Human dendritic cells accumulate in lung disease and contribute to serum IgE clearance via FcERI

Dendritic cells are crucial for the development of the adaptive immune response and have also been implicated in a number of inflammatory diseases. Much of what we know about dendritic cell function is limited to mouse models of disease, as human DCs remain difficult to identify consistently and samples can be difficult to acquire. We undertook a study to identify the prevalence of BDCA1+ DCs in a panel of healthy and diseased lung donors by carefully and comprehensively identifying DCs in parenchymal lung tissue. We found a dramatic increase in the prevalence of BDCA1+ DCs in the fibrotic lung diseases idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (HP) by flow cytometry. We also saw a significant increase in BDCA1+ DCs in Th2-high asthma by using the high-affinity IgE receptor, FcERI and MHCII as identification markers of DCs in biopsy sections. These increased numbers of BDCA1+ DCs could potentially contribute to disease and may represent a novel therapeutic target. Because of the potential role of FcERI in promoting Th2-mediated allergy via DCs, we also investigated regulation of this receptor on human DCs. Surprisingly, we found that human DCs and monocytes constitutively endocytose FcERI and IgE in the absence of crosslinking stimulus. Transgenic mice expressing human FcERIa showed similar FcERI regulation, which resulted in rapid human IgE endocytosis in blood DCs and monocytes in vivo. Serum IgE catabolism was accelerated in FcERI-transgenic mice and was significantly influenced by DC and monocyte numbers. DCs and monocytes may therefore contribute to serum IgE control through constitutive IgE endocytosis and could represent a novel therapeutic strategy for allergic conditions. Further work on the trafficking mechanism of FcERI regulation may provide a significant novel strategy for control of IgE-mediated allergies