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

Maria Harkiolaki, Samantha L Holmes, Pia Svendsen, Jon W Gregersen, Lise T Jensen, Roisin McMahon, Manuel A Friese, Gijs van Boxel, Ruth Etzensperger, John S Tzartos, Kamil Kranc, Sarah Sainsbury, Karl Harlos, Elizabeth D Mellins, Jackie Palace, Margaret M Esiri, P Anton van der Merwe, E Yvonne Jones, Lars Fugger

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)348-357
Number of pages10
JournalImmunity
Volume30
Issue number3
DOIs
Publication statusPublished - 20 Mar 2009

Keywords

  • Animals
  • Autoimmune Diseases
  • Bacterial Proteins
  • Cells, Cultured
  • Cerebellum
  • Cross Reactions
  • Drosophila
  • Escherichia coli
  • HLA-D Antigens
  • HLA-DR2 Antigen
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Mimicry
  • Multiple Sclerosis
  • Peptides
  • Receptors, Antigen, T-Cell
  • Spinal Cord
  • T-Lymphocytes

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