Inflammation-induced IgE promotes epithelial hyperplasia and tumour growth

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.

Is There a Role for Basophils in Cancer?

“… ND, not done . a Several key surface markers are used to characterize human [IgE + , FcεRI + , CCR3 + , (CD123)IL-3Rα + , CD63 + , CD203c + ] ( 15 , 36 , 57 , 61 , 71 ) and murine basophils (FcεRI + , KIT − , CD49b + , CD200R3 + ) ( 35 , 62 , 72 – 76 ) by flow cytometric analysis . b This table essentially includes the phenotypic characteristics of peripheral blood human and mouse basophils.…”

“… b This table essentially includes the phenotypic characteristics of peripheral blood human and mouse basophils. Phenotypic and/or molecular characteristics of human ( 50 ) and mouse basophils in tissues ( 26 , 39 , 44 , 53 , 55 , 62 ) are also included . +: means “expressed”; ++: means “highly expressed”; – means “not expressed”; ±: means “probably expressed under certain circumstances” .…”

“…2.5 days in mice) ( 124 ) and therefore newly generated basophils are constantly supplied from the bone marrow to the blood ( 20 ). It has long been thought that basophils circulate in peripheral blood and are rarely present in tissues unless during specific kinds of inflammation, reported both in mice ( 62 , 73 , 124 – 126 ) and in humans ( 50 , 127 – 131 ). However, this dogma has been recently challenged by a study in mice whereby the authors found that basophils are present in all phases of lung development ( 44 ).…”

“…It is important to emphasize that previous studies using antibody-depleted basophils ( 114 ) and genetically engineered models ( 62 , 91 ) provided contrasting results on the role of basophils in cancer. Moreover, it should be pointed out that even new mouse mutants have some hematological abnormalities ( 177 ).…”

IgE Autoreactivity in Atopic Dermatitis: Paving the Road for Autoimmune Diseases?

“…SinceIgE-induced mast cell or basophil histamine release impairs keratinocytes differentiation, and promote their survival, skin barrier dysfunction and epidermal hyperplasiain AD models, any autoreactive IgE-mediated degranulation should induce the same effects [ 11 , 124 , 125 ]. Indeed, autoreactive IgEinduced basophil activation, histamine release, and an histamine dependent epidermal hyperplasia in a model of chronic atopic skin inflammation [ 126 ]. Thus, autoreactive IgE promote epidermal pathology during chronic skin inflammation.…”