title: T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.
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.
authors.affiliation: Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX37BN, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Harkiolaki
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Holmes
authors.forename: Pia
authors.initials: P
authors.lastname: Svendsen
authors.forename: Jon W
authors.initials: JW
authors.lastname: Gregersen
authors.forename: Lise T
authors.initials: LT
authors.lastname: Jensen
authors.forename: Roisin
authors.initials: R
authors.lastname: McMahon
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.forename: Gijs
authors.initials: G
authors.lastname: van Boxel
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.forename: John S
authors.initials: JS
authors.lastname: Tzartos
authors.forename: Kamil
authors.initials: K
authors.lastname: Kranc
authors.forename: Sarah
authors.initials: S
authors.lastname: Sainsbury
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Jackie
authors.initials: J
authors.lastname: Palace
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000473:pathology; D003429:Cross Reactions / Q000276:immunology; D004330:Drosophila; D004926:Escherichia coli / Q000276:immunology; D006681:HLA-D Antigens / Q000378:metabolism; D015802:HLA-DR2 Antigen / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D018716:Molecular Mimicry / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015802:HLA-DR2 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell