Allergy is an immunological mystery. Immunoglobulin E, hence IgE, mediates the vast majority of allergic reactions. But what is the evolutionary advantage having such a damaging immune response?
I would like to review new paper (1) from Immunity that examined the role of IgE signaling in a mouse model of human peanut allergy. The data in this article are very straightforward.
The authors used mutant mouse model with hyperactive IL-4 receptor alpha mutation (F709 mutation). This model permits study of human-like food allergic response in mice.
First, the authors found that oral gavage (quite stressful procedure) of mice with peanut butter (4 times, weekly, 5 mg protein, sensitization) induced serum peanut-specific IgE and Th2 response (high IgG1, high IL-4) in IL-4 receptor mutant mice, but not in wild-type mice. In contrast, there was an inverse relationship between peanut-specific Foxp3+ T reg cells proliferation and presence of hyperactive IL-4 receptor alpha mutation. Interestingly, this human-like peanut-specific Th2 response was abolished in peanut-sensitized IgE-deficient mice and correspondingly, peanut-specific Foxp3+ T reg cell proliferation was recovered in peanut-sensitized IgE-deficient mice even on IL-4 receptor alpha mutation background.
Moreover, high dose, 100 mg peanut challenge of peanut-sensitized mice revealed that core body temperature reduction (a readout for anaphylaxis) was observed only with IL-4 receptor alpha mutant mice, but absent in (a) unsensitized IL-4 receptor alpha mutant mice, (b) wild-type sensitized mice or (c) obviously on IgE-deficient background. This results suggested that presence of IgE favored antigen-specific Th2 response and inhibited antigen-specific Foxp3+ T reg cell proliferation.
Since anti-IgE therapy has been developed to treat human allergies, the authors used similar approach with anti-IgE injection and found that anti-IgE injection prior to peanut-sensitization stage or even during desensitization stage (when allergy has already been established) prevented anaphylaxis to subsequent high dose peanut challenge. Desensitization with high dose peanut alone did not prevent anaphylaxis. This results indicated that anti-IgE therapy is a viable immunotherapy.
Next, the authors tested the role of mast cells in peanut allergy model. They have tested 3 different mast cell deficient mouse models: Kit-deficiency (naturally lacks mast cells, among other abnormalities), Mcpt5-cre iDTR, and Mcpt5-cre Syk fl/fl mice models. Mcpt5 is a mast cell specific promoter. Mcpt5-cre iDTR permits specific depletion of mast cells and Mcpt5-cre Syk fl/fl model permits mast cell specific IgE-signaling molecule, Syk inactivation.
The authors showed that Kit-deficient mice on IL-4 receptor alpha mutant background were protected against anaphylaxis. However, reconstitution of Kit-deficient / IL-4 receptor alpha mutant mice with wild-type but not IL-4-deficient mast cells restored anaphylaxis. Similarly, selective depletion of mast cells in Mcpt5-cre iDTR mice or selective inactivation of IgE signaling in mast cells in Mcpt5-cre Syk fl/fl mice prevented anaphylaxis, reduced peanut-specific IgE production and augmented peanut-specific Foxp3+ T reg proliferation. This results showed that mast cells derived IL-4 and mast cell specific IgE signaling plays a critical role in this model of human peanut allergy.
Finally, to test the therapeutic effect of Syk inhibitors, the authors injected allergy-prone IL-4 receptor alpha mutant mice with available Syk inhibitor during either peanut sensitization or desensitization stage. In both cases, peanut application under the cover of Syk inhibitor prevented anaphylaxis. Interestingly, treatment with Syk inhibitor specifically reduced peanut-specific IgE production without affecting IgG1 level. Since application of Syk inhibitor led to peanut-specific Foxp3+ Treg expansion, the authors tested therapeutic effect of the adoptive transfer of Foxp3+ T reg cells from Syk inhibitor treated peanut-sensitized IL-4r mutant mice into untreated peanut-sensitized IL-4r mutant mice. Transfer of Foxp3+ T reg cells from Syk inhibitor treated mice into peanut-sensitized mice reduced IgE and prevented anaphylaxis.
In summary, this paper showed that mast cell-specific IL-4 production and mast cell-specific IgE signaling through Syk plays critical role in mouse model of peanut allergy. This allergic reaction however could be prevented by anti-IgE and Syk inhibitor therapy or by antigen-specific Foxp3+ Treg transfer.
There are few good new papers about Foxp3+ T reg cells recently published in high impact journals and I will review some of them next.