Expression of LTC4-synthase in small intestinal mucosa of celiac patients and controls

Abstract

Increased levels of the Th2-associated leukotriene C4 (LTC4) have been described in celiac disease. LTC4 is mainly produced by LTC4-synthase containing mast cells and eosinophils in a Th2 cytokine (IL-4, IL-5) depended manner, cytokines which are not increased in the Th1 dominated celiac inflammation. AIM: Identify the LTC4-synthase containing cells and examine their distribution in small intestinal mucosa from celiac patients and controls. METHODS: Small intestinal biopsies from 28 celiac children (14 untreated, 14 treated), and 15 controls were studied by multicolor immunohistofluorescence microscopy. Antisera to LTC4-synthase and microsomal glutathione transferase-2 (MGST2) were combined with cell specific monoclonal antibodies (mAb) to identify mast cells (c-kit), eosinophils (EG2) or macrophages (CD68 and HLA-DR). RESULTS: Whereas the majority (96%) of submucosal mast cells expressed high levels of perinuclear LTC4-synthase in controls and treated celiac disease, relatively few eosinophils expressed low levels (7% and 5% respectively). This distribution shifted somewhat in untreated celiac disease as fewer mast cells (85%, p<0,003), but more eosinophils (19%, p<0,02) contained LTC4-synthase. There was a high density of extracellular mAb EG2+ granula in untreated celiac disease, suggesting eosinophil activation. Sections contained occasionally some scattered LTC4-synthase positive macrofages and endothelial cells. The intestinal perivascular smooth muscle and lamina muscularis mucosa contained MGST2 but not LTC4-synthase. CONCLUSION: Although the proportion of LTC4-synthase containing eosinophils increased in untreated celiac disease, mast cells remained the dominating LTC4-synthase containing cell. Subepithelial complement activation may activate both mast cells and eosinophils to produce LTC4 in untreated celiac disease. Interesting, a recent case study reported symptom relief and apparently cure of celiac disease (non tropical sprue), after using leukotriene receptor CysLT1 antagonist (Montelukast). Thus increased leukotriene production may have a greater impact on celiac immunopathology than currently acknowledged.