Immediate Hypersensitivity (Type I)

Chapter 23 Immediate Hypersensitivity (Type I)




Summary




The classification of hypersensitivity reactions is based on the system proposed by Coombs and Gell.


Historical observations have shaped our understanding of immediate hypersensitivity. The severity of symptoms depends on IgE antibodies, the quantity of allergen, and also a variety of factors that can enhance the response including viral infections and environmental pollutants.


Most allergens are proteins.


Production of IgE depends on genotype. In genetically predisposed individuals, IgE production occurs in response to repeated low-dose exposure to inhaled allergens such as dust mite, cat dander, or grass pollen.


Allergens are the antigens that give rise to immediate hypersensitivity and contribute to asthma rhinitis or food allergy.


Mast cells and basophils contain histamine. IgE antibodies bind to a specific receptor, FcεRI, on mast cells and basophils. This Fc receptor has a very high affinity, and when bound IgE is cross-linked by specific allergen, mediators including histamine, leukotrienes, and cytokines are released.


Multiple genes have been associated with asthma in different populations. Multiple genetic loci influence the production of IgE, the inflammatory response to allergen exposure, and the response to treatment. Polymorphisms have been identified in the genes, in promoter regions, and in the receptors for IgE, cytokines, leukotrienes, and the β2-receptors.


Skin tests are used for diagnosis and as a guide to treatment.


Several different pathways contribute to the chronic symptoms of allergy.


Immunotherapy can be used for hayfever and anaphylactic sensitivity.


New approaches are being investigated for treating allergic disease.



Classification of hypersensitivity reactions


The adaptive immune response provides specific protection against infection with bacteria, viruses, parasites, and fungi. Some immune responses, however, give rise to an excessive or inappropriate reaction – this is usually referred to as hypersensitivity.


The term hypersensitivity evolved from the observations of Richet and Portier one hundred years ago, who described the catastrophic result of exposing a pre-sensitized animal to systemic antigen. The resulting outcome, termed anaphylaxis, became the prototype of immediate hypersensitivity responses.


Coombs and Gell in 1963 proposed a classification scheme in which allergic hypersensitivity of the type described by Portier and Richet was termed type I, and broadened the definition of hypersensitivity to include:



Immediate (Type I) hypersensitivity responses are characterized by the production of IgE antibodies against foreign proteins that are commonly present in the environment (e.g. pollens, animal danders, or house dust mites) and can be identified by wheal and flare responses to skin tests which develop within 15 minutes.


Antibody-mediated (Type II) hypersensitivity reactions occur when IgG or IgM antibodies are produced against surface antigens on cells of the body. These antibodies can trigger reactions either by activating complement (e.g. autoimmune hemolytic anemia) or by facilitating the binding of natural killer cells (see Chapter 24);.


Immune complex diseases (Type III hypersensitivity) involve the formation of immune complexes in the circulation that are not adequately cleared by macrophages or other cells of the reticuloendothelial system. The formation of immune complexes requires significant quantities of antibody and antigen (typically microgram quantities of each). The classical diseases of this group are systemic lupus erythematosus (SLE), chronic glomerulonephritis, and serum sickness (see Chapter 25).


Cell-mediated reactions (Type IV hypersensitivity) are those in which specific T cells are the primary effector cells (see Chapter 26). Examples of T cells causing unwanted responses are:






The original Coombs and Gell classification is shown in Figure 23.1.



In the past several years it has become apparent that the Coombs and Gell classification artificially divided mechanistically related antibody reactions (such as types I, II, and III), which contribute to the pathophysiology of many common immune-mediated diseases, while including the T cell-mediated reactions of delayed-type hypersensitivity (DTH) in a common classification (termed type IV).


Based on our current understanding of the underlying pathways of inflammation triggered by antigen exposure and the disease conditions observed, common mechanisms appear to operate in types I, II, and III hypersensitivity. These common mechanisms involve the engagement by antibody–antigen complexes with cellular receptors for the Fc region of antibodies (termed Fc receptors).



Historical perspective on immediate hypersensitivity


The first allergic disease to be defined was seasonal hayfever caused by pollen grains (which have a defined season of weeks or months) entering the nose (rhinitis) and eyes (conjunctivitis). In severe cases patients may also get seasonal asthma and seasonal dermatitis. Charles Blackley, in 1873, demonstrated that pollen grains placed into the nose could induce symptoms of rhinitis. He also demonstrated that pollen extract could produce a wheal and flare skin response in patients with hayfever.


The wheal and flare skin response is an extremely sensitive method of detecting specific IgE antibodies. The timing and form of the skin response is indistinguishable from the local reaction to injected histamine. Furthermore, the immediate skin response can be effectively blocked with antihistamines.


