TW-sh/W-sh MCdeficient mice have provided evidence that MCs can contribute significantly to peanutinduced active anaphylaxis242, 244, 245. We recently confirmed these findings using c-kitindependent MC-deficient mice, by showing that selective ablation of CTMCs (induced by repeated injections of diphtheria toxin in Mcpt5-Cre; iDTR mice168) significantly diminished the hypothermia induced by peanut challenge in mice sensitized orally with peanut together with the mucosal adjuvant cholera toxin243. OxaliplatinMedChemExpress Oxaliplatin However, antigen challenge induced significant hypothermia (albeit less than that in the corresponding WT mice) inAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptMucosal Immunol. Author manuscript; available in PMC 2016 February 03.Reber et al.PageCpa3-Cre+; Mcl-1fl/fl mice, which have a marked MC deficiency and a substantial reduction in basophils243. Antigen-induced elevations in serum histamine were abolished in MC- and basophil-deficient Cpa3-Cre+; Mcl-1fl/fl mice, whereas small but significant increases in PAF levels were still detected in spleen specimens from these mice243. Together, these findings implicate the involvement of both the classical and alternative pathways of anaphylaxis in this mouse model of Pan-RAS-IN-1 biological activity peanut-induced active anaphylaxis. The reaction to peanut in some mouse models might be even more complex, since Khodoun et al. found that peanut, but not milk or egg proteins, can induce shock reactions through an innate immune mechanism in mice246. The authors found that this response was almost absent in mice lacking the complement factor C3 or the receptor C3aR, but developed fully in antibody-deficient Rag1 mice (which lack mature T and B cells) and MT mice (in which the development of conventional B cells is arrested at the pro-B cell stage)246. However, some reports indicate that MT mice have B1 B cells and can produce IgE and IgG247?49. Macrophages, basophils and PAF contributed to this shock reaction to a greater extent than did MCs and histamine246. Therefore, depending on the model used, innate components might also participate importantly in peanut-induced anaphylaxis, which perhaps accounts for the fact that peanut allergy is more likely than most other forms of food allergy to cause lethal anaphylaxis. However, it is important to recognize that Khodoun et al. increased the sensitivity of the mice to develop shock reactions in these experiments by pretreating the animals i.v. with a long-acting form of IL-4 (consisting on IL-4/anti L-4 mAb complexes, which slowly dissociate in vivo to release free IL-4) and with the -adrenergic antagonist propranolol246. Although IgE-dependent activation of MCs is widely thought to contribute importantly to anaphylaxis in humans, subjects with food allergy-associated anaphylaxis, unlike those with insect venom-induced anaphylaxis, typically exhibit little or no elevations in blood levels of the MC-associated protease, tryptase250. By contrast, levels of PAF in the serum have been directly correlated with the severity of organ system involvement in patients with acute allergic reactions triggered by foods, medications, or insect stings251, 252. Moreover, the serum activity of PAF acetylhydrolase (an enzyme that converts PAF to the biologically inactive lyso-PAF) was significantly lower in peanut allergic patients with fatal peanut anaphylaxis than in those with mild allergic reactions to peanuts or in control groups251. Although they do not constitute proof, these re.TW-sh/W-sh MCdeficient mice have provided evidence that MCs can contribute significantly to peanutinduced active anaphylaxis242, 244, 245. We recently confirmed these findings using c-kitindependent MC-deficient mice, by showing that selective ablation of CTMCs (induced by repeated injections of diphtheria toxin in Mcpt5-Cre; iDTR mice168) significantly diminished the hypothermia induced by peanut challenge in mice sensitized orally with peanut together with the mucosal adjuvant cholera toxin243. However, antigen challenge induced significant hypothermia (albeit less than that in the corresponding WT mice) inAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptMucosal Immunol. Author manuscript; available in PMC 2016 February 03.Reber et al.PageCpa3-Cre+; Mcl-1fl/fl mice, which have a marked MC deficiency and a substantial reduction in basophils243. Antigen-induced elevations in serum histamine were abolished in MC- and basophil-deficient Cpa3-Cre+; Mcl-1fl/fl mice, whereas small but significant increases in PAF levels were still detected in spleen specimens from these mice243. Together, these findings implicate the involvement of both the classical and alternative pathways of anaphylaxis in this mouse model of peanut-induced active anaphylaxis. The reaction to peanut in some mouse models might be even more complex, since Khodoun et al. found that peanut, but not milk or egg proteins, can induce shock reactions through an innate immune mechanism in mice246. The authors found that this response was almost absent in mice lacking the complement factor C3 or the receptor C3aR, but developed fully in antibody-deficient Rag1 mice (which lack mature T and B cells) and MT mice (in which the development of conventional B cells is arrested at the pro-B cell stage)246. However, some reports indicate that MT mice have B1 B cells and can produce IgE and IgG247?49. Macrophages, basophils and PAF contributed to this shock reaction to a greater extent than did MCs and histamine246. Therefore, depending on the model used, innate components might also participate importantly in peanut-induced anaphylaxis, which perhaps accounts for the fact that peanut allergy is more likely than most other forms of food allergy to cause lethal anaphylaxis. However, it is important to recognize that Khodoun et al. increased the sensitivity of the mice to develop shock reactions in these experiments by pretreating the animals i.v. with a long-acting form of IL-4 (consisting on IL-4/anti L-4 mAb complexes, which slowly dissociate in vivo to release free IL-4) and with the -adrenergic antagonist propranolol246. Although IgE-dependent activation of MCs is widely thought to contribute importantly to anaphylaxis in humans, subjects with food allergy-associated anaphylaxis, unlike those with insect venom-induced anaphylaxis, typically exhibit little or no elevations in blood levels of the MC-associated protease, tryptase250. By contrast, levels of PAF in the serum have been directly correlated with the severity of organ system involvement in patients with acute allergic reactions triggered by foods, medications, or insect stings251, 252. Moreover, the serum activity of PAF acetylhydrolase (an enzyme that converts PAF to the biologically inactive lyso-PAF) was significantly lower in peanut allergic patients with fatal peanut anaphylaxis than in those with mild allergic reactions to peanuts or in control groups251. Although they do not constitute proof, these re.
