Mast cell heterogeneity underlies different manifestations of food allergy in mice (1)
During the allergic response, food allergen cross-links IgE bound to MCs via FcεRI, resulting in activation and release of preformed granule contents, rapidly synthesized lipid mediators or cytokines and chemokines. Histamine and platelet activating factor (PAF) contribute to peanut-induced systemic anaphylaxis in mice and humans, while serotonin and PAF are the main mediators that contribute to gastrointestinal symptoms in mice.
Mast cells (MCs) are derived from hematopoietic stem cells, which give rise to mast cell progenitors that circulate in the blood and enter the tissues, where they undergo differentiation and maturation to become mature MCs. Mouse MCs are classified based on their anatomic location in two groups, mucosal (MMCs) and connective tissue (CTMCs) mast cells.
The first, in Balb/c mice, results in gastrointestinal symptoms (diarrhea) but a lack of systemic anaphylaxis when mice are orally challenged. The second, in C3H/HeJ mice, results in systemic anaphylaxis without gastrointestinal symptoms upon oral challenge.
In the small intestine (SI), there is a predominant expression of MMCP-1 and 2, while in skin, the MC proteases MMCP-4, 5, 6, 7 and carboxypeptidase dominate. In cells from the peritoneal cavity, the protease profile was similar to CTMCs from the skin but lacking expression of MMCP-7. Epicuta- neously sensitized and orally challenged Balb/c mice, but not C3H/HeJ mice, demonstrated an increase in MMCP-1 and MMCP-2 expression in the SI. The expression of MMCP-8, which is a marker of basophils rather than MCs, was restricted to the lungs, and interestingly was upregulated in both sensitized C3H/HeJ and Balb/c mice.
In oral challenge of sensitized C3H/Hej mice, OVA-specific IgE, IgG1 and IgG2a levels measured in mouse sera after oral challenge with OVA did not discriminate responders from non-responders within the sensitized group, but were significantly elevated compared to naïve controls. Similarly, oral challenge with OVA resulted in a significant elevation in serum MMCP-1 in sensitized mice. MMCP-7 levels were significantly higher in those with systemic anaphylaxis than in sensitized and challenged mice without symptoms. Serum histamine levels were slightly increased in sensitized mice compared to native mice.
Systemic (intraperitoneal) challenge of sensitized C3H mice with OVA resulted in anaphy- laxis in most mice, and responders showed elevated levels of OVA-specific IgE, IgG1, IgG2a, MMCP-7, and histamine levels.
There was a significant correlation between temperature and MMCP-7, but not MMCP-1. Plasma histamine levels were significantly correlated with anaphylaxis severity and MMCP-7, but not MMCP-1, in response to either oral or systemic allergen challenge.
In a model of gastrointestinal food allergy, mice with gastrointestinal symptoms had higher levels of IgE, MMCP-1, as well as MMCP-7 levels.
Spearman‘s coefficient indicated a positive correlation between MMCP-1 and MMCP-7, IgE, IgG1, and IgG2a.
Approaches to limit allergen absorption may be effective in suppressing systemic reactions to foods, as heated milk and egg allergens, that are not absorbed across the intestinal epithelium intact, cannot trigger anaphylaxis by the oral route in mice.