Allergic host defences

Abstract

Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macroparasites. Here we present arguments to suggest that allergic immunity has an important role in host defence against noxious environmental substances, including venoms, haematophagous fluids, environmental xenobiotics and irritants. We argue that appropriately targeted allergic reactions are beneficial, although they can become detrimental when excessive. Furthermore, we suggest that allergic hypersensitivity evolved to elicit anticipatory responses and to promote avoidance of suboptimal environments.

Figure 1. Diverse stimuli activate allergic host defenses

Four main classes of stimuli activate the allergic host defense response: helminthes, noxious xenobiotics (e.g., urushiol from poison ivy), venoms (e.g., venom from the honey bee Apis meliffera), and irritants (e.g., diesel exhaust particles). A variety of effector modules constitute the allergic host defense response. Keratinocye and goblet cell hyperplasia (mucus secretion) enhance barrier functions to reduce exposure to noxious environmental allergens and to restrict helminth entry, feeding and growth. Sneezing, coughing, vomiting, diarrhea, and itch serve to remove or expel noxious xenobiotics, irritants, helminths and ectoparasites. Eosinophils can mediate direct helminth killing, while heparin and proteases from mast cells can inactivate venoms through neutralization and detoxification. Granuloma formation and alternatively activated macrophages can restrict helminth spread, lead to disruption of niches and restrict feeding. Granuloma formation also restricts the damage caused by irritants. Additional allergic defense mechanisms, such as mast cell-induced hypotension and vasodilation, may restrict the spread of noxious xenobiotics and venoms. Fibroblasts and alternatively activated macrophages coordinate tissue protection and tissue repair through epithelial metaplasia, extracellular matrix deposition, and barrier restoration. Various allergic host defenses may also condition future avoidance of sources of noxious xenobiotics, irritants and venoms. For example, cutaneous hypersensitivity responses (e.g., itch and dermatitis) to noxious phytochemicals, such as urushiol, may condition future avoidance of poison ivy. Furthermore, anaphylactic responses to bee venom may condition avoidance of honey bees, and sneezing, coughing, vomiting, diarrhea, tearing and mucus production may condition avoidance of various irritants and other noxious environmental substances.

Figure 2. Functional modules of type 2 immunity

a) Innate lymphoid cells and Th2 cells secrete the canonical type 2 cytokines IL-4, IL-5, IL-9, and IL-13. The IL-4Rα-activating cytokines, IL-4 and IL-13, induce epithelial barrier enhancement by promoting goblet cell hyperplasia and mucous secretion at mucosal surfaces, while contributing to epidermal thickening and keratinocyte hyperplasia in the skin. These cytokines also induce alternative activation of macrophages, which play an instrumental role in helminth restriction and tissue repair. IL-5 secretion induces eosinophil recruitment to tissues where they contribute to helminth killing. b) Mast cell secretion of proteases and heparin aids in detoxification, degradation, and clearance of venoms and noxious xenobiotics increasing resistance to these toxins. Mast cells mediate many responses by producing histamine and lipid mediators, such as prostaglandins. Histamine and prostaglandins contribute to activation of endothelial cells, inducing vasodilation and vascular leakage, and smooth muscle cells, inducing bronchoconstriction and various mechanisms that contribute to expulsion (coughing, sneezing, vomiting, diarrhea). Basophils also contribute to antibody-mediated tick resistance. Histamine release from mast cells also can activate C-fibers to induce itch. Notably, crosstalk between these two modules is also common. For example,Th2 cells produce IL-3, which leads to increased basophil and mast cell production, and IL-9, which leads to recruitment of mast cells. Furthermore, basophils can produce Th2-inducing cytokines such as IL-4, and mast cells can produce ILC-activating cytokines, such as IL-33.

Figure 2. Functional modules of type 2 immunity

a) Innate lymphoid cells and Th2 cells secrete the canonical type 2 cytokines IL-4, IL-5, IL-9, and IL-13. The IL-4Rα-activating cytokines, IL-4 and IL-13, induce epithelial barrier enhancement by promoting goblet cell hyperplasia and mucous secretion at mucosal surfaces, while contributing to epidermal thickening and keratinocyte hyperplasia in the skin. These cytokines also induce alternative activation of macrophages, which play an instrumental role in helminth restriction and tissue repair. IL-5 secretion induces eosinophil recruitment to tissues where they contribute to helminth killing. b) Mast cell secretion of proteases and heparin aids in detoxification, degradation, and clearance of venoms and noxious xenobiotics increasing resistance to these toxins. Mast cells mediate many responses by producing histamine and lipid mediators, such as prostaglandins. Histamine and prostaglandins contribute to activation of endothelial cells, inducing vasodilation and vascular leakage, and smooth muscle cells, inducing bronchoconstriction and various mechanisms that contribute to expulsion (coughing, sneezing, vomiting, diarrhea). Basophils also contribute to antibody-mediated tick resistance. Histamine release from mast cells also can activate C-fibers to induce itch. Notably, crosstalk between these two modules is also common. For example,Th2 cells produce IL-3, which leads to increased basophil and mast cell production, and IL-9, which leads to recruitment of mast cells. Furthermore, basophils can produce Th2-inducing cytokines such as IL-4, and mast cells can produce ILC-activating cytokines, such as IL-33.

Figure 3. Somatosensory pathways in allergic immunity

Noxious substances, including allergens can be detected by somatosensory neurons to elicit protective reflexes, including itch, coughing, sneezing, vomiting and diarrhea. These pathways can also elicit aversive behaviors that help to avoid exposure to the noxious allergens. Somatosensory neurons can sense noxious effects of allergens directly, for example through TRP channels expressed on C-fiber neurons. Afferent neurons of vagus nerve can be activated by serotonin produced by chromaffin cells in mucosal epithelia upon exposure to irritants and other noxious substances. Finally, C-fiber neurons can be activated in response to histamine produced by mast cells upon allergen recognition by IgE. The latter mechanism couples immune recognition of allergens with somatosensory pathways. Allergens recognized by IgE can come in three flavors: they can be intrinsically noxious, they can serve as proxies for noxious allergens, or they can be accidentalNeutral environmental stimuli perceived through olfactory, gustatory and visual systems can be temporally associated with somatosensory pathways resulting in Pavlovian conditioning of neutral cues with antigen specific response to allergens.