Allergic Disease

Asthma Free Forever

Asthma Free Forever By Jerry Ericson

Get Instant Access

Pathophysiology and Immunopathology

Gloria E. Akan, md and Robert F. Lemanske, Jr., md

Contents

Introduction

The Allergic Reaction: A Scenario Aspects of IgE Production The Mast Cell

Mediators of the Allergic Response

Activation of the Mast Cell

Effects of Mast Cell Mediators on Target Organs

Allergic Inflammation: A TH2-Mediated Response

Early- and Late-Phase Responses

Conclusion

Suggested Reading

SUMMARY

The incidence of asthma and allergic disease is rising. However, primary care physicians have dealt with allergic conditions far more often than they may expect even before the development of these recent epidemiological trends. Some examples of immunological disease that the primary care physician has encountered include asthma, allergic rhinitis, and atopic dermatitis.

This chapter will review the role of atopy in the development and clinical manifestations of allergy. The two-step process of sensitization will be described. The role of the mast cell, the primary cell involved in allergic disease, will be delineated on a molecular and clinical level. Examples of allergic sensitization and presentation of disease will be provided using an example of food allergy. Descriptions of the early- and late-phase responses will be provided using the nasal tissue and skin as examples. The overall goal is to give the reader a good foundation and understanding of the mechanisms involved in allergic sensitization and the presentation of allergic diseases in a genetically predisposed individual.

Key Words: Immunoglobulin E (IgE) antibody; mast cell; basophil; late-phase response; early-phase response; anaphylaxis; allergy; immediate hypersensitivity.

From: Current Clinical Practice: Allergic Diseases: Diagnosis and Treatment, Third Edition Edited by: P. Lieberman and J. A. Anderson © Humana Press, Totowa, NJ

INTRODUCTION

The incidence of asthma and allergic disease is rising. However, primary care physicians have dealt with allergic conditions far more often than they may expect even before the recent increase in allergic conditions. Some examples of immunological disease that the primary care physician sees include asthma, allergic rhinitis, and atopic dermatitis. To illustrate the importance of allergic disorders in clinical medicine, consider that physicians obtain an allergy history before prescribing any antibiotic because of the high incidence of drug reactions in the population.

Armed with the knowledge of the mechanisms mediating allergic reactions, a clinician can readily appreciate the pathophysiological changes caused by an exposure to a foreign antigen to a normally well-balanced system. This knowledge enables the physician to recognize and anticipate adverse reactions. Knowing that some asthmatics might experience a late-phase allergic response, for example, compels the physician to continue intensive therapy until the reaction has completely subsided.

Atopy, the genetic predisposition to the development of antigen-specific immunoglobulin E (IgE) antibody formation, involves complex genetic and environmental influences that are not fully understood. In other words, simple Mendelian inheritance patterns do not predict which individuals will develop allergies. Nevertheless, there appears to be a higher incidence of allergies among children of allergic parents.

One becomes "allergic" to a substance through a two-step process. The first step begins with sensitization and is outlined in Fig. 1. During the initial stage of sensitization, one develops significant amounts of IgE antibodies against an inhaled, ingested, or injected substance. Memory B-cells appear that are capable of immediately producing more specific IgE antibody when stimulated. The second stage involves adherence of this newly formed IgE antibody to circulating blood basophils or to tissue mast cells located in the mucosal surfaces of the skin, the gastrointestinal tract, and the respiratory system. These tissue mast cells were previously coated with IgE antibodies directed specifically against other potentially allergenic substances. The new exposure simply added to the existing population. There are millions of IgE molecules of different specificities (directed against different allergens) on the surface of each mast cell and basophil. An individual is "sensitized" only after IgE antibodies against a specific substance have been produced and are bound to the surface of mast cells and basophils. The process of sensitization does not produce any of the symptoms that we equate with allergic disease. In fact, a person is usually unaware of these initial molecular and cellular changes. It is not until re-exposure to the allergen that allergic symptoms begin to appear once this immunological response has been programmed to "target" a given organ system. Thus, the process of allergic sensitization does not necessarily equate with the development of allergic disease.

