type 1 hypersensitivity
Tuesday 10 March 2009
Immediate hypersensitivity, or type I hypersensitivity is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.
These reactions are often called allergy, and the antigens that elicit them are allergens. Immediate hypersensitivity may occur as a systemic disorder or as a local reaction.
The systemic reaction usually follows injection of an antigen to which the host has become sensitized. Often within minutes, a state of shock is produced, which is sometimes fatal.
The nature of local reactions varies depending on the portal of entry of the allergen and may take the form of localized cutaneous swellings (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis (food allergy).
Many local type I hypersensitivity reactions have two well-defined phases.
The immediate, or initial, response is characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions. These changes usually become evident within 5 to 30 minutes after exposure to an allergen and tend to subside in 60 minutes.
In many instances (e.g., allergic rhinitis and bronchial asthma), a second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. This late-phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage.
Mast cells are bone marrow-derived cells that are widely distributed in the tissues. They are found predominantly near blood vessels and nerves and in subepithelial sites, where local immediate hypersensitivity reactions tend to occur.
Mast cells have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators. In addition, mast-cell granules contain acidic proteoglycans that bind basic dyes such as toluidine blue. Because the stained granules often acquire a color that is different from that of the native dye, they are referred to as metachromatic granules.
Mast cells (and basophils) are activated by the cross-linking of high-affinity IgE Fc receptors; in addition, mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a (anaphylatoxins), both of which act by binding to their receptors on the mast-cell membrane.
Other mast-cell secretagogues include macrophage-derived cytokines (e.g., IL-8), some drugs such as codeine and morphine, adenosine, mellitin (present in bee venom), and physical stimuli (e.g., heat, cold, sunlight).
Basophils are similar to mast cells in many respects, including the presence of cell-surface IgE Fc receptors as well as cytoplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in extremely small numbers. Most allergic reactions occur in tissues, and the role of basophils in these reactions is not as well established as that of mast cells. Similar to other granulocytes, basophils can be recruited to inflammatory sites.
Most immediate hypersensitivity reactions are mediated by IgE antibodies. IgE-secreting B cells differentiate from naive (membrane IgM and IgD-expressing) B cells, and this process is dependent on the activity of CD4+ helper T cells of the TH2 type. Hence, TH2 cells are pivotal in the pathogenesis of type I hypersensitivity.
The first step in the synthesis of IgE is the presentation of the antigen to naive CD4+ helper T cells by dendritic cells that capture the antigen from its site of entry.
In response to antigen and other stimuli, including cytokines produced at the local site, the T cells differentiate into TH2 cells. The newly minted TH2 cells produce a cluster of cytokines upon subsequent encounter with the antigen.
The signature cytokines of this subset are IL-4, IL-5, and IL-13. IL-4 is essential for turning on the IgE-producing B cells and for sustaining the development of TH2 cells. IL-5 activates eosinophils, which, as we discuss subsequently, are important effectors of type I hypersensitivity.
IL-13 promotes IgE production and acts on epithelial cells to stimulate mucus secretion. In addition, TH2 cells and epithelial cells produce chemokines that attract more TH2 cells, as well as eosinophils and occasionally basophils, to the reaction site.
Mast cells and basophils express high-affinity receptors for the Fc portion of IgE, and therefore avidly bind IgE antibodies. When a mast cell, armed with cytophilic IgE antibodies, is re-exposed to the specific allergen, a series of reactions takes place, leading eventually to the release of a variety of powerful mediators responsible for the clinical expression of immediate hypersensitivity reactions. In the first step in this sequence, antigen (allergen) binds to the IgE antibodies previously attached to the mast cells.
Multivalent antigens bind to more than one IgE molecule and thus cross-link adjacent IgE antibodies and the underlying IgE Fc receptors.
The bridging of IgE molecules activates signal transduction pathways from the cytoplasmic portion of the IgE Fc receptors. These signals initiate two parallel and interdependent processes, one leading to mast cell degranulation with discharge of preformed (primary) mediators that are stored in the granules, and the other involving de novo synthesis and release of secondary mediators.
These mediators are directly responsible for the initial, sometimes explosive, symptoms of immediate hypersensitivity, and they also set into motion the events that lead to the late-phase response.
In addition to inducing mediator release and production, signals from IgE Fc receptors promote the survival of mast cells and can enhance expression of the Fc receptor, providing an amplification mechanism.
Mediators of the inflammatory response
Mast cell-derived TNF and chemokines are important mediators of the inflammatory response seen at the site of allergic inflammation.
Inflammatory cells that accumulate at the sites of type I hypersensitivity reactions are additional sources of cytokines and of histamine-releasing factors that cause further mast-cell degranulation.
The development of immediate hypersensitivity reactions is dependent on the coordinated actions of a variety of chemotactic, vasoactive, and spasmogenic compounds.
Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions characterized by edema, mucus secretion, and smooth muscle spasm; others, exemplified by cytokines, set the stage for the late-phase response by recruiting additional leukocytes.
Not only do these inflammatory cells release additional waves of mediators (including cytokines), but they also cause epithelial-cell damage. Epithelial cells themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as IL-6, IL-8, and GM-CSF.
Primary mediators contained within mast-cell granules can be divided into three categories:
Biogenic amines. The most important vasoactive amine is histamine. Histamine causes intense smooth muscle contraction, increased vascular permeability, and increased secretion by nasal, bronchial, and gastric glands.