In 1903, Portier and Richet discovered that immunization of guinea pigs with a toxin from the jellyfish Physalia could sensitize them so that a subsequent injection of the same protein would cause rapid onset of breathing difficulty, influx of fluid into the lungs, and death. They coined the term anaphylaxis (from the Greek ana, non, and phylaxos, protection) and speculated about the relationship to other hypersensitivity diseases. They noted that:



Subsequently, it became clear that injection of any protein into an individual with immediate hypersensitivity to that protein can induce anaphylaxis. Thus, anaphylaxis occurs when a patient with immediate hypersensitivity is exposed to a relevant allergen in such a way that the antigen enters the circulation rapidly.



Anaphylaxis may also occur as a result of eating an allergen such as peanut or shellfish, or following the rupture of hydatid cysts with the rapid release of parasite antigens (Fig. 23.2).



The term allergen was first used by von Pirquet in 1906 to cover all foreign substances that could produce an immune response. Subsequently, the word ‘allergen’ came to be used selectively for the proteins that cause ‘supersensitivity’. Thus, an allergen is an antigen that gives rise to immediate hypersensitivity.



Characteristics of type I reactions



Most allergens are proteins


Substances that can give rise to wheal and flare responses in the skin and to the symptoms of allergic disease are derived from many different sources (see http://www.allergen.org/). When purified they are almost all found to be proteins and their sizes range from 10–40 kDa. These proteins are all freely soluble in aqueous solution, but have many different biological functions including digestive enzymes, carrier proteins, calycins, and pollen recognition proteins.


Any allergen can be described or classified by its source, route of exposure, and nature of the specific protein (Fig. 23.3).



Extracts used for skin testing or in-vitro measurement of IgE antibodies are made from the whole material, which contains multiple different proteins, any of which can be an allergen. Indeed, it is clear that individual patients can react selectively to one or more of the different proteins that are present in an extract.



Estimates of exposure can be made either by visual identification of particles (e.g. pollen grains or fungal spores) or by immunoassay of the major allergens (e.g. Fel d1 or Der p1).



IgE is distinct from the other dimeric immunoglobulins


In 1921, Küstner, who was allergic to fish, injected his own serum into the skin of Prausnitz, who was allergic to grass pollen but not fish, and demonstrated that it was possible to passively transfer immediate hypersensitivity (the Prausnitz–Küstner or P–K test). Prausnitz also noticed that an immediate wheal and flare occurred at the site of passive sensitization when he ate fish. This showed that some protein or part of fish proteins sufficient to trigger mast cells can be absorbed into the circulation.


Over the next 30 years it was established that P–K activity was a general property of the serum of patients with immediate hypersensitivity and that it was allergen specific (i.e. it behaved like an antibody).


In 1967 Ishizaka and his colleagues purified the P–K activity from a patient with ragweed hayfever and proved that this was a novel isotype of immunoglobulin – IgE. However, it was obvious that the concentration of this immunoglobulin isotype in serum was very low i.e. ≤1 μg/mL.


IgE is distinct from the other dimeric immunoglobulins because it has:



The primary cells that bear FcεRI are mast cells and basophils, which are the only cells in the human that contain significant amounts of histamine.


Low-affinity receptors for IgE – FcεRII or CD23 – are also present on B cells and may play a role in antigen presentation.


In addition in atopic dermatitis dendritic cells in skin can express a high-affinity receptor for IgE, but this receptor lacks the β chain of FcεRI.


The properties of IgE can be separated into three areas:




The half-life of IgE is short compared with that of other immunoglobulins


The concentration of IgE in the serum of normal individuals is very low compared to all the other immunoglobulin isotypes. Values range from <10–10 000 IU/mL, and the international unit (IU) is equivalent to 2.4 ng. Most sera contain <400 IU/mL (i.e. <1 μg/mL). The reasons why serum IgE is so low include:




The half-life of IgE in the serum has been measured both by injecting radiolabeled IgE and by infusing plasma from allergic patients into normal and immune-deficient patients.


The half-life of IgE in serum is less than 2 days; by contrast, IgE bound to mast cells in the skin has a half-life of approximately 10 days.


The low quantities of IgE in the serum must reflect a more rapid breakdown of IgE, as well as removal from the circulation by binding onto mast cells.


The most important site of breakdown of IgE is thought to be within endosomes where the low pH facilitates breakdown of free immunoglobulin by cathepsin.


Serum is constantly being taken up by endocytosis. Many macromolecules including IgE degrade in the endosome. One major exception is IgG, which is protected by binding to the neonatal Fc gamma receptor, FcγRn (Fig. 23.4).





T cells control the response to inhalant allergens



IgE production is dependent on TH2 cells


Experiments in animals have established that the production of IgE is dependent on T cells. It is also clear that T cells can suppress IgE production.


T cells that suppress TH2 responses including IgE production:



This adjuvant, which includes bacterial cell walls and probably bacterial DNA, is a very potent activator of macrophages.


With the discovery of TH1 and TH2 cells, it became clear that IgE production is dependent on TH2 cells and that any priming that generates a TH1 response will inhibit IgE production.