The second step in the two-step process of developing allergic disease involves the re-exposure of a sensitized person to the allergen. Symptoms range from negligible rhinorrhea to sudden death. Most cases lie somewhere in the middle of the two extremes. The biochemical events that lead to allergic symptoms will be discussed in some detail later, using an anaphylactic reaction to peanuts as an example. However, one should keep in mind that although the cellular and molecular events for all immediate hypersensitivity reactions are similar, differences in target organ responses ultimately dictate the clinical patterns of disease activity once a reaction has been induced. The mechanisms underlying differential target organ responses (i.e., rhinitis, atopic dermatitis, urticaria, asthma, and/

  1. 1. Allergic sensitization and degranulation. The process of sensitization and degranulation in mast cells is analogous to the construction and detonation of a bomb. Initial binding of specific IgE to the naive mast cell surface "primes" the cell for activity, in effect building the bomb. Subsequent binding of allergen to the mast cell is akin to lighting the fuse of the bomb. Intracellular biochemical events lead to the ultimate "explosion"—a cellular degranulation leading to mediator release.
  2. 1. Allergic sensitization and degranulation. The process of sensitization and degranulation in mast cells is analogous to the construction and detonation of a bomb. Initial binding of specific IgE to the naive mast cell surface "primes" the cell for activity, in effect building the bomb. Subsequent binding of allergen to the mast cell is akin to lighting the fuse of the bomb. Intracellular biochemical events lead to the ultimate "explosion"—a cellular degranulation leading to mediator release.

or anaphylaxis) in relationship to "atopic," immunological, genetic backgrounds, subsequent environmental exposures, and the development of these disease states have not been defined.

THE ALLERGIC REACTION: A SCENARIO

An 8-mo-old girl was in the care of her aunt. Unfortunately, peanut butter crackers were given to the girl as part of a snack. She ingested the crackers without incident. While she was enjoying playtime with her cousins, the peanut proteins were being absorbed in her gut and filtered through the bloodstream and lymphatics, and lodging in the regional lymph nodes. The antigens encountered T- and B-cells and were recognized as foreign proteins. The interaction with lymphocytes leads to IgE production in genetically predisposed or atopic individuals. This IgE was specifically directed against the peanut protein and circulated briefly through the bloodstream before binding to IgE receptors on the tissue mast cells and blood basophils. These receptors bound the antibody at the Fc end of the molecule, leaving the Fab (antigen-binding) region exposed and free to bind circulation antigen. By this time the peanut protein had been cleared by the reticuloendothelial system. The only evidence that the girl was sensitized to the peanut protein was the presence of the specific peanut IgE on her mast cells and the presence of a few memory B-cells capable of producing more specific peanut IgE if they encounter the protein again.

One year later the girl attended a birthday party and ate a cookie containing peanuts. Within minutes, she developed urticaria around her mouth, wheezing, and cough. She was gasping for air as paramedics were summoned and was cyanotic by the time they arrived. Fortunately, prompt treatment allowed her to recover. At the molecular level, her immune system made her a living time bomb, ready to detonate when she came in contact with the peanut antigen "trigger." Despite the 12-mo gap, the immune system never forgot its initial exposure to the peanut. On being exposed to peanuts the second time, the peanut antigen circulated through the blood stream and lymphatics. This time, the antigen flowed past the IgE peanut-specific antibodies already situated on the surface of the mast cells. These IgE molecules, like hands, grabbed the antigen as it passed by. When the number of peanut antigen molecules bound to the IgE on the mast cell surface was sufficient, some IgE antibodies crosslinked and caused a chain reaction. The mast cells released preformed chemicals that were quiescent in their intracellular granules. These chemicals cause bronchoconstriction, vasodilatation, and upper airway edema. Additionally, the triggering and degranulation of mast cell caused the de novo production of other substances that also contributed to the reaction. The effect of the re-exposure to the peanut antigen in this girl's case is called anaphylaxis and represents the most severe type of allergic reaction. Fortunately, such a reaction is rare and can often be prevented, or at least attenuated. We will now explore the pathophysiology of such a reaction in greater detail, starting with the effector cell in immediate hypersensitivity, the mast cell. We will also mention the basophil, a granulocyte that releases mediators similar to those of the mast cell.

ASPECTS OF IgE PRODUCTION

The key intermediary in allergic conditions is IgE antibody. As discussed previously, it is the individual's propensity to produce IgE in response to an "allergic antigen" (also known as an allergen) that makes one atopic. The same allergen that stimulates B-cells to produce IgG or IgM in a nonallergic person may stimulate IgE antibody production in an atopic individual.

