Effector Pathways in Peanut-Induced Anaphylaxis Figure 3. PE-induced mucosal mast cell degranulation, ear swelling and systemic anaphylaxis in different mouse strains. C3H/HeOuJ (C3H), C57BL/6 and BALB/c mice were exposed to PBS+CT (cont) or PE+CT (PE) during a 4 week period, as described in material and methods. A, Mice were challenged intragastrically (i.g.) or intraperitonially (i.p.) and blood was taken to measure MMCP-I. B, Mice were challenged intradermally with PE in the ear and ear swelling was measured after 3 hours. Ear swelling was calculated by correcting the thickness of the right ear with the left control ear thickness minus the basal ear thickness before challenge. C, Mice were challenged i.p. and rectal temperature was measured at indicated time points after challenge. In addition, peak anaphylactic scores were taken. Data are represented as mean 6 SEM of 6–8 mice. *: p,0.05 compared to control. #: p,0.05 compared to BALB/c PE group. ‘: p,0.05 compared to BALB/c PE and C57BL/6 PE group. doi:10.1371/journal.pone.0028917.g003 It has been demonstrated that PAF was an important mediator of systemic anaphylaxis in the earlier mentioned models [9,27]. We now append these studies showing that the role of PAF, and additionally of monocytes/macrophages is strain-dependent. PAF is produced by monocytes/macrophages, mast cells and many other immune cells, activates platelets but also has effects on vascular and endothelial cells, explaining its possible role in systemic anaphylaxis [28]. A human study showed increased levels of PAF during anaphylaxis and more severe anaphylaxis in individuals who slowly catabolize PAF [8]. Moreover, it was suggested that PAF secretion by monocytes/macrophages, via platelets, contributes to pathophysiology of allergic asthma [29]. We therefore can envision a situation in food-induced anaphylaxis where initial activation of mast cells and secretion of histamine and PAF is followed by activation of monocytes/macrophages leading to secretion of additional PAF and activation of platelets. However, the present findings suggest that this may be determined by predisposing genetically factors in man as it is in the mouse. We consider it very well possible that the relatively high level of mast cell degranulation in C3H/HeOuJ mice and humans displaying the classical pathway obscures a possible activation and involve- ment of components of the alternative pathway. Previous mechanistic studies indicate that the present mouse model of peanut allergy resembles the situation in human patients to a great extent. Classically, in humans, food allergy and food- induced anaphylaxis is suggested to be mostly IgE mediated [6]. However, the current study showing strain-dependent differences in the role of classical versus alternative pathways may be translational to the human situation. Some patients may also display alternative pathway-driven clinical effects (e.g. PAF expression) and thus resemble a genetically predisposed mouse strain as the C57BL/6 mouse. Our studies are in line with the suggestion by Finkelman that the differences between mouse and man in this respect may be caused by the used mouse models more than by a difference in immune system between mouse and human [6]. Figure 4. Humoral immunity and PE-induced systemic anaphylaxis. C57BL/6 and FcRc 2/2 mice were exposed to PBS+CT (cont) or PE+CT (PE) during a 4 week period, as described in material and methods. A, Serum levels of PE-specific IgE, IgG1 and IgG2a at day 36. B, Temperature after i.p. challenge. Data are represented as mean 6 SEM of 4–6 mice. *: p,0.05 compared to control. doi:10.1371/journal.pone.0028917.g004 PLoS ONE | www.plosone.org 7 December 2011 | Volume 6 | Issue 12 | e28917