A fine balance of IgG4 and interleukin-10 is required for a tolerogenic response in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic gastrointestinal disorder first described in 19771. The disease is defined by massive infiltration and homing of mature eosinophilic granulocytes in the esophageal mucosa2. The pathogenesis of the disease is believed to be caused by epithelial barrier dysfunction resulting in the ill-balanced immune responses to ‘non-replicating’ foreign antigens primarily derived from food. The disease is established as rare worldwide, including in North America, Europe, Australia and Asia3. The treatment of EoE includes: (i) drugs such as proton pump inhibitors and topical corticosteroids; or (ii) diet therapy such as elemental diet, empirical diet, or targeted diet4. The clinical manifestations of the disease are generally reduced by removal of certain foods, but re-exacerbations seem to be occurring upon reintroduction of the same foods. The effectiveness of the diet therapy only ranges 70-80% in patients with six-food elimination diet, 50-60% in patients with two-food elimination diets and 30-60% with milk elimination alone5,6. We have conducted a study on ten patients diagnosed with EoE and under two-food elimination diet therapy. We looked at the infiltrating eosinophilic granulocytes, the overall histological changes and the frequencies of IgG4 and IL-10 expressing leukocytes7,8 in esophageal mucosa before and after elimination diet. We also measured the serum levels of IgG4 specific to six different food antigens in these patients. Our results, while preliminary, collectively suggest a fine balance between IgG4 and IL-10 expression. These molecules seem to be required for a progressive tolerogenic response to food antigens in patients responding to diet therapy. Conversely, in non-responders the inflammatory response appears to be skewed towards increased eosinophil and IL-10 levels with a drastic loss of IgG4, which suggests that a sufficient level of high-affinity tolerogenic IgG4 probably was not achieved.