Immunoglobulin E Production

Atopic individuals are predisposed to generate Th2 cells. The Th2 cells produce interleukin-4 (IL-4), IL-5, and IL-13. These cytokines, together with co-stimulation from CD40, trigger B cell IgE synthesis. IL-4 is also produced in significant amounts by stimulated mast cells. This mast cell–derived IL-4 may alter the helper cell balance and enhance yet more Th2 cell production and IL-4 release (Figure 28-2). Some allergic humans overexpress IL-4, leading to excessive Th2 cell activity and enhanced IgE production.

Immunoglobulin E Receptors

There are two types of IgE receptors: high-affinity FcεRI and low-affinity FcεRII (CD23). There are two forms of FcεRI. One form is found on mast cells, basophils, neutrophils, and eosinophils. This form consists of four chains, one α, one β, and two γ chains (αβγ₂) (Figure 28-3). The α chain binds IgE, the β chain stabilizes the complex, and the γ chains serve as signal transducers. (This same γ chain is also a signal transducer in FcγRI, FcγRIII, and γ/δ TCR.) The affinity of FcεRI for IgE is very high (10⁻¹⁰ M), so they bind almost irreversibly. The presence of FcεRI ensures that mast cells are constantly coated with IgE.

The second form of FcεRI consists of three chains: one α and two γ chains (αγ₂). It is found on antigen-presenting dendritic cells and monocytes. When an antigen binds to IgE and the complex binds to this receptor, it is ingested and treated as exogenous antigen. The expression of FcεRI on antigen-presenting cells is enhanced by IL-4 from Th2 cells. Thus a positive feedback loop (the allergy loop) develops (Figure 28-4). The antigen processing cells present antigen more effectively to Th2 cells. The Th2 cells then secrete IL-4 and enhance IgE production.

The second IgE receptor, FcεRII (CD23), is a selectin found on B cells, natural killer (NK) cells, macrophages, dendritic cells, eosinophils, and platelets. In addition to binding IgE, FcεRII also binds to the complement receptor CR2 (CD21) (Figure 28-5). Thus B cells expressing FcεRII will bind CR2 on other B cells, T cells, and dendritic cells. By binding B cells to dendritic cells, FcεRII enhances B cell survival and promotes IgE production.

Structure and Location

Mast cells are large, round cells (15 to 20 µm in diameter) scattered throughout the body in connective tissue, under mucosal surfaces, in the skin, and around nerves (Figure 28-6). They are found in greatest numbers at sites in the body exposed to potential invaders such as under the skin or in the intestine and airways. In these locations they are located close to blood vessels, where they can regulate blood flow and influence cellular migration. They are easily recognizable because their cytoplasm is densely packed with large granules that stain very strongly with dyes such as toluidine blue. These granules often mask the large, bean-shaped nucleus (Figure 28-7). (Mast cells are so called because, being full of granules, they were considered to be “well-fed cells” [German Mastzellen]).

Life History

Mast cells originate from myeloid stem cells in the bone marrow. Their precursors emigrate to tissues, where they mature and survive for several weeks or months. In rodents, mast cells from connective tissue and skin and from the intestinal mucosa differ both chemically and structurally (Table 28-1). For example, connective tissue and skin mast cells are rich in histamine and heparin, whereas intestinal mast cells contain chondroitin sulfate and have little histamine in their granules. Although connective tissue mast cells remain at relatively constant levels, mucosal mast cells can proliferate. It has been suggested that the mucosal mast cells respond specifically to invasion by parasitic worms.

Mast cells play a key role in inflammation because when they encounter invading microorganisms they degranulate, releasing their granules into the tissues. Their granules then release molecules that cause acute inflammation. Many different stimuli can trigger mast cell degranulation. The best recognized of these involves IgE. IgE and antigen together can trigger mast cell degranulation and generate allergic diseases. However, allergies are but a special type of inflammation. Numerous other signals can activate mast cells, including cytokines, chemokines, chemical agents, physical stimuli, insect and animal venoms, and viruses. Many damage-associated molecular patterns (DAMPs), including the defensins, anaphylatoxins, neuropeptides, adenosine, and endothelins (small peptides from endothelial cells), also trigger mast cell degranulation.

Mast cells express diverse pattern-recognition receptors (PRRs) that permit them to recognize pathogens. These include TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, and TLR9 and a mannose receptor (CD48). The expression of and the response to TLR ligands may differ between populations and locations. Mast cells also possess receptors for some complement components. Triggering their TLRs causes mast cells to release different mixtures of mediators. Thus bacterial peptidoglycans acting through TLR2 stimulate histamine release, whereas lipopolysaccharides acting through TLR4 do not. Mast cells can use their receptor sets to distinguish between different pathogens and release a select combination of cytokines, chemokines, and other inflammatory mediators, depending the nature of the stimulus.

