Type 2 immunity in allergic diseases

Abstract

Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.

Keywords: Alarmins; allergic diseases; biologics; epithelial barrier; type 2 immunity.

Fig. 1

Overview of the mechanisms of type 2 immune responses. Epithelial barrier disruption during exposure to allergens, bacteria, fungi, viruses and environmental epithelial barrier-damaging agents and inflammation can lead to the opening of the epithelial barrier and allow the penetration of allergens through tissues. In addition, microbial dysbiosis occurs with the colocalization of opportunistic pathogens and the loss of commensals. Damaged epithelial cells release chemokines and alarmins, which activate innate lymphoid cells and dendritic cells. Matured DCs migrate to local lymph nodes and present processed allergen peptides to naive T cells through MHC class II molecules. Naive T cells in the presence of IL-4 differentiate into Th2 cells. The type 2 cytokines IL-4, IL-5, IL-9 and IL-13 are produced not only by Th2 cells but also by ILC2s. IL-4 and IL-13 are involved in IgE class switching in B cells. IgE binds to FcεRI on the surface of mast cells and sensitizes them. The subsequent release of mast cell-associated mediators, such as histamine, tryptase, prostaglandins, leukotrienes and cytokines, induces goblet cell hyperplasia, smooth muscle contraction, and increased vascular permeability. IL-5 induces eosinophilia. Immunoregulatory cytokines, such as IL-10, TGF-β, and IL-35, released by T regulatory (Treg) cells can suppress type 2 as well as Th1, Th9 and Th-17 responses. IL-10-producing Breg cells also inhibit effector T cells. DC dendritic cells, EOS eosinophil, EPO eosinophil peroxidase, GM-CSF granulocyte‒macrophage colony‒stimulating factor, IL interleukin, ILC innate lymphoid cells, LT leukotriene, LTC4 leukotriene C4, MBP major basic protein, MC mast cells, PGD2 prostaglandin D2, TGF-β transforming growth factor-β, TSLP thymic stromal lymphopoietin

Fig. 2

Type 2 response and remodeling in the pathogenesis of asthma. Exposure of the epithelial barrier and microbiome to damaging environmental agents can lead to airway damage and induce alarmin production, followed by type 2 inflammation. Increased activation of the epithelium leads to signaling to migrating inflammatory cells and activation of resident tissue mesenchymal cells, such as smooth muscle cells and fibroblasts. IL-4 and IL-13 produced by Th2 cells and ILC2s lead to extracellular matrix propagation and airway remodeling. In addition, IL-5 recruits eosinophils to periepithelial tissues and leads to an eosinophilic response. Both stromal and inflammatory cells produce proinflammatory cytokines and chemokines. Progressive structural changes, including mucus production, goblet cell metaplasia, subepithelial fibrosis, epithelial shedding, basement membrane thickening, iNOS production and smooth muscle proliferation, may lead to airway remodeling. The proinflammatory environment generated by airway remodeling sustains the inflammatory response. EGF epidermal growth factor, EMT epithelial mesenchymal transition; EOS, eosinophils; FGF, fibroblast growth factor; IL, interleukin; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor

Fig. 3

Type 2 response in AD. A Skin barrier disruption by toxic substances leads to the upregulation of alarmins such as TSLP, IL-25, IL-33 and type 2 chemokines. These alarmins activate ILC2s and Th2 cells, triggering type 2 inflammation. Additionally, the activation of DCs, M2 macrophages, and fibroblasts results in the production of type 2 chemokines, which attract Th2 helper T cells to the lesion. This cascade contributes to further barrier dysfunction, mast cell activation, IgE production by B cells, and direct activation of sensory nerves, causing itch. The following itch-scratch cycle exacerbates barrier dysfunction, initiating a vicious cycle of inflammation and barrier disruption in AD skin. B Description of receptors for IL-4, IL-13, IL-22, TSLP, and Janus kinases alongside biologics that have been approved for the treatment of AD. AD atopic dermatitis, DC dendritic cell; Ig immunoglobulin, IL interleukin, ILC2 type 2 innate lymphoid cell, JAK Janus kinase, TSLP thymic stromal lymphopoietin

Fig. 4

Initiation of the type 2 immune response. Exposure to allergens, helminths or epithelial barrier-damaging toxic substances causes epithelial alarmin release (TSLP, IL-25, and IL-33) and epithelial barrier impairment. Allarmins activate DCs, and activated DCs increase their OX40L or Notch receptor ligands and migrate to the draining lymph node, where they present antigens/allergens to naive T cells and activate these T cells to become Th2, Tfh and TCM cells. Th2 cells migrate to epithelial tissue and release type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. Epithelial alarmins further activate Th2 cells to produce more cytokines and cause an increase in TSLPR in Th2 cells. Tfh cells in the lymph node help IgE class switching and affinity maturation in B cells. Ig immunoglobulin, IL interleukin. OX40L ligand for OX40. TCM central memory T cell, Tfh T follicular helper cells, Th2 T helper 2 cells, TRM tissue-resident memory T cells, TSLP thymic stromal lymphopoietin

Fig. 5

The role of DCs in type 2 inflammation and tolerance and tissue homeostasis. DCs are antigen-presenting cells that are able to process and integrate signals from the microenvironment. Upon exposure to proinflammatory stimuli, immature DCs develop into stimulatory DCs and promote an effector immune response by stimulating T-cell proliferation and shaping T-cell responses toward Th2 phenotypes via the indicated signals. DCs play a crucial role in antigen presentation to CD4 + T cells, shaping the subsequent immune response. The interaction between DCs and T cells can lead to different outcomes depending on the antigen dose and environmental signals. For example, a low allergen dose typically primes Th2 cells, promoting the allergic response. A high allergen dose, combined with tolerogenic signals such as vitamin D3 and RA, can induce tolerance. In a tolerogenic environment, DCs acquire regulatory functions that suppress T-cell activation and proliferation and provide signals for Treg differentiation and expansion. Treg and Breg cells support each other’s regulatory functions. These regulatory functions of DCs are key for maintaining immune tolerance and tissue homeostasis. Various factors contribute to this tolerogenic environment, including TSLP, RA, flavonoids, and SCFAs. Bas basophil, Breg regulatory B cells, DC dendritic cells, RA retinoic acid, SCFA short-chain fatty acid, Th2 T helper 2 cells, Treg regulatory T cells, TSLP thymic stromal lymphopoietin

Fig. 6

Activation and polarization of macrophages. Macrophages adopt different functional states in response to environmental signals. The transition from the M0 (naive) phenotype to the M1 and M2 phenotypes is a key aspect of their plasticity and role in the immune response. Upon proinflammatory triggers such as TNF-α and IFN-γ, M0 macrophages can polarize toward the M1 phenotype, also known as classically activated macrophages, and acquire proinflammatory features. They promote inflammation, and M1 macrophages produce proinflammatory cytokines (e.g., TNF-, IL-1β, IL-6, and IFN-), leading to wound clearance, phagocytosis, and tissue degradation. Alternatively, upon IL-4 and IL-13 signaling, M0 macrophages polarize toward the M2 phenotype or alternatively become activated. M2 macrophages produce IL-10, TGF-β, and VEGF. M2 macrophages contribute to tissue remodeling, immunoregulation (tolerance), and angiogenesis. IFN-γ interferon-γ, IL interleukin, TGF-β transforming growth factor-β, TNF-α tumor necrosis factor-α, VEGF vascular endothelial growth factor

Fig. 7

Immune and inflammatory responses to allergens. Exposure to various triggers, such as protease allergens, helminths, fungi, and viruses, leads to the release of the alarmins IL-25, IL-33, TSLP, TL1A and eDNA by epithelial cells. TSLP, IL-25, IL-33, TL1A, and eDNA activate ILC2s, promoting the production of the type 2 cytokines IL-5 and IL-13. ILC2s also promote eosinophilia, goblet cell hyperplasia, and IgE production via immunoglobulin class switch recombination in B cells. DCs and LCs are activated by TSLP to stimulate allergen-specific Th2 cells. Mast cell and basophil degranulation, along with cytokine production, is increased by IL-33 and IL-25 following IgE cross-linking. Furthermore, ILC2s facilitate fibrosis and tissue repair through IL-5, IL-13, or amphiregulin. TSLP and IL-33 also directly stimulate itch-sensory neurons, leading to pruritus. Bas basophil, DC dendritic cell, eDNA extracellular DNA, DR3 death receptor 3, DcR3 decoy receptor 3, IL interleukin, ILC2 type 2 innate lymphoid cell, IL-1RAcP IL-1 receptor accessory protein, LC Langerhans cell, MC mast cell, Th2 T helper 2 cell, TSLP thymic stromal lymphopoietin

Fig. 8

Existing and emerging biological treatments for asthma. Mepolizumab and reslizumab target IL-5. Benralizumab targets the α chain of the IL-5 receptor. All three antibodies lead to the suppression of eosinophil activation and number. Omalizumab functions as an antibody that inhibits IgE. Dupilumab interacts with the α subunit of the interleukin-4 receptor, inhibiting signaling pathways for the type 2 cytokines IL-4 and IL-13. Itepekimab and tozorakimab target IL-33, and astegolimab targets ST2, the IL-33 receptor. Tezepelumab targets TSLP. There are several new treatments in development that target DNA. IL, interleukin; TSLP, thymic stromal lymphopoietin

Fig. 9

Overview of the epithelial barrier theory. Epithelial inflammation, epithelitis, and opportunistic pathogen colonization are caused by epithelial barrier dysfunction induced by genetic deficiencies in barrier molecules or exposure to environmentally toxic substances. A healthy epithelial barrier is linked to high microbiome diversity. Microbial dysbiosis and the translocation of commensal and opportunistic pathogens across epithelial barriers increase alarmin and chemokine production and alter the activation thresholds of cells and migrating immune cells. This leads to an inflammatory state that contributes to allergic, autoimmune, and metabolic diseases. The inability of the epithelium to fully repair and close the barrier perpetuates a vicious cycle of leaky barriers, microbial dysbiosis, and chronic inflammation. Individuals with barrier dysfunction exhibit elevated levels of proinflammatory cytokines and chemokines in the circulation, further exacerbating systemic and chronic inflammation

Fig. 10

Pathways involved in inborn errors of immunity with a Type 2 response. A Genes involved in the regulation of the actin cytoskeleton. B Role of the BCM complex in transducing signals to the NFKB pathway. C IL-6 cytokine family and STAT3-related pathways. D IL-4- and IL-13-related STAT6 signaling. ARBC1B; Actin-related protein 2/3 complex, subunit 1B, BCL-10 B-cell CLL/lymphoma 10, CARD-11 Caspase Recruitment Domain Family Member 11, DOCK8; Dedicator of Cytokinesis 8, GATA3 GATA-binding protein 3, IL6R Interleukin 6 receptor, IL6ST Interleukin 6 cytokine family signal transducer, JAK Janus kinase, MALT-1 Mucosa-associated lymphoid tissue lymphoma translocation protein 1, MHC-II Major histocompatibility Complex II, NFKB Nuclear factor-kappa B, STAT Signal transducer and activator, TCR T-cell receptor, WASP Wiskott–Aldrich syndrome protein, ZNF341 Zinc finger protein 341