The main cytokines that are specifically relevant to a TH1 response include:



By contrast, the primary cytokines relevant to a TH2 response are:




It is clear from experiments in mice and humans that the expression of the gene for IgE is dependent on IL-4. Thus, if immature human B cells are cultured with anti-CD40 and IL-4, they will produce IgE antibodies.



Cytokines regulate the production of IgE


In humans IgE antibodies are the dominant feature of the response to a select group of antigens and most other immune responses do not include IgE.


The classical allergens are inhaled in very small quantities (5–20 ng/day) either perennially indoors or over a period of weeks or months outdoors. Immunization of mice with repeated low-dose antigen is a very effective method of inducing IgE responses.


By contrast, the routine immunization of children with diphtheria and tetanus toxoid does not induce persistent production of IgE antibodies. This is clear because we do not routinely take precautions against anaphylaxis when administering a booster injection of tetanus.



As T cells differentiate, TH1 cells express the functional IL-12 receptor with the IL-12 β2 chain. By contrast, TH2 cells express only part of the IL-12 receptor and this part is non-functional.


IL-4 is important in the differentiation of TH2 cells and is also a growth factor for these cells. Because it is produced by TH2 cells, it is at least in part acting on the cell that produced it (i.e. in an autocrine fashion). The interaction of IL-4 with T cells can be blocked either with:



The release of soluble IL-4R from T cells may be a natural mechanism for controlling T cell differentiation. However, recent evidence suggests that in-vivo responses are controlled by T cells producing either IL-10 or transforming growth factor-β (TGFβ).



Both IgE and IgG4 are dependent on IL-4


The genes for immunoglobulin heavy chains are in sequence on chromosome 14. The gene for ε occurs directly following the gene for γ4. Both of these isotypes are dependent on IL-4 and they may be expressed sequentially (Fig. 23.6).



The mechanisms by which IgG4 is controlled separately from IgE are not well understood, but this may include a role for IL-10. Thus, immunotherapy for patients with anaphylactic sensitivity to honey bee venom will induce IL-10 production by T cells, decreased IgE, and increased IgG4 antibodies to venom antigens.


Recently, it has been shown that children raised in a house with a cat can produce an IgG response, including IgG4 antibody, without becoming allergic. A modified TH2 response (increased IgG4 and decreased IgE) therefore represents an important mechanism of tolerance to allergens (Fig. 23.7). IgG4 antibody responses without IgE antibody are a feature of immunity/tolerance to insect venom, rat urinary allergens, and food antigens as well as cat allergens.




Characteristics of allergens



Allergens have similar physical properties


In mice a wide range of proteins can be used to induce an IgE antibody response. The primary factors that influence the response are:



Thus, repeated low-dose immunization with alum or pertussis (but not complete Freund’s adjuvant) will produce IgE responses. However, the dose necessary to induce an optimal response varies greatly from one strain to another.


The allergens that have been defined have similar physical properties (i.e. freely soluble in aqueous solution with a molecular weight of 10–40 kDa), but are diverse biologically. Cloning has revealed sequence homology between allergens and proteins including calycins, pheromone binding proteins, enzymes, and pollen recognition proteins. Although many of the allergens have homology with known enzymes, this is not surprising because enzymic activity is an important property of proteins in general. Some important allergens, for example Der p2 from mites, Fel d1 from cats, and Amb a5 from ragweed pollen, have neither enzymic activity nor homology with known enzymes. Thus, enzymic activity is not essential for immunogenicity.


Nevertheless, the group I allergens of dust mites are cysteine proteases and in several model situations it has been shown that this enzymic activity influences the immunogenicity of the protein. Thus cleavage of CD23 or CD25 on lymphocytes by Der p1 can enhance immune responses. Alternatively, it has been shown that Der p1 can disrupt epithelial junctions and alter the entry of proteins through the epithelial layer. The interest in this property is increased because many different mite allergens are inhaled together in the fecal particles so the enzymic activity of one protein (i.e. Der p1) could facilitate either the physical entry or the immune response to other mite proteins.


The primary characterization of allergens relates to their route of exposure. The routes includes:



The routes are important because they define the ways in which the antigens are presented to the immune system. Antigen presentation may well be the site at which genetic influences play the biggest role, the properties of the different groups of allergen need to be considered separately.



The inhalant allergens cause hayfever, chronic rhinitis, and asthma


The inhalant allergens are the primary causal agents in hayfever, chronic rhinitis, and asthma among school-aged children and young adults and they play an important role in atopic dermatitis.


Allergens can only become airborne in sufficient quantity to cause an immune response or symptoms when they are carried on particles. Pollen grains, mite fecal particles, particles of fungal hyphae or spores, and animal skin flakes (or dander) are the best defined forms in which allergens are inhaled (Fig. 23.8).



In each case it is possible to define the approximate particle size and the quantity of protein on the particle as well as the speed with which the proteins in the particle dissolve in aqueous solution (see Fig. 23.3).


Thus, for grass pollen, mite fecal pellets, and cat dander:


Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Immediate Hypersensitivity (Type I)

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