Enzymes. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement (e.g., C3a) by acting on their precursor proteins.
Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate. The proteoglycans serve to package and store the other mediators in the granules.
Secondary mediators include two classes of compounds (1) lipid mediators and (2) cytokines.
The lipid mediators are generated by sequential reactions in the mast-cell membranes that lead to activation of phospholipase A2, an enzyme that acts on membrane phospholipids to yield arachidonic acid. This is the parent compound from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways.
- Leukotrienes. Leukotrienes C4 and D4 are the most potent vasoactive and spasmogenic agents known. On a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. Leukotriene B4 is highly chemotactic for neutrophils, eosinophils, and monocytes.
- Prostaglandin D2. This is the most abundant mediator derived by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion.
- Platelet-activating factor (PAF). PAF is produced by some mast-cell populations. It causes platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, and vasodilation. In addition, it has important pro-inflammatory actions. PAF is chemotactic for neutrophils and eosinophils. At high concentrations, it activates the newly recruited inflammatory cells, causing them to aggregate and degranulate. Because of its ability to recruit and activate inflammatory cells, it is considered important in the initiation of the late-phase response. Although the production of PAF is also triggered by the activation of phospholipase A2, it is not a product of arachidonic acid metabolism.
Mast cells are sources of many cytokines, which play an important role in the late-phase reaction of immediate hypersensitivity because of their ability to recruit and activate inflammatory cells. The cytokines include TNF, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF, as well as chemokines, such as macrophage inflammatory protein (MIP)-1α and MIP-1β.
Among the cells that are recruited in the late-phase reaction, eosinophils are particularly important. They are recruited to sites of immediate hypersensitivity reactions by chemokines, such as eotaxin and others, that may be produced by epithelial cells under the influence of mediators such as TNF, TH2 cells, and mast cells.
The survival of eosinophils in tissues is favored by IL-3, IL-5, and GM-CSF, and IL-5 is the most potent eosinophil-activating cytokine known. These cytokines, as mentioned earlier, are derived from TH2 cells and mast cells.
The armamentarium of eosinophils is as extensive as that of mast cells, and in addition they produce major basic protein and eosinophil cationic protein, which are toxic to epithelial cells. Activated eosinophils and other leukocytes also produce leukotriene C4 and PAF and directly activate mast cells to release mediators.
Thus, the recruited cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen.
It is now believed that this late-phase inflammatory response is a major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma. Therefore, treatment of these diseases requires the use of broad-spectrum anti-inflammatory drugs, such as steroids.
A final point that should be mentioned in this general discussion of immediate hypersensitivity is that susceptibility to these reactions is genetically determined.
The term atopy refers to a predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens. Atopic individuals tend to have higher serum IgE levels, and more IL-4-producing TH2 cells, compared with the general population. A positive family history of allergy is found in 50% of atopic individuals. The basis of familial predisposition is not clear, but studies in patients with asthma reveal linkage to several gene loci.
Candidate genes have been mapped to 5q31, where genes for the cytokines IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF are located, consistent with the idea that these cytokines are involved in the reactions.
Linkage has also been noted to 6p, close to the HLA complex, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens. Another asthma-associated locus is on chromosome 11q13, the location of the gene encoding the β chain of the high-affinity IgE receptor, but many studies have failed to establish a linkage of atopy with the FcεRI β chain or even this chromosomal region.
To summarize, immediate (type I) hypersensitivity is a complex disorder resulting from an IgE-mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition.
These events are regulated in large part by the induction of TH2-type helper T cells that promote synthesis of IgE and accumulation of inflammatory cells, particularly eosinophils.
The clinical features result from release of mast-cell mediators as well as the accumulation of an eosinophil-rich inflammatory exudate. With this consideration of the basic mechanisms of type I hypersensitivity, we turn to some conditions that are important examples of IgE-mediated disease.
Local Immediate Hypersensitivity Reactions
Local immediate hypersensitivity, or allergic, reactions are exemplified by so-called atopic allergy. About 10% of the population suffers from allergies involving localized reactions to common environmental allergens, such as pollen, animal dander, house dust, foods, and the like.
Specific diseases include urticaria, angioedema, allergic rhinitis (hay fever), and some forms of asthma, all discussed elsewhere in this book. The familial predisposition to the development of this type of allergy has been mentioned earlier.
In pre-disposed individuals, initial exposure(s) to allergen leads to the activation of allergen-specific T helper 2 (TH2) cells and IgE synthesis, which is known as allergic sensitization.
Subsequent exposures to allergen cause inflammatory-cell recruitment and activation and mediator release, which are responsible for early (acute) allergic responses (EARs) and late allergic responses (LARs).
In the EAR, within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both pre-formed and newly synthesized mediators in sensitized individuals.
These include histamine, leukotrienes and cytokines, which promote vascular permeability, smooth-muscle contraction and mucus production.
Chemokines released by mast cells and other cell types direct recruitment of inflammatory cells that contribute to the LAR, which is characterized by an influx of eosinophils and TH2 cells.
Eosinophils release an array of pro-inflammatory mediators, including leukotrienes and basic proteins (cationic proteins, eosinophil peroxidase, major basic protein and eosinophil-derived neurotoxin), and they might be an important source of interleukin-3 (IL-3), IL-5, IL-13 and granulocyte/macrophage colony-stimulating factor.
Neuropeptides are also proposed to contribute to the pathophysiology of allergic symptoms.