T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.
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.
Harkiolaki
Maria
M
Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX37BN, UK.
Holmes
Samantha L
SL
Svendsen
Pia
P
Gregersen
Jon W
JW
Jensen
Lise T
LT
McMahon
Roisin
R
Friese
Manuel A
MA
van Boxel
Gijs
G
Etzensperger
Ruth
R
Tzartos
John S
JS
Kranc
Kamil
K
Sainsbury
Sarah
S
Harlos
Karl
K
Mellins
Elizabeth D
ED
Palace
Jackie
J
Esiri
Margaret M
MM
van der Merwe
P Anton
PA
Jones
E Yvonne
EY
Fugger
Lars
L
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
D001426:Bacterial Proteins; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015802:HLA-DR2 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell