The development of allergic inflammation

Abstract

Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.

Figure 1. Sensitization to allergens in the airway

Allergen can be sampled by dendritic cells in the airway lumen, and can enter tissues through disrupted epithelium (not shown) or, for some allergens with protease activity, can gain access to submucosal dendritic cells by cleaving epithelial-cell tight junctions. Activated dendritic cells mature and migrate to regional lymph nodes or to sites in the local mucosa, where they present peptides derived from the processed allergen in the context of major histocompatibility complex (MHC) class II molecules to naive T cells. In the presence of ‘early interleukin 4’ (IL-4) (potentially derived from a range of cells, including basophils, mast cells, eosinophils, natural killer T cells and T cells), naive T cells acquire the characteristics of T helper 2 (T_H2) cells, a process that may be enhanced by engagement of Notch at the surface of T cells with Jagged on dendritic cells). T_H2 cells produce IL-4 and IL-13. In the presence of these cytokines and the ligation of suitable co-stimulatory molecules (CD40 with CD40 ligand, and CD80 or CD86 with CD28), B cells undergo immunoglobulin class-switch recombination, in which the gene segments that encode the immunoglobulin heavy chain are rearranged such that antibody of the IgE class is produced. Basophils and mast cells also can produce IL-4 and/or IL-13, and can stimulate B cells through CD40 (not shown). IgE diffuses locally and enters the lymphatic vessels. It subsequently enters the blood and is then distributed systemically. After gaining access to the interstitial fluid, allergen-specific or non-specific IgE binds to the high-affinity receptor for IgE (FcεRI) on tissue-resident mast cells, thereby sensitizing them to respond when the host is later re-exposed to the allergen. Sensitization does not produce symptoms (for example, if sensitization occurs by way of the airways, bronchoconstriction does not occur). This T_H2-cell response to allergen can be downregulated or modified by various mechanisms (not shown).

Figure 2. Highly simplified scheme of FcεRI signalling events in mast cells

Crosslinking of FcεRI-bound IgE with antigen induces aggregation of two or more FcεRI molecules and activates the protein tyrosine kinases LYN and FYN. LYN, in turn, phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) in FcεRI and activates the protein tyrosine kinase SYK (after SYK has bound to an ITAM). FYN phosphorylates the adaptor GAB2, activating the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. LYN and SYK phosphorylate many adaptor molecules (such as LAT, not shown) and enzymes, thereby regulating the activation of the RAS–MAPK (mitogen-activated protein kinase), phospholipase C-γ (PLC-γ) and PI(3)K pathways, as well as other pathways. (LYN also can negatively regulate FYN activity.) The RAS–MAPK pathway — a protein-kinase cascade that involves RAS, RAF, MEK and ERK — activates transcription factors (thereby regulating the synthesis of protein mediators) and activates PLA₂, which participates in arachidonic acid metabolism (thereby regulating the production of lipid-derived mediators). PLC-γ activation regulates calcium (Ca²⁺) responses, by generating inositol-1,4,5-trisphosphate (InsP₃), and protein kinase C (PKC) activation, by generating diacylglycerol (DAG). The PI(3)K product phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P₃) is an important lipid mediator that regulates the formation of other lipid mediators, such as DAG and sphingosine 1-phosphate (S1P), and the activity of various enzymes, such as Bruton’s tyrosine kinase (BTK) and AKT. FcεRI can be induced to co-aggregate with FcγRIIB (a low-affinity receptor for IgG), for example when IgE and IgG1 are bound to the same antigen. This process inhibits FcεRI signalling events, and therefore mast-cell activation and product secretion, through the LYN-mediated phosphorylation of the FcγRIIB ITIM (immunoreceptor tyrosine-based inhibitory motif) and the recruitment of the inositol phosphatase SHIP1 (which catalyses the hydrolysis of PtdIns(3,4,5)P₃ to PtdIns(3,4)P₂) (not shown). Some arrows do not indicate direct interactions or targets. NF-κB, nuclear factor-κB; SPHK1, sphingosine kinase 1.

Figure 3. Early phase of allergen-induced airway inflammation

The individual IgE molecules that are bound to the FcεRI molecules on a single mast cell can be specific for different antigens. The recognition of a particular allergen by FcεRI-bound IgE specific for antigen derived from that allergen (allergen-specific IgE) induces FcεRI aggregation, which activates mast cells to secrete preformed mediators and lipid-derived mediators and to increase the synthesis of many cytokines, chemokines and growth factors. The rapidly secreted mediators result in bronchoconstriction (lower left), vasodilation, increased vascular permeability and increased mucus production. Mast cells also contribute to the transition to the late-phase reaction (Fig. 4) by promoting an influx of inflammatory leukocytes, both by upregulating adhesion molecules on vascular endothelial cells (for example, through TNF-α) and by secreting chemotactic mediators (such as LTB₄ and PGD₂) and chemokines (such as IL-8 and CC-chemokine ligand 2 (CCL2)).

Figure 4. Late phase of allergen-induced airway inflammation

Late-phase reactions have many features in common with early-phase reactions (Fig. 3). But late-phase reactions typically occur hours after allergen challenge and are thought to reflect the actions of innate and adaptive immune cells that have been recruited from the circulation, as well as the secretion of inflammatory mediators by tissue-resident cells. The innate immune cells include neutrophils, monocytes (not shown), eosinophils and basophils. Other cells that secrete inflammatory mediators include mast cells that have been activated by IgE- and allergen-dependent FcεRI aggregation, and tissue-resident or recruited T cells that recognize allergen-derived peptides. Therefore, in a late-phase reaction, for example, elastase released by neutrophils promotes the activation of matrix metalloproteinases (MMPs) and the degradation of type III collagen. In addition, basic proteins released by eosinophils can injure epithelial cells, and several other mediators produced by recruited or tissue-resident cells can induce bronchoconstriction. CGRP, calcitonin-gene-related peptide; GM-CSF, granulocyte–macrophage colony-stimulating factor; T_H17 cell, IL-17-producing T_H cell.

Figure 5. Chronic stage of allergen-induced airway inflammation

In chronic allergic inflammation, repetitive or persistent exposure to allergens has several effects. Innate immune cells (including eosinophils, basophils, neutrophils and monocyte–macrophage lineage cells) and adaptive immune cells (including T_H2 cells, other types of T cells, and B cells) take up residence in the tissues. In addition, more mast cells develop in the tissue, and these cells display large amounts of IgE bound to FcεRI and have an altered anatomical distribution. Last, complex interactions are initiated between recruited and tissue-resident innate and adaptive immune cells, epithelial cells and structural cells (such as fibroblasts, myofibroblasts and airway smooth muscle cells) and blood vessels and lymphatic vessels, and nerves (not shown). Repetitive epithelial injury due to chronic allergic inflammation can be exacerbated by exposure to pathogens or environmental factors, and the consequent repair response results in an epithelial–mesenchymal trophic unit (EMTU) being established. This unit is thought to sustain T_H2-cell-associated inflammation, to promote sensitization to additional allergens or allergen epitopes (for example, epithelial-cell-derived TSLP can upregulate the expression of co-stimulatory molecules such as OX40, CD40 and CD80 by dendritic cells), and to regulate the airway remodelling process. These processes result in many functionally important changes in the structure of the affected tissue. These changes include substantial thickening of the airway walls (including the epithelium, lamina reticularis, submucosa and smooth muscle), increased deposition of extracellular-matrix proteins (such as fibronectin, and type I, III and V collagen), and hyperplasia of goblet cells, which is associated with increased mucus production. In individuals who have such thickened airway walls, bronchoconstriction can result in more severe narrowing of the airway lumen than occurs in airways with normal wall thickness. In some individuals, especially those with severe asthma, T_H17 cells (which secrete IL-17) may also contribute to the recruitment of neutrophils to sites of inflammation (not shown). EGF, epidermal growth factor; FGF, fibroblast growth factor; HBEGF, heparin-binding EGF-like growth factor; IGF, insulin-like growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; SCF, stem-cell factor (also known as KIT ligand).

Figure 6. Chronic allergic inflammation and tissue remodelling in asthma

Tissue sections from the airway of a non-asthmatic person (a–c) and a patient with severe asthma (d–f) are shown. Specimens were taken from lung resections (carried out for other indications), fixed in 10% neutral buffered formalin and processed routinely; sections 5 μm thick, from the same area of tissue, were stained with haematoxylin and eosin (a and d), periodic acid–Schiff with diastase (to stain mucus red; b and e), or pinacyanol erythrosinate (to stain mast cells purple; c and f). Scale bars, 500 μm (a and d), 100 μm (inset a and d), 400 μm (b and e), 100μm (inset b and e) and 100 μm (c and f). a–c, A normal small bronchus. There are few goblet cells (black arrows in insets) in the epithelium. The basement membrane and underlying lamina reticularis (at asterisk in a, hardly visible at this magnification) are normal. The submucosa (the length of the double-headed arrows in a) contains few leukocytes and the occasional mast cell (blue arrows in c), and the bronchial smooth muscle (SM) has few adjacent mast cells (red arrow in c). d–f, A small bronchus from a patient with a history of severe asthma. Mucus (M) fills the airway lumen (d and e). There are many goblet cells (black arrows in insets) and the occasional intra-epithelial mast cell (black arrows in f). The lamina reticularis (asterisk in inset in d) is markedly thickened. The submucosa (double-headed arrows in d) contains many eosinophils (green arrows in inset in d) and other leukocytes, as well as mast cells (blue arrows in f). There is more bronchial smooth muscle (SM) than in a–c, and there are many mast cells (red arrows in f) among bundles of smooth muscle cells. (Figure courtesy of G. J. Berry, Stanford University, California.)