Computerised image-analysis was used to define the spectrum of immunopathological changes in small intestinal mucosa in established celiac sprue disease; dermatitis herpetiformis; 1 degree relatives of celiac sprue patients, and treated celiac sprue patients challenged with varying doses of a peptic-tryptic digest of gluten. Typically, in flat ('Type 2') lesion there was a reduced number of large, mitotically active lymphocytes in surface epithelium, but an increased lymphocyte population in crypts. In approximately 50% untreated DH patients and in 20% 1 degree celiac sprue relatives, mucosal architecture was well-preserved although surface (villous) epithelium contained an expanded population of small, non-mitotic lymphocytes ('Type 1' lesion), with or without crypt hyperplasia. Similar changes were also induced by small dose gluten challenge. Larger dose challenges caused a progression from a Type 1 to a Type 2 lesion during a 5 day period of observation. In addition, observations on a few patients over 2-4 years showed a similar sequence of mucosal changes. A major feature of this sequence was the early appearance of crypt hypertrophy, before significant villous flattening had occurred. These changes parallel T lymphocyte-mediated graft- versus-host reactions in animals, suggesting that the specific immunopathologic features seen in gluten sensitivity are fundamentally cell-mediated in type, the degree of change probably dependent on host genetic factors. Finally, these data show that in becoming flat the mucosa must initially pass through the earlier Type 1 lesion in which crypt hypertrophy is a prominent response.