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Review
. 2013 Aug;13(8):607-14.
doi: 10.1038/nri3476. Epub 2013 Jul 5.

Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths

William C Gause  1 , Thomas A Wynn, Judith E Allen
Affiliations
Review

Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths

William C Gause et al. Nat Rev Immunol. 2013 Aug.

Abstract

Helminth-induced type 2 immune responses, which are characterized by the T helper 2 cell-associated cytokines interleukin-4 (IL-4) and IL-13, mediate host protection through enhanced tissue repair, the control of inflammation and worm expulsion. In this Opinion article, we consider type 2 immunity in the context of helminth-mediated tissue damage. We examine the relationship between the control of helminth infection and the mechanisms of wound repair, and we provide a new understanding of the adaptive type 2 immune response and its contribution to both host tolerance and resistance.

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Conflict of interest statement

Competing interests statement

The authors declare competing financial interests: see Web version for details.

Figures

Figure 1
Figure 1. The type 2 immune response promotes tissue repair and immunity against helminths
When helminth parasites infect their mammalian host, epithelial and endothelial barriers are damaged, which induces a wound repair and an anti-parasite immune response that is driven by the type 2 cytokines interleukin-4 (IL-4), IL-5 and IL-13. This figure is not meant to imply that all of these pathways, cell types and cytokines are crucial to the development of immunity against every helminth parasite; rather, it simply illustrates the many different innate and adaptive mechanisms that have been shown to participate in type 2 immunity, and each parasite is often affected by different components. Dendritic cells (DCs) are the only antigen-presenting cell type that has been shown to be indispensable for the initiation of CD4+ T helper 2 (TH2) cell responses; indeed, basophils, natural killer T (NKT) cells, eosinophils and group 2 innate lymphoid cells (ILC2s) function as accessory cells by producing the key TH2-regulating cytokine IL-4. B cells also participate in secondary type 2 responses by producing parasite-specific IgE, which, following engagement of the high-affinity Fc receptor for IgE (FcεR), can augment the production of IL-4 by basophils and mast cells. Epithelial cells might also help to guide type 2 responses by producing the alarmins thymic stromal lymphopoietin (TSLP), IL-25 and IL-33. TSLP regulates type 2 immunity by suppressing DC-derived IL-12 production, whereas IL-25 and IL-33 primarily target ILC2s, which secrete large quantities of IL-5 and IL-13. Type 2 cytokines in turn target epithelial cells, goblet cells, smooth muscle cells and macrophages, which together coordinate parasite expulsion by increasing fluid and mucus production, encapsulation and barrier formation, epithelial cell turnover, smooth muscle contraction and the production of anti-parasite effector molecules such as resistin-like molecule-β (RELMβ). In addition to activating several anti-parasite effector mechanisms, the type 2 immune response facilitates wound repair, which is important following infection by these large multicellular tissue-invasive organisms. M2 macrophages (also known as alternatively activated macrophages) are intimately involved in this process as they produce matrix metalloproteinases (MMPs), arginase 1 (ARG1), insulin-like growth factor 1 (IGF1), vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGFβ), which together promote myofibroblast activation, angiogenesis, epithelial cell turnover and extracellular matrix (ECM) deposition. The helminth-induced type 2 immune response also promotes effective wound healing by suppressing the pro-inflammatory axis that is mediated by M1 macrophages and TH1 and TH17 cells, which could further exacerbate tissue injury if not quickly controlled. M2 macrophages and IL-10-producing TH2 cells have been shown to have important roles in the suppression of this pro-inflammatory axis and can also control potentially harmful type 2 immune responses. ROS, reactive oxygen species; TNF, tumour necrosis factor.
Figure 2
Figure 2. The role of the immune system in homeostasis
Homeostasis is influenced by the diversity of pathogens that infect host populations during the course of evolution. In the case of vertebrates, frequent exposure to parasites and microorganisms induces regulatory mechanisms, including regulatory T (TReg) cells, which control potentially harmful inflammatory effects (not shown). The absence of these pathogens in the host might result in a dysregulated immune system. In the case of harmful type 1 and type 17 inflammation, autoimmune diseases and metabolic disorders might result. Type 2 inflammation has a particularly important role in preventing the development of these disorders by promoting homeostasis. Conversely, harmful type 2 inflammation might result in the development of fibrosis and allergy. An environment that includes exposure to chronic infections or, perhaps, therapeutic surrogates could therefore promote homeostasis. Allergens seem to be capable of inducing type 2 immunity in the absence of the regulatory networks that are associated with helminth infection, thereby exacerbating the harmful effects of type 2 immunity. In addition, in many cases, the same cell lineages participate in both type 1 and type 2 immune responses but have different activation states. Representative examples are shown. IFNγ, interferon-γ; IL, interleukin; ILC2, group 2 innate lymphoid cell; TH, T helper.
Figure 3
Figure 3. Helminth infections as a selective force for evolution of the type 2 immune response
The adaptive type 2 immune response might have originally evolved from a progenitor wound-healing response, with the development of specific adaptations promoting tolerance and resistance during helminth–vertebrate co-evolution. a | After the evolution of adaptive immunity, these innate wound-healing pathways started to be controlled by T helper 2 (TH2) cells, which direct and enhance the responses to specific antigens. b | During a type 2 immune response, damaging inflammation is kept to a minimum through reduced chemokine expression and the local proliferation of macrophages rather than through the recruitment of inflammatory monocytes and neutrophils. If monocyte recruitment does occur, as would be the case in a gut-dwelling helminth infection, then the presence of interleukin-4 (IL-4) or IL-13 facilitates monocyte conversion to M2 macrophages (also known as alternatively activated macrophages). ILC2s, group 2 innate lymphoid cells.
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