Oral sensitization to whey proteins induces age- and sex-dependent behavioral abnormality and neuroinflammatory responses in a mouse model of food allergy: a potential role of mast cells. (1)

Although less recognized, food allergy has also been linked to abnormal psychosocial behavior and mood disorders, such as depression, anxiety, attention-deficit hyperactivity disorder, and autism. Whey proteins (WP) from cow’s milk, one of the most common food allergens, in the presence of cholera toxin (CT) were chosen to induce sensitization in mice.

When placed in a new cage filled with fresh, thick bedding material, the male mice, in general, exhibited more robust digging activity compared to female mice. The digging frequency of WP-sensitized male mice was decreased by approximately 30% in young mice and by 50% in old mice.

The level of IgE was found to be elevated in the young WP-sensitized male group by approximately 40%.

The expression of tryptase (Tpsab1) was elevated by 7-fold in young WP-sensitized male mice. Occludin expression (Ocln) in these mice was decreased by approximately 20%. In young WP-sensitized female mice, the Ocln levels were slightly but significantly increased. In older mice, WP sensitization increased the expression of Tpsab1 in female mice but not in male mice, even though TB stained mast cells were more readily found in the ileum sections from the latter group.

Approximately 2-fold more degranulated mast cells were present in young WP-sensitized male mouse brains than the corresponding shams. This WP-sensitization-dependent variation in the mast cell numbers was not observed in young female mice or older mice of either sex.

BALB/c and C3H/HeJ are more commonly used for immunological studies. These mice have been reported to have greater tendencies to exhibit severe anaphylactic reactions often resulting in hypothermia, breathing difficulty, immobility, and death after sensitization. Males are more afflicted by IgE-mediated food allergy than females in younger populations, although the trend becomes reversed in older populations. Tryptase is a protease present in mast cell granules and it has been shown to decrease the level of a tight junction protein, occludin. Inflammatory factors such as interleukin (IL)-4, IL-5, IL-13, IL-15, eotaxin-3, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, are found to be elevated in non-IgE-mediated food allergy. In a study using casein as a food allergen, it was shown that serum casein level increased in orally sensitized mice after food challenge, indicating that food antigen is capable of entering into the circulation in a similar milk-allergy model. Patients with mastocytosis, a condition in which abnormal accumulation and/or degranulation of mast cells occur in various tissues, suffer from depres- sion, anxiety, memory loss, attention and concentration deficits, poor motivation, and cognitive impairment, in addition to gastrointestinal and cardiovascular problems.

1. D. L. Germundson, N. A. Smith, L. P. Vendsel, A. V. Kelsch, C. K. Combs, K. Nagamoto-Combs, Oral sensitization to whey proteins induces age- and sex-dependent behavioral abnormality and neuroinflammatory responses in a mouse model of food allergy: a potential role of mast cells. J. Neuroinflammation. 15 (2018), doi:10.1186/s12974-018-1146-0.