Gluten sensitivity is associated with a spectrum of mucosal lesions, arbitrarily termed pre-infiltrative, infiltrative-hyperplastic, flat-destructive and atrophic-hypoplastic. Histologically and immunohistologically these lesions are all compatible with T-cell-driven events operative at a local mucosal level. They are classifiable either in terms of antibody titres (pre-infiltrative) (see Chapter 10) or by the characteristic disposition of IELs throughout the surface and crypt epithelium. From in-vivo challenges, it has been demonstrated: (i) that all these lesions comprise a dynamically interrelated series of events, culminating in the severe flat-destructive lesion; and (ii) that gluten evokes a dose-responsive infiltration of IELs (CD3+ CD8+ and TCR alpha beta + or gamma delta +) into the epithelium. Apart from that, little is known of the functions of IELs; it is possible they may have little to do with the evolving mucosal pathology of gluten sensitivity. Increasing work seems to support a view, proposed from this laboratory over 10 years ago, that the immune-mediated responses in jejunal tissue in gluten sensitivity arise in the lamina propria, in association with DR+ macrophages and an abundance of CD4(+)-activated lymphocytes. Many other inflammatory consequences flow from these interactions, involving activation of mast cells, eosinophils and neutrophils, elaboration of cytokines and other products of inflammation, and increased hyperpermeability of the microvasculature with upregulation of adhesion molecules. The result is a doubling of lamina propria volumes in the severe flat lesion. Evidence is also given to show that measurable changes in lamina propria inflammation occur with the infiltrative-hyperplastic lesion. Symptomatology is not related to the degree of proximal mucosal pathology, but to the extent of the mucosal lesion. Data, although scanty, suggests that lesional pathology involves only 30-50% of the entire small bowel mucosa. Thus, most patients, irrespective of proximal mucosal damage, have latent (or asymptomatic) gluten sensitivity. Symptom development requires additional environmental triggers, of which infection is a major contributor. It should also be noted that, while these various environmental triggers may precipitate symptomatology, they do not advance the severity of the mucosal lesion.