Why does the body respond to an allergen exposure by making IgE as opposed to other classes of antibodies? Antibody molecules consist of a variable region responsible for recognizing and binding the offending antigen and a constant region whose purpose is to dictate the fate of the antigen-antibody complex. For example, a person may make both IgA and IgG antibodies against a virus. Both are capable of binding to that virus, but the IgA is found mainly in secretions (as in the nasal mucosa), whereas the IgG predominates in the bloodstream. The mechanisms by which a particular antigen favors the production of one class of antibody over another are not firmly established; nevertheless, several factors that may favor IgE formation are worth discussing.

All antigens initially elicit the production of IgM antibodies against an injected or inhaled allergen. With repeated exposure, the antigen may stimulate an event known as class switching, whereby the constant portion of the antibody will "switch" to another class (i.e., IgG, IgA, or IgE). The new antibody will still have the same antigen-recognition region, but it will now be sitting on another constant region (e.g., IgG or IgA). IgE production by B-cells as a result of class switching is regulated by T-cells and macrophages, predominantly, and the cytokines they produce. Cytokines are small molecular-

  1. 2. The TH1 and TH2 paradigm. T-helper cells uncommitted to an atopic or nonatopic cytokine profile (TH0) receive stimulation from cytokines IL-4 and IL-12 to polarize to a TH1 or TH2 phenotype. The TH1 profile is consistent with a nonatopic phenotype, whereas the TH2 profile is consistent with an atopic phenotype. TH1 cells produce IFN-y, which inhibits IgE production from B-cells and TH0 differentiation into TH2 cells. TH2 cells, on the contrary, produce IL-4 and IL-13, both potent stimulators of IgE production from B-cells. IL-4 also feeds back to inhibit THq differentiation into TH1 cells; it can also further self-promote Th differentiation into TH2 cells to perpetuate the cycle of an atopic cytokine response.
  2. 2. The TH1 and TH2 paradigm. T-helper cells uncommitted to an atopic or nonatopic cytokine profile (TH0) receive stimulation from cytokines IL-4 and IL-12 to polarize to a TH1 or TH2 phenotype. The TH1 profile is consistent with a nonatopic phenotype, whereas the TH2 profile is consistent with an atopic phenotype. TH1 cells produce IFN-y, which inhibits IgE production from B-cells and TH0 differentiation into TH2 cells. TH2 cells, on the contrary, produce IL-4 and IL-13, both potent stimulators of IgE production from B-cells. IL-4 also feeds back to inhibit THq differentiation into TH1 cells; it can also further self-promote Th differentiation into TH2 cells to perpetuate the cycle of an atopic cytokine response.

weight molecules that affect cell function at the local level. Two primary cytokines that favor IgE class switching are interleukin (IL)-4 and IL-13. IL-4 and IL-13 are produced by a subset of CD4+ T-cells, also known as T-helper 2 (TH2) cells.

IL-4 is such an essential signal for IgE production that mice that have been genetically engineered to be devoid of IL-4 (IL-4 knockout mice) are unable to synthesize IgE. In contrast, the primary cytokine that inhibits IgE class switching is called interferon (IFN)-y. IFN-y is produced by a subset of T-cells that have a T-helper 1 (TH1) cytokine profile. The cytokines produced by TH1 and TH2 cells reciprocally inhibit the other's development. These stimulatory and inhibitory interactions are outlined in Fig. 2. In atopic individuals the balance of TH1 and TH2 responses seems to favor the TH2 response and IgE production. In nonatopic individuals, the balance between TH1 and TH2 favors a TH1 dominant response.

The ability to produce polyclonal IgE antibody is present as early as 8-10 wk of gestation. Because IgE antibody cannot cross the placenta, any IgE present in cord blood has been produced entirely by the fetus. During the first year of life, antigen-specific IgE antibody is directed primarily against food antigens; by age 2-3 yr, aeroallergen sensitivity begins to become more prevalent.

The biochemical structure of an antigen appears to play a role in determining the isotype response. A polysaccharide antigen, from the surface of Streptococcus, for instance, will prompt B-cells to produce IgG but not IgE antibodies. In contrast, certain proteins from parasites can cause the B-lymphocytes (with help from the T-cells and IL-4) to cease production of IgG or IgM and to churn out vast quantities of IgE. However, exactly what it is about the structure of proteins that preferentially leads them to become allergens, thus stimulating IgE synthesis, remains unresolved.

THE MAST CELL

A medical student, named Paul Ehrlich, first described the mast cell in 1877. He chose the name Mastzellen (well-fed cells) based on the cells' characteristic cytoplasmic granules (he incorrectly thought that the mast cells were phagocytes and that the granules were ingested debris). We now recognize the central role that mast cells play in the immediate hypersensitivity response.

As with all hematopoietic cells, the mast cells are formed by the action of soluble factors on a pluripotent stem cell (progenitor cell) in the bone marrow. The cells emerge from the bone marrow and migrate to the connective tissues, where they mature, acquiring both cytoplasmic granules and a coating of high-affinity IgE receptors (called FcsRI-a) on their cell surface. Despite gross morphological homogeneity, it is now apparent that mast cells are a heterogeneous cell population. Most pulmonary mast cells contain primarily one neutral protease, tryptase. Skin mast cells, on the other hand, contain large amounts of both tryptase and another protease, chymase (described below). Mast cells in humans are divided and named on the basis of this biochemical difference and are termed MCT (for mast cells containing tryptase) or MCtc (for mast cells containing chymase). The tissue distribution of these subtypes of mast cells is shown in Table 1. The relative numbers of MCT or MCTC may change locally with tissue inflammation, fibrosis, or the cytokine microenvironment. There are no accurate means of discerning from what tissue an isolated mast cell population is derived, because mixtures of both MCT and MCTC cells are found in all tissues.

MEDIATORS OF THE ALLERGIC RESPONSE

The mediators released by mast cells and basophils can be grouped into two categories: (1) preformed substances contained within granules and (2) newly generated chemicals synthesized following cellular activation. These mediators comprise the effector function of the mast cell. Together they are able to increase vascular permeability, dilate vessels, cause bronchospasm, contract smooth muscle, and summon inflammatory cells, as summarized in Fig. 3. Few cells in the body produce compounds with such a large and varied spectrum of activity.

Histamine is a prominent preformed vasoactive amine contained within the mast cell granule. It is formed by the action of histidine decarboxylase on the amino acid histidine. Histamine is the only preformed mediator of the human mast cell with direct vasoactive

Table 1

Relative Distribution of the Two Predominant Human Mast Cell Phenotypes in Immunologically Relevent Tissues and Cell Population

Table 1

Relative Distribution of the Two Predominant Human Mast Cell Phenotypes in Immunologically Relevent Tissues and Cell Population

Organ

% MCt Cells

%MCtc Cells

Skin

5

95

Intestinal mucosa

80

20

Intestinal submucosa

30

70

Alveolar wall

95

5

Bronchial subepithelium

40

60

Dispersed lung mast cells

90

10

Tonsils

40

60

Nasal mucosa

65

35

Adapted from Holgate and Church, Allergy. London: Gower Medical Publishing, 1993.

Adapted from Holgate and Church, Allergy. London: Gower Medical Publishing, 1993.

and smooth muscle spasmogenic effects. It can increase mucus production from airway epithelial cells and contract airway smooth muscle, thus contributing to both mucous plugging and bronchospasm. Histamine also acts to increase vascular permeability as well as to promote vasodilatation, thus causing extravasation of fluid into the tissues. In extreme cases, such intravascular fluid shifts can lead to hypotension and shock.

Neutral proteases are compounds that catalyze the cleavage of certain peptide bonds in proteins and facilitate protein degradation. Their activity is optimum at a neutral pH, hence the name. The two major proteases of human mast cells and basophils are tryptase and chymase. Basophils have negligible but detectable levels of proteases. Maintaining the interior of the granules at an acidic pH, thus inhibiting protease activity, controls the potentially dangerous proteolytic activity of these compounds.

Other accessory molecules have prominent roles in the allergic response. Proteoglycans, including heparin and chondroitin sulfate A, are important in mast cell and basophil biochemistry, respectively. Their exact function is unclear, although many believe that proteoglycans stabilize the enzymes to which they are bound until degranulation occurs.

Two predominant classes of mediators are synthesized de novo following activation of the mast cells and basophils: (1) lipid derivatives and (2) cytokines. The lipid derivatives include leukotrienes and prostaglandins. They represent byproducts of the metabolism of arachidonic acid formed upon activation of the mast cell. The mast cell is able to catabolize essential membrane components and convert them into biologically active mediators through a complex cascade of membrane-bound and soluble enzymes. The overall pathway is seen in Fig. 4. The leukotrienes, produced by the action of the 5-lipoxygenase system on arachidonic acid, demonstrate many different activities, of which the most prominent is immediate bronchoconstriction. They also can cause vasoconstriction in both the pulmonary and vascular beds. The primary leukotrienes made by human mast cells are B4, C4, D4, and E4. The leukotrienes, especially D4, are greater than 10 times more potent than histamine.

Arachidonic acid is also broken down by the action of the cyclooxygenase pathway, resulting in the formation of prostaglandins, prostacyclins, and thromboxanes. These compounds generally function as local hormones and produce many of the same symptoms as the leukotrienes, such as bronchoconstriction, cough, and vasodilatation. The

MEDIATORS OF ALLERGIC REACTIONS

Molecules released from activated mast cells and basophils account for many allergic symptoms. This list includes a sampling of those chemicals and some of their effects, which can be redundant.

CHEMICAL

ACTIVITY

SYMPTOMS

Constricts bronchial airways

Wheezing; difficulty breathing

w Ü

Histamine

Dilates blood vessels

Local redness at sites of allergen delivery-widespread dilation can contribute to potentially lethal hypotension (shock)

H

Increases permeability of small blood vessels

Swelling of local tissue; if widespread, increased permeability can contribute to shock

g

Stimulates nerve endings

Itching and pain in skin

Stimulates secretion of mucus in airways

Congestion of airways

Platelet-activating factor

Constricts bronchial airways

Same as for histamine

Dilates blood vessels

Same as for histamine

2 O H

Leukotrienes

Constricts bronchial airways

Same as for histamine

O

Increase permeability of small blood vessels

Same as for histamine

NN

Prostaglandin D

Constricts bronchial airways

Same as for histamine

Fig. 3. Mast cell mediators and their effects. (Adapted from Lichtenstein L. Allergy and the immune system. Sci Am 1993;369:117-124, with permission.)

main prostaglandin produced by human mast cells is PGD2, a compound at least 30 times as potent as histamine in causing bronchoconstriction. Thromboxane A2 and prostacyclin (PGI2) produce bronchoconstriction and bronchodilatation, respectively. Together they function as a mechanism to maintain bronchial and vascular tone.

Platelet-activating factor (PAF) is a phospholipid. PAF is produced by mast cells (as well as macrophages, neutrophils, and eosinophils) and functions to activate platelets and neutrophils and vasoconstrict smooth muscle. Perhaps most importantly, PAF stimulates chemoattraction of eosinophils to endothelial surfaces and eosinophil release of other cell mediators. PAF is rapidly inactivated in vivo, suggesting that it serves as a trigger of inflammatory events rather than a major mediator itself.

The identification of cytokines synthesized by mast cells and basophils is currently an area of intense investigation. Cytokines represent the primary mechanism by which cells

Cell Membrane Phospholipids

Phospholipase A2

Arachidonic Acid

  1. 4. Arachidonic acid metabolic pathways. Arachidonic acid, released as a result of phospholipase on the cellular membrane, is broken down by two distinct biochemical pathways: The lipoxygenase pathway results in formation of the leukotrienes (LT), whereas the cyclooxygenase pathway generates prostacyclin, thromboxane, and the prostaglandins (PG).
  2. 4. Arachidonic acid metabolic pathways. Arachidonic acid, released as a result of phospholipase on the cellular membrane, is broken down by two distinct biochemical pathways: The lipoxygenase pathway results in formation of the leukotrienes (LT), whereas the cyclooxygenase pathway generates prostacyclin, thromboxane, and the prostaglandins (PG).

can influence the activity and development of unrelated cells and related cells in an exocrine and autocrine fashion. Human mast cells produce IL-4 and IL-5 as well as tumor necrosis factor (TNF)-a. The IL-4 stimulates mast cell differentiation and promotes immunoglobulin class switching to the IgE isotype. IL-5 is the most influential cytokine involved in eosinophil production and survival in humans. TNF-a increases vascular permeability and leukocyte migration.

Basophils have long been incorrectly viewed as the bloodborne equivalent of mast cells with analogous granules and functions. However, these cells represent a hematopoietic lineage distinct from mast cells, can also infiltrate tissues, and contain neither tryptase nor chymase. In addition, basophils seem to have a different role in the allergic reaction scenario. They tend to release abundant amounts of histamine but little, if any, PGD2. This finding has been cited as evidence of their contribution to late-phase allergic inflammatory events in the nose, skin, and lung. The presence of increased histamine, but undetectable PGD2, during late responses implies that basophils are recruited to sites of allergic inflammation (see Early- and Late-Phase Responses).

ACTIVATION OF THE MAST CELL

The mechanism by which the external signal of IgE crosslinking is translated into cellular activation, granule release, and de novo synthesis of new molecules is a fascinating tale of cellular adaptation and biochemistry. An overview of the reactions is illustrated in Fig. 5.

  1. 5. Mast cell activation: biochemical reactions. Following IgE crosslinking by antigen, a series of protein kinase reactions culminate in the activation of phospholipase C, releasing diacylglycerol (DAG) and inositol triphosphate (IP3) from the plasma membrane. The IP3 releases calcium stores from the endoplasmic reticulum, which, along with DAG-stimulated kinases, leads to granule release. The intracellular calcium also activates phospholipase A2, which generates arachidonic acid, a compound metabolized to form leukotrienes and prostaglandins.
  2. 5. Mast cell activation: biochemical reactions. Following IgE crosslinking by antigen, a series of protein kinase reactions culminate in the activation of phospholipase C, releasing diacylglycerol (DAG) and inositol triphosphate (IP3) from the plasma membrane. The IP3 releases calcium stores from the endoplasmic reticulum, which, along with DAG-stimulated kinases, leads to granule release. The intracellular calcium also activates phospholipase A2, which generates arachidonic acid, a compound metabolized to form leukotrienes and prostaglandins.

The process begins with the crosslinking of two or more IgE molecules on the mast cell surface. This requires a multivalent antigen (i.e., more than one IgE-binding site on the same molecule). Monovalent antigens will not trigger mast cell activation. Once the antigen is attached to the mast cell by more than one IgE molecule, a series of cytoplasmic signals occur causing activation. This process is called signal transduction and is a method of cellular communication with the external environment. In this case, the signal enters the cell via a conformational change in the FcsRI-a receptor.

Once the antigen is bound to the mast cell via the IgE molecules, the cell begins a series of biochemical events that culminates in the release of its granules and the production of lipid mediators (arachidonic acid metabolites). The production of the lipid mediators requires effective intracellular scavenging by the mast cell. The principle is to cannibalize lipids from the membrane and transform them into potent mediators. PLA2, activated by the calcium released from the endoplasmic reticulum, starts degrading phosphatidyl choline. In turn, arachidonic acid is formed and metabolized via the two pathways men tioned earlier: the lipoxygenase pathway (which produces leukotrienes) and the cyclooxygenase pathway (which produces prostaglandins). As stated previously, the main prostaglandin produced by mast cells is PGD2. Leukotrienes B4 and C4 are the primary leukotrienes made. Leukotriene C4 is subsequently converted to active compounds LTD4 and LTE4. The activities of these lipid mediators are described elsewhere.

In summary, the mast cell needs to accomplish two functions following activation: to release its granules with their associated biologically active compounds and to synthesize additional mediators of the allergic reaction using its cell membrane constituents as precursors. These activities utilize a great deal of cellular energy, most of which is obtained from the high-energy phosphate bonds generated by the action of protein kinases. The initiation of these cascades depends on interaction of the mast cell with antigen. The prerequisite crosslinking of the IgE molecules probably evolved as a safety mechanism to prevent premature activation of the cell. A sufficient quantity of specific IgE must be bound to the mast cell to achieve a crosslink, which is possible only if sensitization had occurred previously.

Allergic (IgE-mediated) activation of the mast cell was summarized earlier, but there is an alternate, IgE-independent mechanism of mast cell degranulation that should be mentioned. This degranulation is the result of mast cell membrane perturbation at a molecular level, often requiring calcium influx. This nonimmunological degranulation may be triggered by opioids, anaphylatoxins (complement components), and radiological contrast dyes. In fact, the majority of patients who report a history of "allergic reactions" to contrast dyes have experienced non-IgE-mediated reactions.

