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Allergic Inflammation—Innately Homeostatic Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Allergic Inflammation—Innately Homeostatic Laurence E. Cheng1 and Richard M. Locksley2,3,4 1Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143 2Department of Medicine, University of California, San Francisco, San Francisco, California 94143 3Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143 4Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143 Correspondence: [email protected] Allergic inflammation is associated closely with parasite infection but also asthma and other common allergic diseases. Despite the engagement of similar immunologic pathways, par- asitized individuals often show no outward manifestations of allergic disease. In this per- spective, we present the thesis that allergic inflammatory responses play a primary role in regulating circadian and environmental inputs involved with tissue homeostasis and meta- bolic needs. Parasites feed into these pathways and thus engage allergic inflammation to sustain aspects of the parasitic life cycle. In response to parasite infection, an adaptive and regulated immune response is layered on the host effector response, but in the setting of allergy, the effector response remains unregulated, thus leading to the cardinal features of disease. Further understanding of the homeostatic pressures driving allergic inflammation holds promise to further our understanding of human health and the treatment of these common afflictions. uoyed by the successes of prophylactic im- of the transferable nature of the activating agent Bmunization against toxins at the turn of the in serum, first noted by Richet, as immuno- 20th century, Portier and Richet began studies globulin E (IgE) (Ishizaka et al. 1966). The rap- with hypnotoxin from the cnidarian, Physalia id advances in molecular biology, genetics, and physalis, commonly known as the Portuguese genomics from 1970 to 2000 elucidated the cen- man o’ war, and a related toxin from the sea tral role for cytokines, particularly the dupli- anemones, Actinia equina and Anemonia sul- cated genes for interleukin (IL)-4, IL-13, IL-5, cata. These investigations led to the paradoxical and IL-9, in mediating the effector functions discovery of immediate hypersensitivity reac- of allergic immunity. Although initial studies tions and even death among some immunized fueled by the discoveries of helper T-cell sub- animals by a process termed “anaphylaxis” (Ri- sets focused on T cells, designated Th2 cells, as chet 1913). Recognized by a Nobel Prize, these sources of these cytokines, recent findings have seminal findings underpinned the modern field increasingly highlighted the role of innate cells of allergy and led to the eventual identification in allergic immunity. These discoveries have Editors: Ruslan M. Medzhitov Additional Perspectives on Innate Immunity and Inflammation available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016352 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a016352 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press L.E. Cheng and R.M. Locksley raised hopes that insights regarding the initia- eosinophils in feral vertebrates are associated tion and/or maintenance of tissue pathology with widespread parasitism, particularly intes- mediated by interactions between innate and tinal helminths (usually multiple species) and adaptive cells might translate to new therapeutic ectoparasites, such as mites and ticks. Croco- modalities for diseases underpinned by type 2 diles, Antarctic petrels, Icelandic minke whales, immunity. penguins, and arctic mammals including bears, wolves, and cervids all show evidence of ecto- and endoparasitism (Jones 1988; Frenot et al. PREVALENCE OF TYPE 2 IMMUNE 2001; Lavikainen et al. 2011; La Grange et al. MANIFESTATIONS AND THE PARADOX 2013; Olafsdottir and Shinn 2013). Taken to- OF ALLERGY gether, these data suggest that manifestations Clinical manifestations of type 2 immune re- of allergic inflammation are universal in non- sponses are commonplace worldwide in asso- human vertebrate populations in association ciation with parasite infections and allergic dis- with high levels of parasitism but there is little eases. It is estimated that 2–4 billion people evidence for pathology associated with human worldwide harbor parasitic infections with the allergic disease. vast majority concentrated in developing na- By extrapolation, it is likely that human evo- tions (Chan 1997). Despite the paucity of par- lution was marked by a higher “set point” for the asitic infections in