Mast Cell–Derived Mediators

Mast cell granules are loaded with a complex mixture of inflammatory mediators, enzymes, and cytokines. Triggering of receptor-bound IgE by antigen causes the mast cells to degranulate and release stored molecules, which triggers the productions of new mediators. All these molecules (both preformed and newly synthesized) generate the acute inflammation characteristic of type I hypersensitivity response (Figure 28-11). The most important include histamine, serotonin, prostaglandins, and the leukotrienes. Mast cells secrete multiple cytokines, chitinases, and the chemokine CCL3. These cytokines are proinflammatory or promote Th2 responses, or both. High levels of these cytokines are found in tissue fluids in allergic reactions. It is no coincidence that mast cells also produce and secrete chitinases. Chitin is characteristically found in insects, fungi, and helminths, and the production of chitinases supports the suggestion that allergic reactions may have evolved to combat these invaders. Chitin itself is a key allergen in some helminth infections.

During infection, mast cells also release small heparin-containing granules that also contain a cytokine mixture. They are especially rich in TNF-α. These particles are carried in the afferent lymph to draining lymph nodes, where they trigger changes in cell behavior. The presence of heparin stabilizes the TNF-α so that it persists for a long time after delivery to a lymph node.

Interleukin-33

IL-33 is a member of the IL-1 family that plays an important role in inflammation and promotes Th2 responses leading to allergies (Figure 28-12). Unlike IL-1 and IL-18, it is produced as an active 18-kDa molecule that does not require cleavage of a precursor. It is produced by smooth muscle cells, epithelial cells, fibroblasts keratinocytes, dendritic cells, and activated macrophages. IL-33 also escapes when cells undergo necrosis and has similar activities to HMGB1. In the presence of IgE, IL-33 binds to a receptor on mast cells, basophils, and Th2 cells. When bound to mast cells, it induces their degranulation and so triggers acute anaphylaxis in the absence of antigen. IL-33 cannot mediate this degranulation alone. The mast cells must be sensitized by prior exposure to IgE. It also activates basophils and induces basophil differentiation from bone marrow cells.

IL-33 is elevated in humans suffering anaphylactic shock and in atopic human tissues. It is found in high concentrations in the lungs of humans with severe asthma. IL-33 is mainly produced on mucosal surfaces in the lungs and intestine. It stimulates mucus overproduction and goblet cell hypertrophy. IL-33 also plays a role in rheumatoid arthritis by stimulating the release of mast cell inflammatory mediators. Endothelial cells are the major source of IL-33 in affected joints. It is possible that IL-33 is a key mediator of other forms of atopic disease such as atopic dermatitis as well as an activator of mast cells in acute cellular injury.

Regulation of Mast Cell Degranulation

Mast cells express two surface receptors for catecholamines called the α and β adrenoceptors. These G-protein–linked receptors have opposing effects. Molecules that stimulate the α adrenoceptors (such as norepinephrine and phenylephrine) or block the β adrenoceptors (such as propranolol) enhance mast cell degranulation (Table 28-2). In contrast, molecules that stimulate β receptors or block α receptors inhibit mast cell degranulation. β Stimulators include isoproterenol, epinephrine, and salbutamol and are widely used in the treatment of allergies. β Receptor blockers enhance mast cell degranulation and promote allergies. Some respiratory pathogens such as Bordetella pertussis and Haemophilus influenzae can cause β blockade. As a result, the airways of infected animals are more likely to become severely inflamed because of mast cell degranulation. These infections may also predispose animals to the development of respiratory allergies.

Regulation of the Response to Mast Cell Mediators

The α and β adrenoceptors are found not only on mast cells but also on secretory and smooth muscle cells throughout the body. α Stimulators cause vasoconstriction and may be of use treating severe allergic reactions, reducing edema, and raising blood pressure. β Stimulators mediate smooth muscle relaxation and may therefore reduce the severity of smooth muscle contraction. Pure α and β stimulators are of only limited use in the treatment of allergic diseases because each alone is insufficient to counteract all the effects of mast cell–derived factors. Epinephrine (or adrenaline), on the other hand, has both α and β adrenergic activity. In addition to causing vasoconstriction in skin and viscera, its β effects cause smooth muscle to relax. This combination of effects is well suited to combat the vasodilation and smooth muscle contraction produced in type I hypersensitivity. Ideally, epinephrine should be available whenever potential allergens are administered to animals.

Mast Cells in Infections

Mast cells play important roles in both antimicrobial and antiparasite immunity. They can respond within seconds or minutes to microbial invasion. They possess a large array of PRRs as well as being able to recognize antigen indirectly through their Fc receptors. Lipopolysaccharide stimulation of mast cell TLR4 can induce cytokine production in the absence of degranulation. Increased vascular permeability due to mast cell–derived mediators promotes the inflammatory process. They also release preformed antimicrobial peptides such as the cathelicidins. Mast cell tryptase and chymases have antibacterial and antiparasite activity. Neutrophils are attracted by mast cell–derived leukotrienes.

Late-Phase Reaction

When antigen is injected into the skin of an allergic animal, two waves of inflammation occur. There is an immediate acute inflammatory response that occurs within 10 to 20 minutes as a result of the release of the preformed mast cell mediators. This is followed several hours later by a second wave called the late-phase reaction, which peaks at 6 to 12 hours and then gradually diminishes. This late-phase reaction is characterized by redness, edema, and pruritus. It is believed that this late reaction results from the release of inflammatory mediators by T cells, endothelial cells, neutrophils, and macrophages attracted by mast cell chemotactic factors. Th17 cells may play a role in this late process (Chapter 20).