Histamine-Releasing Factor and Immunoglobulins in Asthma and Allergy

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.

Most Highly Cytokinergic IgEs Have Polyreactivity to Autoantigens

PURPOSE: Monomeric IgE molecules, when bound to the high-affinity receptor, exhibit a vast heterogeneity in their ability to induce survival promotion and cytokine production in mast cells. At one end of this spectrum, highly cytokinergic (HC) IgEs can induce potent survival promotion, degranulation, cytokine production, migration, etc., whereas at the other end, poorly cytokinergic (PC) IgEs can do so inefficiently. In this study, we investigated whether IgEs recognize autoantigens and whether IgEs' binding of autoantigens correlates with difference s in HC versus PC properties. METHODS: Enzyme-linked immunosorbent assays were performed to test whether IgEs bind antigens. Histamine-releasing factor in human sera was quantified by western blotting. Cultured mast cells derived from human cord blood were used to test the effects of human sera on cytokine production. RESULTS: Most (7/8) of mouse monoclonal HC IgEs exhibited polyreactivity to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), beta-galactosidase, thyroglobulin and/or histamine-releasing factor. By contrast, mouse PC IgEs failed to react with these antigens. A human monoclonal HC IgE also showed polyreactivity to histamine-releasing factor, dsDNA and ssDNA. Interestingly, sera from atopic dermatitis patients showed increased reactivity to ssDNA and beta-galactosidase and increased levels of histamine-releasing factor. Some atopic dermatitis patients, but not healthy individuals, had substantial serum levels of HRF-reactive IgE. Sera from atopic dermatitis patients with high titers of DNA-reactive IgE could induce several fold more IL-8 secretion in human mast cells than sera from healthy individuals. CONCLUSIONS: The results show that most HC, but not PC, IgEs exhibit polyreactivity to autoantigens, supporting the autoimmune mechanism in the pathogenesis of atopic dermatitis.

Parasite-origin IgE-dependent Histamine-releasing Factors in Inducing Histamine Release from Sensitized Mast Cells / 中国寄生虫学与寄生虫病杂志

Objective To obtain the recombinant IgE-dependent histamine-releasing factors of Schistosoma japonicum and Clonorchis sinensis (rSjHRF and rCsHRF) and to study the effect of recombinant HRFs to induce histamine release from sensitized rat mast cells. Methods The complete coding regions of SjHRF and CsHRF were cloned separately, and the recombinant plasmids were respectively transformed and expressed in BL21 cells. The soluble recom-binant rSjHRF and rCsHRF were purified. Aliquots of the mast cells obtained from the lungs of OVA-immunized rats were separately incubated with rSjHRF and rCsHRF and the released histamine was measured by the OPT spectrofluorometric procedure. The dose-dependent curves and the kinetics of histamine release induced by rSjHRF and rCsHRF were prepared. Results The recombinant plasmids pET-30-rSjHRF and pET-30-rCsHRF were constructed successfully and the purified soluble recombinant proteins rSjHRF and rCsHRF were obtained by affinity chromatography. rSjHRF and rCsHRF induced histamine release from sensitized mast cells in a dose-dependent manner. At the concentration of 150 mg/L, the average rate of histamine release from sensitized mast cells induced by rSjHRF and rCsHRF were 49.78% and 32.63%, respectively. Histamine release increased with prolonged reaction time and the maximal release occurred at 35min. Conclusion The recombinant parasite-originated IgE-dependent HRFs show an effect of inducing histamine release from sensitized mast cells, suggesting that this protein would play a role in type I hypersensitivity in hosts with parasitic infections.