My first trip was London/Bath with my grandmother (quite the Anglophile) when I was 14, and I haven't stopped since then. I agree with the posters that the UK is an easy starter trip and tossing in France could also be okay.

When I was 21 I backpacked Europe with a friend who turned out to be incredibly homesick and a very bad traveler. She ended up feeling much happier in the smaller towns - they didn't need to be English-speaking towns, just not big cities. They felt much more manageable to her. Brugge was a treat. Wonder if your wife might feel the same.