EFFECTS OF MAST CELL MEDIATORS ON TARGET ORGANS

The examination of the mechanisms contributing to the release of mast cell mediators is only half the story of allergic pathophysiology. The spectrum of symptoms that prompts a visit to the allergist begins only after these substances are released from mast cells and interact with resident and infiltrating cells in various target organs. In the case involving the 8-mo-old girl sensitized to peanut, these mediators combined to cause anaphylaxis. Histamine was liberated from the mast cell granules and was quickly dispersed through the bloodstream. Histamine receptors are located on many target organs, including the skin, the nasal mucosa, the smooth muscle of the lungs and gastrointestinal tract, and vascular epithelial cells. Once bound to its receptor, histamine causes such diverse effects as vasodilatation of small vessels with subsequent exudation of fluid into surrounding tissue; smooth muscle contraction, an effect of particular import when one is considering the muscles surrounding the bronchial airways; and increased glandular mucus secretion, an annoyance in the nasal mucosa but dangerous in the small bronchioles. Extremely high doses of histamine cause these effects to occur on a systemic level, possibly leading to hypotensive shock in the case of massive vasodilatation.

The lipid mediators cause symptoms that are very similar to histamine; however, their effects are more persistent. Histamine is rapidly degraded in the serum with a half-life of 1 min, but the lipid mediators are slowly metabolized. As you recall, both leukotrienes and prostaglandins are synthesized only after an allergic reaction has begun, thus accounting for the delay in onset of action. Historically, leukotrienes were collectively termed the slow-reacting substance of anaphylaxis because of this delay in activity. Once released in the serum, the prostaglandins bind to specific receptors and lead to bronchial smooth muscle contraction in the lungs, vasodilatation in the skin, and nasal blockage. Leukotrienes are also highly potent bronchoconstrictors but utilize distinct receptors on the smooth muscle cells. They also increase permeability at postcapillary venules, leading to localized tissue edema.

ALLERGIC INFLAMMATION: A TH2-MEDIATED RESPONSE

Just as IgE production and mast cell activation are key components to the initial allergic response, several other cells play a role in propagating this allergic inflammatory response. After the immediate release of mast cell mediators following allergen exposure, leukocytes influx into affected tissues. This occurs approx 2-8 hr after allergen exposure and has been termed the late-phase reaction (LPR) or the late allergic response (LAR). It is explained in detail later. The primary cell types recruited to sites of LPR include basophils, eosinophils, neutrophils, lymphocytes, and macrophages. The main attractants for these cells are cytokines secreted by mast cells, T-cells, and epithelial cells. Cells present during the initial allergic response, such as mast cells, as well as cells that migrate into tissues following an increase in vascular permeability, generate cytokines. Many cytokines contribute to this influx; however, IL-4, IL-5, TNF-a, and chemotactic cytokines termed chemokines play major roles. TNF-a and IL-4 attract basophils. IL-5 is a potent eosinophil activator, and C-C chemokines such as RANTES (regulated on activation, normal T-cell expressed and secreted) promote eosinophil migration into tissues. These responses collectively parallel the TH2 cytokine profile shown in Fig. 2. In cases of perennial allergic rhinitis, perennial asthma, and acute atopic dermatitis, T-cells isolated from the affected tissues (nose, lung, or skin, respectively) exhibit a predominantly TH2 cytokine profile. However, it is important to remember that any T-cell population will express heterogeneity and not uniformly possess one cytokine profile.

EARLY- AND LATE-PHASE RESPONSES

An important aspect of allergic disease, with scientific and clinical implications, is the concept of the late-phase IgE-mediated reaction. The mast cell activation pathway (described above) occurs within minutes of allergen exposure. All mechanisms and components of the system are designed for almost instantaneous responses. Once the initial surge of mediator release is completed, there is regeneration of the mast cell granules, although this process may take days to weeks to be completed. If one were to speculate that an allergic reaction represents an exaggerated host response to a foreign invader (or allergen), then it might make sense to have a backup system in place in case the immediate response is not completely successful. In the teleological sense, that is precisely what the late-phase response does.

