Abstract
IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE antibodies is unclear but it has been suggested that they provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show, in mice, that skin inflammation enhances levels of IgE antibodies that have natural specificities and a repertoire, VDJ rearrangements and CDRH3 characteristics similar to those of IgE antibodies in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and thymic stromal lymphopoietin (TSLP)/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE antibodies support skin barrier defences, but that during chronic tissue inflammation this role may be subverted to promote tumour growth.
Highlights
IgE is present at low concentrations in the blood and is the least abundant circulating antibody class
Skin inflammation increases IgE levels locally and systemically. Both basophils and mast cells carry a high number of FceRI receptors, which are usually occupied with IgE (Lawrence et al, 2017)
Basophil numbers further increased at 48 hr after cessation of TPA treatment and declined as the inflammation subsided, while mast cells returned to the skin (Figure 1i)
Summary
IgE is present at low concentrations in the blood and is the least abundant circulating antibody class. All epithelial tissues contain resident cells constitutively binding IgE antibodies. IgE is bound with high affinity to its receptor, FceRI, and can remain bound for the life of the FceRI-bearing cell (MacGlashan, 2008). Mast cells and basophils are the only two cell types that express the complete high-affinity receptor for IgE (FceRI) with all four polypeptide subunits (abg). Subsets of dendritic cells, monocytes and eosinophils can express low levels of FceRI but only as a trimer, lacking the b chain (ag). The density of mast cell and basophil FceR1 expression correlates with serum IgE levels, so an increase in IgE antibody may directly increase FceRI signalling (Lawrence et al, 2017). Mast cells are constitutively resident in tissues, such as the skin, whereas basophils are circulating cells that rapidly
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