Eosinophils preference for peanut can lead to allergy

Peanut allergy is a very serious medical condition. Usually, gut immune system tolerates antigens derived from orally consumed food. In rare situations, however, immune system mistakes food antigens for noxious stimuli and mounts exaggerating IgE response. IgE response is basically a highly skewed Th2 response. No one knows how or why it happens.

I am going to review one paper published in Journal of Experimental Medicine (JEM) that studied animal model of peanut allergy (1). I would like to point out here that this mouse model of peanut allergy is an experimental model and may not fully or even partially recapitulate the mechanism of initiation of peanut allergy in humans.

First, analysis of gut lymphoid tissue showed that small intestine contained higher percentage of eosinophils (~ 20%). Interestingly, there was inverse relationship between number of eosinophils and level of gut microbiome.

Second, the authors showed that 4 consecutive, weekly, intra-gastric application of peanut (P) + cholera toxin (CT) induced peanut allergy. This allergic response was dependent on the presence of eosinophils since it was absent in GATA1 mutant mice with low GATA1 promoter activity lacking eosinophils. Adoptive transfer of wild-type eosinophils rescued peanut allergy development in GATA1 mutant mice.

Third, the authors found that IL-4 secretion by eosinophils was not necessary to induce peanut allergy in this model.

Fourth, it turned out that gut CD11c+ /CD103+ dendritic cells were also required to induce peanut allergy in this model since it was abolished in CD11c-DTR bone marrow chimera mice upon DT (diphtheria toxin) application.

Next, the authors found peanut + cholera toxin combination induced eosinophil degranulation releasing eosinophil peroxidase (EPO), similar to positive control reagent, L-PAF.

Incubation of mouse BMDCs or human in vitro derived DCs with native EPO, but not heat-inactivated EPO, induced their activation and IL-6 secretion without compromising their viability.

To confirm that EPO played a role in mouse model of peanut allergy, the authors tested EPO-deficient mice. As shown below, EPO-deficient mice failed to generate peanut specific IgE response similar to eosinophil-deficient GATA1 mutant mice.

In summary, the authors proposed that mechanism of peanut sensitization as following: food peanut antigen activates gut eosinophils to release EPO to drive local DCs migration into local LN to prime Th2 response.

Some consideration: (1) do eosinophils sense peanut? The authors do not show if peanut alone can activate eosinophils. (2) while data from EPO-deficient mice is impressive, the authors did not explain whether EPO-deficient mice selectively lacks EPO in eosinophils as the name would suggest (BM chimera would have been a good experiment).

David