Factors that can induce the release of
histamine from basophils have been studied for more than 30 years. A
protein termed
histamine-releasing factor (HRF) was purified and molecularly cloned in 1995. HRF can stimulate histamine release and
IL-4 and
IL-13 production from
IgE-sensitized basophils and mast cells. HRF-like activities were found in bodily fluids during the late phase of
allergic reactions, implicating HRF in allergic diseases. However, definitive evidence for the role of HRF in allergic diseases has remained elusive. On the other hand, we found effects of monomeric
IgE on the survival and activation of mast cells without the involvement of a specific
antigen, as well as heterogeneity of IgEs in their ability to cause such effects. The latter property of
IgE molecules seemed to be similar to the heterogeneity of IgEs in their ability to prime basophils in response to HRF. This similarity led to our recent finding that ~30% of
IgE molecules can bind to HRF via their Fab interactions with two binding sites within the HRF molecule. The use of
peptide inhibitors that block HRF-
IgE interactions revealed an essential role of HRF to promote skin
hypersensitivity and airway
inflammation. This review summarizes this and more recent findings and provides a perspective on how they impact our understanding of
allergy pathogenesis and potentially change the treatment of allergic diseases.