The late-phase response is a delayed-in-time inflammatory response that occurs following mast cell activation. It may function to amplify an initial signal resulting from the first wave of allergen "attack." In response to a barrage of chemotactic and differentiative cytokines, multiple cell lineages (e.g., eosinophils, neutrophils) are summoned to the site of this breach of the immune system. Together, these summoned cells constitute the inflammatory or late allergic response (LAR). The LAR lacks the speed of the immediate response, but it more than makes up for this in terms of magnitude. The LAR typically occurs 2-8 h after initial allergen exposure. Subtle differences in the nature and effect of the mediators involved in the LAR have been observed in each anatomical location in which it has been described. We will consider two such environments: the skin and the nose.

The cutaneous early reactions are well described: a characteristic wheal-and-flare reaction is seen with a positive skin test in an atopic individual. It resembles a mosquito bite in that it consists of a pale, circumscribed central area of edema surrounded by an erythematous diffuse border. This typical early-phase reaction will peak in 15 min and resolve in 30-60 min. In some cases, however, the early-phase response will persist for hours and progress into a late-phase response that peaks 6-8 h following allergen exposure and lasts up to 24 h. The cellular infiltrate observed 6-12 h after a cutaneous allergen challenge consists of a mixed population of neutrophils, eosinophils, and lymphocytes. Mediators produced in the cutaneous LAR reflect the nature of the cells summoned to the area and include various interleukins (IL-1, IL-4, IL-6).

The nasal late-phase response is characterized by a cellular infiltrate of eosinophils, mono-nuclear cells, and neutrophils and is often accompanied by fibrin deposition. The mediators produced in the nasal LAR are identical to those present in the early response with one exception: PGD2 is absent. As mentioned earlier, the presence of histamine without PGD2 suggests that basophils may play a prominent role in the nasal LAR. They characteristically produce negligible amounts of PGD2 while maintaining a high histamine content. Nasal congestion is the predominant symptom associated with the nasal LAR (rhinorrhea and sneezing are generally associated with the early response).

CONCLUSION

Several generalities apply to all tissues in which an allergic reaction can occur. The immediate result of an interaction between a sensitized mast cell and a specific allergen, also known as the early-phase response, results in the release of preformed mediators. Both local and distal target organ effects are exhibited as a result of the early-phase response. Although the cellular effects of these mediators are similar on each tissue, the clinical symptoms produced may differ. For example, increases in vascular permeability may present as angioedema in the skin or as congestion in the nose. The presence of a late-phase response is also seen in various issues and represents the inflammatory response. Because the goal of the late-phase response is to attract inflammatory cells, the cytokine profile differs slightly from the immediate response.

How does this relate to the 8-mo-old girl with the allergy to peanuts? Her primary care physician wisely sent her to a specialist. The girl was skin-tested to peanuts and had a positive testing indicating sensitization. In combination with her history, this confirmed the suspected diagnosis of peanut allergy. Her family was instructed on avoidance measures, and Epipen Jr was prescribed and instructions given on its use. She diligently avoids peanuts without other sweeping food restrictions. As we will see in later chapters, there are many immunological and pharmacological interventions that may be useful in preventing both immediate and late-phase allergic reactions. An appreciation of the pathophysiology of the allergic reaction is essential to the proper use of these treatments.

SUGGESTED READING

Charlesworth EN. The skin as a model to study the pathogenesis of IgE-mediated acute and late phase responses. J Allergy Clin Immunol 1994;94:1240-1250.

Costa J, Weller PF, Galli SJ. The cells of the allergic response: mast cells, basophils, and eosinophils. JAMA 1997;278:1815-1822.

James JM, Sampson HA. An overview of food hypersensitivity. Pediatr Allergy Immunol 1992;3:67-78. Kaliner MA, Lemanske RF. Rhinitis and asthma. JAMA 1992;268:2807-2829.

Niazi S, Batra V, Awsare B, Zangrilli JG, Peters SP. Allergic inflammation: initiation, progression, and resolution. In: Adkinson Jr, NF, et al., eds. Middleton's Allergy Principles & Practice, 6th ed., vol 1. Philadelphia: Mosby, 2003:453-463. Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999;103:717-728.

White M. Mediators of inflammation and the inflammatory process. J Allergy Clin Immunol 1999;103:S378-S381.

Was this article helpful?

0 0
Curing Eczema Naturally

Curing Eczema Naturally

Do You Suffer From the Itching, Redness and Scaling of Chronic Eczema? If so you are not ALONE! It strikes men and women young and old! It is not just

Get My Free Ebook


Post a comment