Allergy Asthma Immunol Res.  2014 Jan;6(1):6-12. 10.4168/aair.2014.6.1.6.

Histamine-Releasing Factor and Immunoglobulins in Asthma and Allergy

• Kawakami T
• Kashiwakura JI
• Kawakami Y

• KMID: 2166922
• DOI: http://doi.org/10.4168/aair.2014.6.1.6

Abstract

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.

Keyword

Asthma; allergy; histamine-releasing factor; IgE; mast cell; basophil

MeSH Terms

Asthma*
Basophils
Binding Sites
Clone Cells
Hand
Histamine
Histamine Release
Hypersensitivity*
Immunoglobulin E
Immunoglobulins*
Inflammation
Interleukin-13
Interleukin-4
Mast Cells
Population Characteristics
Skin
Histamine
Immunoglobulin E
Immunoglobulins
Interleukin-13
Interleukin-4

Figure

• 

  Fig. 1 Interaction sites between HRF and IgG. Ig-binding sites were mapped to the N-terminal 19 residues (N19) and the H3 (residues 107-135) portion of mHRF, while HRF binds to the Fab portion of Igs. The top left and bottom left panels show the domain structure and the 3-D structure of human HRF (Protein Data Bank, 1YZ1), respectively. The N19 and H3 portions are highlighted. The TCTP1 portion is omitted because it does not form electron-dense structures. The right panel depicts a cartoon of an IgG molecule.

• 

  Fig. 2 Working model of HRF-mediated FcεRI crosslinking. IgE binds FcεRI α chain via the interaction between Cε3 and D2 domains. HRF can exist as a dimer, and one HRF molecule can bind to two molecules of IgE via interactions with the N19 and H3 regions of HRF. The top view (Top) of IgE at the level of Fab and the side view (Bottom) of IgE and IgE-bound FcεRI α chain are shown on the left. After binding the HRF dimer, four FcεRI α chain-nucleated complexes will be formed (Right). The cytoplasmic portion of FcεRI α as well as β and γ chains of FcεRI are omitted for clarity.

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