Current Topics In Microbiology And Immunology, Volume 296, Molecular Mimicry: Infection Inducing Autoimmune Disease, 1st Edition

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The conceptual basis for molecular mimicry was first defined in the early 1980s when monoclonal antibodies against viruses were also shown to react with non-viral host protein; in this case, measles virus phosphoprotein cross-reacted with host cell cytokeratin, herpes simplex virus type 1 with host-cell vimentin and vaccinia virus with host-cell intermediate filaments. Following this discovery, others emerged, again at the clonal level, that T cell clones against proteins from a variety of infectious agents also reacted with host antigenic determinants. The clonal distinction was imperative for the initial definition of mimicry. At least 30 years prior to our initial description of molecular mimicry involving cross-reactions between numerous microbes, on the polyclonal antibody level, streptococcus was believed to react with renal glomeruli, heart and basal ganglia to account for the glomerulonephritis, heart and valvular disease and chorea, respectively. However, subsequent research showed that the nephritis was caused by immune complex deposits and the tissue damage they produced. Later, in 1990, the cross-reactivity of streptococcal antigen with myocardial antigens on a clonal level was uncovered. Hence, for both historical reasons and mechanistic understanding, it is best to provide evidence for cross-reactivity at the clonal level to prove that molecular mimicry exists.

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296 Current Topics in Microbiology and Immunology Editors R. W. Compans, Atlanta/Georgia M. D. Cooper, Birmingham/Alabama T. Honjo, Kyoto · H. Koprowski, Philadelphia/Pennsylvania F. Melchers, Basel · M. B. A. Oldstone, La Jolla/California S. Olsnes, Oslo · M. Potter, Bethesda/Maryland P. K. Vogt, La Jolla/California · H. Wagner, Munich M.B.A. Oldstone (Ed.) Molecular Mimicry: Infection-Inducing Autoimmune Disease With 28 Figures and 9 Tables 123 Michael B.A. Oldstone, M.D. The Scripps Research Institute Department of Neuropharmacology 10550 N. Torrey Pines Road La Jolla, CA 92037 USA e-mail: [email protected] Cover illustration by Melissa Nicholson and Kai W. Wucherpfenning The cover shows the crystal structure of the first human autoimmune T cell receptor bound to its self-peptide/MHC target. The T cell receptor originated from a patient with relapsing-remitting multiple sclerosis and is specific for a myelin basic protein peptide bound to HLA-DR2 (DRA, DRB1*1501). This structure showed a highly unusual binding topology in which the T cell receptor only contacted the N-terminal part of the self-peptide. This binding mode reduces the interaction surface with the MHC bound peptide, and places physical limits on the peptide specificity of this T cell receptor. This structure thus provides an explanation for the finding that this myelin basic protein specific T cell clone can be activated by a number of different microbial peptides that have limited sequence similarity with the self-peptide. The MHC molecule is colored blue, and the TCR alpha and beta chains yellow and red, respectively. The peptide is shown as a stick and ball model. Library of Congress Catalog Number 72-152360 ISSN 0070-217X ISBN-10 3-540-25597-4 Springer Berlin Heidelberg New York ISBN-13 978-3-540-25597-0 Springer Berlin Heidelberg New York This work is subject to copyright. All rights reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September, 9, 1965, in its current version, and permission for use must always be
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