.willcox{at}imm.ox.ac.uk.

	Abstract

In early-onset myasthenia gravis, the thymus contains lymph node-type infiltrates with frequent acetylcholine receptor (AChR)-specific germinal centers. Our recent evidence/two-step hypothesis implicates hyperplastic medullary thymic epithelial cells (expressing isolated AChR subunits) in provoking infiltration and thymic myoid cells (with intact AChR) in germinal center formation. To test this, we screened for complement attack in a wide range of typical generalized myasthenia patients. Regardless of the exact serology, thymi with sizeable infiltrates unexpectedly showed patchy up-regulation of both C5a receptor and terminal complement regulator CD59 on hyperplastic epithelial cells. These latter also showed deposits of activated C3b complement component, which appeared even heavier on infiltrating B cells, macrophages, and especially follicular dendritic cells. Myoid cells appeared particularly vulnerable to complement; few expressed the early complement regulators CD55, CD46, or CR1, and none were detectably CD59⁺. Indeed, when exposed to infiltrates, and especially to germinal centers, myoid cells frequently labeled for C1q, C3b (25 to 48%), or even the terminal C9, with some showing obvious damage. This early/persistent complement attack on both epithelial and myoid cells strongly supports our hypothesis, especially implicating exposed myoid cells in germinal center formation/autoantibody diversification. Remarkably, the similar changes place many apparent AChR-seronegative patients in the same spectrum as the AChR-seropositive patients.

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