Gastroenterology. 2006 Jul;131(1):85-96.

Does cross-reactivity between mycobacterium avium paratuberculosis and
human intestinal antigens characterize Crohn's disease?

Polymeros D, Bogdanos DP, Day R, Arioli D, Vergani D, Forbes A.

University College London, London, United Kindgom.

BACKGROUND & AIMS: Most Crohn's disease (CD) patients show seroreactivity
against Mycobacterium avium paratuberculosis (MAP), suggesting a
pathogenic role for this organism. Our aim was to seek amino acid
similarities between MAP and intestinal proteins that, through molecular
mimicry, could serve as targets for cross-reactive immunity in CD.
METHODS: Fifty-three peptides comprising 23 sets of MAP/human intestinal
peptidyl mimics chosen for maximal homology were constructed and tested
for immunologic cross-reactivity by enzyme-linked immunosorbent assay in
50 patients with CD, 50 with ulcerative colitis, and 38 healthy controls.
RESULTS: Antibody reactivity was present in only 7 of 23 peptide sets.
MAP/self-reactivity in at least 1 of the 7 reactive sets was present in 21
(42%) CD patients but was virtually absent in the controls. Significant
double-reactivity was found against MAP glycosyl transferase d
(gsd)(230-244)/human gastrointestinal glutathione peroxidase
(GPg)(111-125) homologues in 15 of 50 (30%) CD patients; MAP
alkylohydroperoxidase C (ahpC)(20-34)/human tumor overexpressed protein
(TOG)(637-651) double-reactivity was present in 10 (20%) CD patients, but
in none of the controls. Inhibition studies confirmed that simultaneous
reactivity to mimics was caused by cross-reactivity. Three-dimensional
modeling predicts GPg(111-125) will be exposed in a solvent-accessible
surface region of the protein compatible with antibody recognition.
Antibody affinity was greater for the MAP mimics than for the
self-sequences, suggesting that reactivity to the mycobacterial sequences
precedes that against self-sequences. CONCLUSIONS: We describe
MAP/self-mimics as targets of cross-reactive antibody responses
characterizing patients with CD. Our findings indicate gastrointestinal
glutathione peroxidase as a novel autoantigen in CD.