developed countries, type 2 cells and effector molecules, such as eosinophils immunity significantly impacts human health and IgE, which are now associated with aller- in the form of allergic diseases, including gic manifestations that remain unusual or in- IgE-mediated anaphylaxis, allergic rhinitis, frequent in wild and indigenous vertebrates. A asthma, atopic dermatitis, eosinophilic gastro- number of possibilities have been considered intestinal diseases, and food allergies. World- to explain this apparent paradox. First, as a var- wide, it is estimated that 300 million people iant of the hygiene hypothesis, exposure to have asthma and 400 million have allergic rhi- pathogens during critical developmental peri- nitis (WHO 2007). In the United States, annual ods may be necessary to entrain the immune asthma costs approximate 56 billion dollars system to focus on exogenous organisms rather (CDC 2011). than innocuous allergens. Mechanisms pro- In humans, “normal” values for IgE and eo- posed to underlie such “training” include in- sinophils are defined using populations from duction of regulatory T cells or blocking anti- developed countries where elevated levels are bodies that function to establish tolerance to associated with pathologic states. In less devel- antigens acquired later through food or inhala- oped countries, however, parasitic infestation tion. The data underlying such explanations is more widespread, and IgE levels and eosino- have been reviewed elsewhere (Soyer et al. phils are high. Indeed, hypereosinophilia was 2013). Such a mechanism may also underlie the commonest criteria underlying exclusion the dysregulated inflammatory responses that of healthy Uganda volunteers for vaccine trials accompany many diseases of developed coun- (Eller et al. 2008). Although data collection is tries, including atherosclerosis, dementia, and imperfect, the consensus view is that allergic obesity. A variant of this possibility, based on diseases such as asthma are less prevalent in un- increasing information regarding immune cells derdeveloped countries (Godfrey 1975; ISAAC that develop during fetal but not adult hemato- 1998; Eller et al. 2008). In considering nonhu- poiesis (e.g., Langerhans cells and microglia) man vertebrates, domestic dogs have IgE levels (Ginhoux et al. 2010; Mold et al. 2010; Hoeffel 100 times greater than that in humans, and pop- et al. 2012), is that certain cells in tissues may ulations of Scandinavian wolves and a variety function in “anticipatory” roles, awaiting termi- of horses show even higher levels (Ledin et al. nal differentiation by developmental or envi- 2006, 2008; Wagner 2009). As in humans from ronmental signals, such as microbes and food, less developed countries, elevated IgE and that the organism encounters postbirth. Alter- 2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a016352 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press The Paradox of Allergic Inflammation ations in these environmental signals during COMPONENTS OF THE ALLERGIC MODULE early developmental periods may bypass win- IN HOST DEFENSE AND ALLERGIC DISEASE dows of differentiation that leave the organism Studies in humans as well as model organisms more prone to inflammatory states in later life, have detailed the immunologic constituents of whether or not accompanied by excesses of Th1- allergic inflammation. Here, we summarize re- or Th2-associated pathology (Mold et al. 2010). cent insights regarding the functions of these A final possibility considered here is that intes- various components (Fig. 1). tinal helminths and ectoparasites elicit immune responses that mimic homeostatic responses used by the vertebrate host, but to facilitate as- IgE, Mast Cells, and Basophils pects of the differentiation or development of the parasite. By this scenario, parasites have IgE is the least represented serum immunoglob- evolved to elicit tissue reactions that promote ulin, consistent with a short serum half-life and their own parasitism. Although the advantages distribution within peripheral tissues (Gould of such evolution are not always readily appar- and Sutton 2008). Isotype switching of B ent, the consideration is warranted owing to the cells to IgE requires IL-4-producing T follicular extreme penetrance of parasitic infestation on helper (TFH) cells (Reinhardt et al. 2009; Crot- the vertebrate immune system and the relatively ty 2011). T-cell–B-cell collaboration is likely small impact of these infections on survival short-lived because IgE-switched B cells egress through the reproductive age. rapidly
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