Role of TLR4 in allergic sensitization to food proteins in mice

Abstract

Allergic sensitization to food proteins and other allergens is increasing in prevalence. One hypothesis for this increase is that the decreased rate of infections or exposure to microbial products leaves the immune system susceptible to inappropriate reactivity to innocuous antigens through the lack of development of regulatory cells. We hypothesized that constitutive Toll-like receptor (TLR)4 signaling (presumably via the commensal flora) could inhibit the development of allergic sensitization to food proteins. We tested this hypothesis by sensitizing TLR4+ and TLR4- mice on two genetic backgrounds, C3H and BALB/c, to two common food allergens [beta-lactoglobulin (betaLG) and peanut (PN)]. B-cell responses were not significantly influenced by TLR4 status. T-cell responses were Th2 skewed in TLR4-deficient C3H mice compared with TLR4 sufficient C3H mice, but this pattern of Th2 skewing was not observed in TLR4-deficient mice on a BALB/c background. In anaphylaxis-susceptible C3H mice, TLR4 deficiency was associated with increased severity of anaphylaxis to PN, and decreased severity of anaphylaxis to betaLG. In anaphylaxis-resistant BALB/c mice, TLR4 deficiency was not sufficient to render mice susceptible to PN-induced anaphylaxis. We conclude that although TLR4 status can influence T-cell responses and anaphylaxis severity, the nature of the influence is highly antigen- and strain-dependent.

Regulatory T Cells Control Type I Food Allergy to Beta-Lactoglobulin in Mice

“…These data are in line with previous studies reporting that immediate allergy to BLG can be generated by oral BLG challenge in C3H/HeOuJ orally immunized with BLG/CT [17,24]. However, in our model we did not observed a drop in body temperature (data not shown) in anaphylactic mice and symptoms were only mild, as compared to previous reports [17,24]. One possible explanation for these discrepancies may relate to the age of mice at the onset of sensitization (in our case 5–8 weeks, compared to 3 weeks in the study of Berin et al [24]) or to the dose of BLG used for challenge (50 mg in our study, compared to 100 mg in the study of Frossard et al [18]).…”

“…In addition, oral BLG challenge induced systemic symptoms of anaphylaxis associated with the release in the serum of the preformed mast cell mediator mMCP-1. These data are in line with previous studies reporting that immediate allergy to BLG can be generated by oral BLG challenge in C3H/HeOuJ orally immunized with BLG/CT [17,24]. However, in our model we did not observed a drop in body temperature (data not shown) in anaphylactic mice and symptoms were only mild, as compared to previous reports [17,24].…”

Allergic Sensitization to Bovine β-Lactoglobulin: Comparison between Germ-Free and Conventional BALB/c Mice

“…commun.]. In a study from Berin et al [30], IFN-γ production by BLG-reactivated splenocytes from TLR4-deficient BALB/c mice sensitized to BLG was suppressed compared to TLR4+ mice, thus suggesting a role of LPS in the development of the BLG-specific IFN-γ release. Despite sterilization of food and bedding, the GF environment still contains trace amounts of LPS and dead microorganisms that may thus have influenced the development of the immune response toward BLG.…”

Epicutaneous Sensitization Results in IgE-Dependent Intestinal Mast Cell Expansion and Food Anaphylaxis

“…This is in agreement with several published studies on oral immunization with a variety of antigens that include OVA, and peanut antigens using CT as an adjuvant. [26][27][28] However, other groups have reported anaphylaxis following oral challenge of mice orally immunized with OVA+CT. 29,30 Differences in the doses and schedules of immunization, and in the intestinal flora may be important in determining whether oral immunization leads to anaphylaxis.…”