Knowledge of the immune system is advancing rapidly. This review provides an update on the allergy players—the cells and major mediators—and the form and function of each; discusses how these cells and mediators weave together in the elegant but destructive dance of allergy; and details how specific immunotherapy can cure allergy.
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Understanding of the roles of the white blood cells in allergic reactions is continually expanding.
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T-regulatory (Treg) cells are recently described as immune modulators that probably play a key role in allergy immunotherapy.
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Basophils and eosinophils, originally thought to be mainly reactive cells, are proving to have extensive input in the developing balance between helper T cells T h 1 and T h 2 influences.
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Multiple chemical mediators play a role in modulating the allergic response, including histamine, cytokines, prostaglandins (PGs), leukotrienes (LTs), and chemokines.
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T h 2 cells are dominant in the allergic response and release interleukin (IL)-4, IL-5, IL-9, IL-13, IL-25, and IL-31 predominantly to promote T h 2 proliferation and recruitment of other inflammatory cells as well as IgE class switching.
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IL-17 family originates from a unique T h 17 cell and has a role in inducing chemokines, cytokines, PGE 2 , neutrophil recruitment, and fibroblast activation. This family serves as a potential target for future therapies.
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PGE 2 is the most abundant PG with inflammatory effects dependent on receptor binding consisting of bronchoconstriction, bronchodilation, mast cell stabilization, and activation.
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LTB 4 and LTC 4 are the predominant LTs resulting in bronchoconstriction, vascular leakage, edema, and mast cell proliferation as well as cytokine generation.
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Chemokines are small proteins that function via a G protein–coupled receptor that serve as inducers of chemotaxis for various cell types with key roles identified in allergic disorders.
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IL-10, IL-35, transforming growth factor (TGF-), lipoxins, resolvins, IL receptor antagonist (IL-1ra), and suppressors of cytokine signaling (SOCS) molecules play a key role in down-regulating the immune response by decreasing the secretion of chemical mediators and promoting apoptosis of inflammatory cells.
Knowledge of the immune system is advancing rapidly. Thirty years ago it was taught that specific immunotherapy for allergies worked by creating IgG antibodies that blocked incoming antigens before they had a chance to meet the IgE on mast cells and cause degranulation. Since then, it has been found that induction of allergen-specific, IL-10–producing Treg cells is a major mechanism driving the immune changes that occur during immunotherapy. This review provides an update on the allergy players—the cells and major mediators—and the form and function of each; discusses how these cells and mediators weave together in the elegant but destructive dance of allergy; and details how specific immunotherapy can cure allergy.
Inflammatory cells
The cells of the immune system all begin as bone marrow stem cells. The initial differentiation is into either a common lymphoid progenitor cell or common myeloid progenitor cell (CMP). Common lymphoid progenitor cells become lymphocytes: T cells, B cells, or natural killer (NK) cells. CMPs become erythrocytes, monocytes, and granulocytes. B cells and T cells along with dendritic cells (DCs) or antigen-presenting cells (APCs) play major roles in starting an allergic response.
Dendritic Cells
DCs (APCs) are the first stop for a new antigen entering a human body. DCs originate in the bone marrow and circulate peripherally as monocyte-like cells before entering tissue to become DCs. They station themselves mainly near skin and mucosa, the places where human tissue interacts with the outside world. Their primary job is to process pathogen or antigen for presentation to and activation of T cells. Monocytes and macrophages can also function as APCs.
When needed, this immature APC is activated, either by cytokines from other leukocytes of the innate immune system or by pattern recognition. Pattern recognition receptors, such as toll-like receptors, allow an immature DC to recognize incoming pathogens.
On activation, these DCs take up samples of pathogen or antigen from their local environment. The activated DC with antigen inside then travels via lymph to a nearby lymph node. The antigen phagocytized by the DC is broken up enzymatically into short polypeptide fragments. These fragments are loaded onto major histocompatibility complex (MHCs) molecules for display on the surface of the cell.
