Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.