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T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.immuni.2009.01.009 Byline: Maria Harkiolaki (1), Samantha L. Holmes (1)(2), Pia Svendsen (3), Jon W. Gregersen (3), Lise T. Jensen (3), Roisin McMahon (1)(2), Manuel A. Friese (2)(5), Gijs van Boxel (1), Ruth... Full description

Journal Title: Immunity 2009, Vol.30(3), pp.348-357
Main Author: Harkiolaki, Maria
Other Authors: Holmes, Samantha L , Svendsen, Pia , Gregersen, Jon W , Jensen, Lise T , Mcmahon, Roisin , Friese, Manuel A , van Boxel, Gijs , Etzensperger, Ruth , Tzartos, John S , Kranc, Kamil , Sainsbury, Sarah , Harlos, Karl , Mellins, Elizabeth D , Palace, Jackie , Esiri, Margaret M , van Der Merwe, P. Anton , Jones, E. Yvonne , Fugger, Lars
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1074-7613 ; E-ISSN: 1097-4180 ; DOI: 10.1016/j.immuni.2009.01.009
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recordid: elsevier_sdoi_10_1016_j_immuni_2009_01_009
title: T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides
format: Article
creator:
  • Harkiolaki, Maria
  • Holmes, Samantha L
  • Svendsen, Pia
  • Gregersen, Jon W
  • Jensen, Lise T
  • Mcmahon, Roisin
  • Friese, Manuel A
  • van Boxel, Gijs
  • Etzensperger, Ruth
  • Tzartos, John S
  • Kranc, Kamil
  • Sainsbury, Sarah
  • Harlos, Karl
  • Mellins, Elizabeth D
  • Palace, Jackie
  • Esiri, Margaret M
  • van Der Merwe, P. Anton
  • Jones, E. Yvonne
  • Fugger, Lars
subjects:
  • Molimmuno
  • Cellimmuno
  • Humdisease
  • Medicine
  • Biology
ispartof: Immunity, 2009, Vol.30(3), pp.348-357
description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.immuni.2009.01.009 Byline: Maria Harkiolaki (1), Samantha L. Holmes (1)(2), Pia Svendsen (3), Jon W. Gregersen (3), Lise T. Jensen (3), Roisin McMahon (1)(2), Manuel A. Friese (2)(5), Gijs van Boxel (1), Ruth Etzensperger (2)(5), John S. Tzartos (5), Kamil Kranc (2), Sarah Sainsbury (1), Karl Harlos (1), Elizabeth D. Mellins (4), Jackie Palace (5), Margaret M. Esiri (6), P. Anton van der Merwe (7), E. Yvonne Jones (1), Lars Fugger (2)(3)(5) Keywords: MOLIMMUNO; CELLIMMUNO; HUMDISEASE Abstract: Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS. Author Affiliation: (1) Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK (2) MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (3) Clinical Institute, Aarhus University Hospital, Skejby Sygehus, DK-8200 N Aarhus, Denmark (4) Department of Pediatrics, Stanford University, Stanford, CA 94305, USA (5) Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (6) Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (7) Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK Article History: Received 10 August 2007; Revised 31 October 2008; Accepted 8 January 2009 Article Note: (miscellaneous) Published onl
language: eng
source:
identifier: ISSN: 1074-7613 ; E-ISSN: 1097-4180 ; DOI: 10.1016/j.immuni.2009.01.009
fulltext: fulltext
issn:
  • 1074-7613
  • 10747613
  • 1097-4180
  • 10974180
url: Link


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titleT Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides
creatorHarkiolaki, Maria ; Holmes, Samantha L ; Svendsen, Pia ; Gregersen, Jon W ; Jensen, Lise T ; Mcmahon, Roisin ; Friese, Manuel A ; van Boxel, Gijs ; Etzensperger, Ruth ; Tzartos, John S ; Kranc, Kamil ; Sainsbury, Sarah ; Harlos, Karl ; Mellins, Elizabeth D ; Palace, Jackie ; Esiri, Margaret M ; van Der Merwe, P. Anton ; Jones, E. Yvonne ; Fugger, Lars
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descriptionTo link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.immuni.2009.01.009 Byline: Maria Harkiolaki (1), Samantha L. Holmes (1)(2), Pia Svendsen (3), Jon W. Gregersen (3), Lise T. Jensen (3), Roisin McMahon (1)(2), Manuel A. Friese (2)(5), Gijs van Boxel (1), Ruth Etzensperger (2)(5), John S. Tzartos (5), Kamil Kranc (2), Sarah Sainsbury (1), Karl Harlos (1), Elizabeth D. Mellins (4), Jackie Palace (5), Margaret M. Esiri (6), P. Anton van der Merwe (7), E. Yvonne Jones (1), Lars Fugger (2)(3)(5) Keywords: MOLIMMUNO; CELLIMMUNO; HUMDISEASE Abstract: Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS. Author Affiliation: (1) Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK (2) MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (3) Clinical Institute, Aarhus University Hospital, Skejby Sygehus, DK-8200 N Aarhus, Denmark (4) Department of Pediatrics, Stanford University, Stanford, CA 94305, USA (5) Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (6) Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK (7) Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK Article History: Received 10 August 2007; Revised 31 October 2008; Accepted 8 January 2009 Article Note: (miscellaneous) Published online: March 19, 2009
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description

Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections...

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abstract

Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections...

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doi10.1016/j.immuni.2009.01.009
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