T Cells
T cells, in the meantime, travel from the bone marrow to the thymus. After acquiring T-cell–specific surface markers, they travel back out into the bloodstream and thence to lymph nodes. Some are CD4 + (often called helper T cells), some are CD8 + (often called cytotoxic T cells), and a few are T cells, which are CD4/CD8. They can also become Treg cells (formerly named suppresser T cells). NK cells are non–B-cell, non–T-cell lymphocytes.
Digested peptide fragments from within DCs in the lymph node can be loaded on major histocompatibility complex class 1 (MHC1) or major histocompatibility complex class 2 (MHC2) molecules. Peptide fragments plus MHC1 molecules present to CD8 + T cells (cytotoxic T lymphocytes [CTLs]). Polypeptides with MHC2 molecules on the cell surface are meant to be read by naive CD4 + cells. The DC with MHC 2 and peptide fragment sits in the lymph node, waiting to see if a naive T cell with its cognate comes by. Cognate means that the unactivated T cell is looking for exactly the same protein as is displayed on the APC’s surface. If this match occurs and a second signal also occurs—in this case usually B7 on the APC surface plugging into a CD28 on the T-cell surface—activation of the T helper (CD4 + ) cell occurs. These antigen-activated T cells then proceed with proliferation, making many copies of themselves.
Exactly which type of T cell develops depends on the local cytokines and other chemical mediators in the immediate environment. Traditional T h 1 cytokines—IL-2, TGF-, interferon (IFN)-, and IL-12—drive these naive T cells to become T h 1 cells. Similarly, IL-4 drives development of T h 2 cells; IL-23, TGF-, and IL-6 help drive development of T h 17 cells ; thymic stromal lymphopoietin (TSLP) influences DCs toward making more T h 2 cells.
Cytokines produced by T cells make an interwoven determination of immune responses, each dependent on many other cells and mediators. T cells are morphologically identical, differing in the cytokines they produce. T h 1 cells produce IFN- and tumor necrosis factor (TNF)-. T h 2 cells produce IL4, IL-5, IL-9, IL-13, IL-25, and IL-31. Both T h 1 cells and T h 2 cells make TNF-, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, IL-3, and IL-10. T h 17 cells make IL-17A and IL-17F, IL-21, and IL-22. T h 3 cells make TGF- and IL-10, and Treg cells and Tr1 cells make only IL-10.
Treg cells suppress both T h 1 and T h 2 immune responses and help regulate self-tolerance and prevent autoimmunity. Naturally occurring Treg cells are CD4 + CD25 + Foxp3 + . T h 3 cells are active in gastrointestinal mucosal tolerance, and Treg suppression of gastrointestinal T cells helps maintain tolerance to commensal gut bacteria. Induction of CD4 + cells producing IL-10 is one mechanism by which immunotherapy may be effective.
B Lymphocytes
In the bone marrow, the pre–B cell becomes a mature naive B cell. This part of the maturation is antigen independent and these cells all express IgM and IgD on the surface. These B cells are incredibly diverse in the antigens they are capable of recognizing—but each cell can only recognize a single antigen. The total universe of unactivated B cells can probably recognize just about any antigen the body might encounter. Each unactivated B cell roams through the lymph, hoping to meet up with the antigen it can recognize. If this unactivated B cell never meets its cognate, it dies unactivated.
This unactivated B cell has IgD and IgM on its surface. These are the same immunoglobulins the cells eventually secrete, with the addition of an amino acid sequence at the tip of the heavy chain that anchors it to the surface of the B cell, making a B-cell receptor. Once this B cell becomes activated, it produces both forms—immunoglobulin with the anchor to continually repopulate the cell surface and immunoglobulin without the anchor for external secretion.
Activation of the B cell requires more than just meeting up with its cognate antigen. It requires costimulation. Once the B cell meets its cognate, the still-unactivated B cell takes that antigen within the cell and then places it back on the cell surface with its own MHC2. This is recognized and joined by the appropriate CD4 + T cell. In addition, the CD40 on the B-cell surface joins with the CD40L on the T-cell surface. These contacts initiate many actions and changes, including cytokine production and gene expression. The end result is activation of the B cell into an antibody-producing plasma cell. A few of these cells become B memory cells, which facilitate a quick response (rapid buildup of antibody production) if that particular antigen is encountered again in the future.
After activation, the B cells can also undergo isotype switching by somatic hypermutation. This changes the heavy chain DNA sequence so the cell can make IgA, IgG, or IgE. Each individual cell, however, responds only to one antigen, and this does not change through the lifespan of the cell. Thus, a mature unactivated B cell with IgM and IgD on its surface that recognizes a specific amino acid sequence that becomes an activated IgE-producing plasma cell still makes only antibody to that original specific amino acid sequence.
These antibodies circulate looking for their antigen. When encountered, the typical antibody joins with the antigen to make an antigen-antibody complex, which is eliminated by complement or in the spleen or liver. IgE, however, mostly populates the surface of cells that express IgE receptors, such as basophils, mast cells, eosinophils, and others cells.
Mast Cells
Mast cells are granulocytes developing from bone marrow–derived progenitor cells under the influence of IL-3. They leave the bone marrow as immature cells, travel through the vascular system, out into tissue, where differentiation is completed. As with DCs, they live primarily in skin and mucosa, the locations where contact with antigens occurs.
Once IgE antibodies are formed, they circulate in the blood for a short while before going into tissue and attaching to IgE receptors on mast cells, among others cells. When the appropriate antigen comes along, it can cause cross-linking of the surface IgEs, triggering release of preformed granules containing histamine and other allergic mediators. These include eosinophil chemotactic factors, bringing a concentration of eosinophils and release of their preformed mediators.
Increasing numbers of IgE molecules on a mast cell increase its sensitivity to antigen, requiring a lower dose to trigger degranulation. Anti-IgE therapy (omalizumab [Xolair]) takes advantage of this. The omalizumab combines with free serum IgE, making it incapable of binding onto mast cells, basophils, and other cells. This gradually reduces each cell’s IgE surface population, making degranulation signals more difficult and thus less common.
Eosinophils
Eosinophils are also granulocytes that develop from CMPs. They develop fully in the bone marrow and exit into the vasculature as mature eosinophils. They evolved originally to help bodies respond to parasitic infections. They stain deep pink on hematoxylin-eosin stain. Eosinophils also express the high affinity IgE receptor, Fc-epsilon R1. When this receptor is activated, they release their granules containing peroxidases, lysozymes, major basic protein and eosinophil cationic protein. These cells increase in number during allergic inflammation and contribute to tissue damage.
The IL-5 produced by T h 2 cells is critical in the esoinophil life cycle, assisting with differentiation and maturation. Recent work suggests that eosinophils also have a role in initiating the T h 2 response and are present from early in this response cycle, rather than just responding after mast cell degranulation.
Monocytes and Macrophages
Monocytes originate in the bone marrow and exit into the vasculature. Typically they circulate for a few days and then move out into the tissue where they mature into macrophages. These form an important part of the innate immune system. Macro means large and phage refers to eating. This big eater destroys pathogens by engulfing or phagocytizing them.
Macrophages express on their surfaces receptors for IgE and IgG. They can function as APCs. Mediators expressed by macrophages influence what type of T cell is expressed after activation. Monocytes and macrophages express both MHC1 and MHC2 molecules, so they can present antigen to both CTL and helper T cells.
Basophils
Basophils are the least common leukocytes in the peripheral blood, making up less than 1% of circulating white blood cells. They are histologically nearly identical to mast cells and were for many years considered the circulating poor relation of the tissue-based mast cell. Both cells stain deep purple on hematoxylin-eosin stain. Both also express high-affinity IgE receptors, enabling cross-linking to initiate release of preformed inflammatory mediators. Unlike mast cells, basophils complete their maturation in the bone marrow, then enter the peripheral circulation for their lifespan of approximately 60 hours.
Basophils were formerly regarded as primarily responder cells, meaning they released mediators in response to various stimuli. It now seems that these have a much larger role in the allergic response. They produce large amounts of IL-4, IL-13, platelet-activating factor, and TSLP, setting the stage for a T h 2 slant to helper T-cell activation. IL-3 is required by basophils for optimal productivity. Basophils can also serve as APCs.
Neutrophils
Like eosinophils, mast cells, and basophils, neutrophils contain preformed granules, with inflammatory mediators. Neutrophils are the most numerous circulating white blood cells and are the first responding cells to any injury or inflammatory challenge. They live predominantly within the vascular system, going out into tissue in response to specific chemotactic and other mediator signals. These cells make up the majority of pus.
Chemical mediators
The allergic response is a complex orchestration of these inflammatory cells and chemical mediators. The inflammatory mediators function to regulate the inflammatory response in many ways, such as promoting the migration of additional inflammatory cells, promoting the release of other chemical mediators, and modifying vascular permeability, mucus secretion, and bronchial smooth muscle tone.
Histamine
Histamine is probably the most commonly associated mediator of the allergic response and serves as a therapeutic target for controlling the inflammatory reaction via histamine blockers, such as antihistamines or H 2 blockers. Derived from the Greek word for tissue, histos , histamine can be found in various tissues of the body, including the lung, liver, and brain. It is a low-molecular-weight amine synthesized from l -histidine and serves as a rapid, potent vasodepressor and smooth muscle constrictor. Mast cells, basophils, histaminergic neurons, and gastric enterochromaffin cells are the predominant source of histamine but mononuclear phagocytes, DCs, platelets, T lymphocytes, and B lymphocytes can also produce histamine. Histamine effects are primarily initiated by binding of histamine to various histamine receptors (HRs). Four histamine receptor types have been identified (HR 1 , HR 2 , HR 3 , and HR 4 ), present on nerve cells, airway and vascular smooth muscles, hepatocytes, chondrocytes, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes/macrophages, B lymphocytes and T lymphocytes, DCs, and other organs of the body, such as the heart, colon, and lung. Histamine effects on HR 1 are responsible for the development of allergic rhinitis, atopic dermatitis, asthma, and anaphylaxis. HR 2 primarily functions as a negative feedback control of histamine release.
Cytokines
Cytokines are secreted proteins that modulate the immune response on multiple levels determining the onset of the response as well as the type of immune response. Through genomic studies, further classification and identification of new cytokines have been outlined and at least 70 cytokines have been proposed. Table 1 outlines the various cytokine families and the associated members. These proteins can function as proinflammatory, anti-inflammatory, or both.
| Family | Members |
|---|---|
| Hematopoietic | — |
| Common γ chain | IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 |
| Shared β chain (CD131) | IL-3, IL-5, GM-CSF |
| Shared | IL-2, IL-15 |
| IL-2 β chain (CD122) | — |
| Other Hematopietic | IFN-γ, IL-7, IL-13, IL-21, IL-31, TSLP |
| IL-1 Family | IL-1α, IL-1β, IL-1ra, IL-18, IL-33 |
| gpl30-Utilizing | IL-6, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin-1, leukemia inhibitory factor, oncostatin M, osteopontin |
| IL-12 | IL-12, IL-23, IL-35 |
| IL-10 Superfamily | IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29 |
| IL-17 | IL-17A-F, IL-25 (IL-17E) |
| Interferons | — |
| Type I | INF-α, IFN-β, IFN-ω |
| Type II | IFN-γ |
| Type III | IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) |
| TNF Superfamily | TNF-α, TNF-β, a proliferation-inducing signal (APRIL), B-cell activation factor from the TNF family (BAFF) |
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