Immunology_Janeway

Immunology_Janeway. Although allergic asthma is initially driven by a response to a specific allergen, the subsequent chronic inflammation seems to be perpetuated even in the apparent absence of ongoing exposure to allergen. The airways become characteristically hyperreactive, and factors other than antigen can trigger asthma attacks. Asthmatics characteristically show hyperresponsiveness to environmental chemical irritants such as cigarette smoke and sulfur dioxide. Viral agents, especially rhinovirus, or, to a smaller extent, bacterial respiratory tract infections can also exacerbate the disease. Both irritant agents and the infectious agents can induce IL-25 and IL-33 release from airway epithelial cells, leading to activation of ILC2s and exacerbation of the chronic asthmatic inflammation. The significance of viral augmentation of the asthmatic response is evident from the fact that rhinovirus infection is one of the main causes of hospitalizations for asthma and is associated with the majority of


Immunology_Janeway

Immunology_Janeway. of viral augmentation of the asthmatic response is evident from the fact that rhinovirus infection is one of the main causes of hospitalizations for asthma and is associated with the majority of deaths from asthma.


Immunology_Janeway

Immunology_Janeway. 14-12 Allergy to particular foods causes systemic reactions as well as symptoms limited to the gut. Adverse reactions to particular foods are common, but only some are due to an immune reaction. ‘Food allergy’ can be classified into IgE-mediated allergic reactions, non-IgE-mediated food allergy (celiac disease, discussed in Section 14-17), idiosyncrasies, and food intolerance. Idiosyncrasies are abnormal responses to particular foods whose cause is unknown but which can provoke symptoms resembling those of an allergic response. Food intolerances are nonimmune adverse reactions due mainly to metabolic deficits, such as intolerance of cow’s milk due to the inability to digest lactose.


Immunology_Janeway

Immunology_Janeway. IgE-mediated food allergies affect about 1–4% of American and European adults and are slightly more frequent in children (around 5%). About 25% of food allergy in children is due to peanuts, and peanut allergy is increasing in incidence. Figure 14.15 lists risk factors for developing IgE-mediated food allergy. IgE-mediated food allergy can manifest itself in a variety of ways, ranging from a swelling of the lips and oral tissue on contact with the allergen, to gastrointestinal cramping, diarrhea, or vomiting. Local gastrointestinal symptoms are due to activation of mucosal mast cells, leading to transepithelial fluid loss and smooth muscle contractions. Food allergens that subsequently reach the bloodstream can lead to urticaria, asthma, and, in the most severe cases, systemic anaphylaxis that can lead to cardiovascular collapse (see Section 14-10). Certain foods, most importantly peanuts, tree nuts, and shellfish, are particularly associated with severe anaphylaxis. Around 150 deaths


Immunology_Janeway

Immunology_Janeway. that can lead to cardiovascular collapse (see Section 14-10). Certain foods, most importantly peanuts, tree nuts, and shellfish, are particularly associated with severe anaphylaxis. Around 150 deaths occur each year in the United States as a result of a severe allergic reaction to food, with peanut and tree nut allergies accounting for most of the deaths. Peanut allergy is a significant public health problem, especially in schools, where children may be unwittingly exposed to peanuts, which are present in many foods. Recent studies offer hope for reducing the incidence of severe food allergy. In one study, infants with severe eczema who were at high risk for developing peanut allergy were randomly assigned either to be fed peanuts regularly, starting between ages 4 and 11 months, or to be on a peanut-avoidance diet for 5 years. At the age of 5, the children who had consumed peanuts showed more than a threefold reduction in the frequency of peanut allergy; the reduction was associated


Immunology_Janeway

Immunology_Janeway. on a peanut-avoidance diet for 5 years. At the age of 5, the children who had consumed peanuts showed more than a threefold reduction in the frequency of peanut allergy; the reduction was associated with decreased production of peanut-specific IgE. This suggests that deliberate introduction into the diet of allergen at the appropriate time to at-risk individuals may suppress the development of food allergy.


Immunology_Janeway

Immunology_Janeway. Of interest is that one of the characteristic features of food allergens is a high degree of resistance to digestion by pepsin in the stomach. This allows them to reach the mucosal surface of the small intestine as intact allergens. Cases of IgE-mediated food allergies arising in small numbers of previously unaffected adults who were taking antacids or proton-pump inhibitors for ulcers or acid reflux have been proposed to be due to impaired digestion of potential allergens in the less acidic stomach conditions produced by these medications. 14-13 IgE-mediated allergic disease can be treated by inhibiting the effector pathways that lead to symptoms or by desensitization techniques that aim at restoring biological tolerance to the allergen.


Immunology_Janeway

Immunology_Janeway. Most of the current drugs that are used to treat allergic disease either treat only the symptoms—examples of such drugs are antihistamines and β-agonists—or are general anti-inflammatory or immunosuppressive drugs such as the corticosteroids (Fig. 14.16). Treatment is largely palliative, rather than curative, and the drugs often need to be taken throughout life. Anaphylactic reactions are treated with epinephrine, which stimulates the re-formation of endothelial Fig. 14.16 Approaches to the treatment of allergic disease. Examples of treatments in current clinical use for allergic reactions are listed in the top half of the table, with approaches under investigation listed below.


Immunology_Janeway

Immunology_Janeway. tight junctions, promotes the relaxation of constricted bronchial smooth muscle, and stimulates the heart. Antihistamines that target the H1 receptor reduce the symptoms that follow the release of histamine from mast cells in allergic rhinoconjunctivitis and IgE-triggered urticaria. In urticaria, for example, the relevant H1 receptors include those on blood vessels and unmyelinated nerve fibers in the skin. Anticholinergic drugs bronchodilate constricted airways and reduce respiratory secretions. Antileukotriene drugs act as antagonists of leukotriene receptors on smooth muscle, endothelial cells, and mucous-gland cells, and are also used to relieve the symptoms of allergic rhinoconjunctivitis and asthma. Inhaled bronchodilators that act on β-adrenergic receptors to relax constricted muscle relieve acute asthma attacks. In chronic allergic disease it is extremely important to treat and prevent the chronic inflammatory injury to tissues, and regular use of inhaled corticosteroids is


Immunology_Janeway

Immunology_Janeway. relieve acute asthma attacks. In chronic allergic disease it is extremely important to treat and prevent the chronic inflammatory injury to tissues, and regular use of inhaled corticosteroids is now recommended in persistent asthma to help suppress inflammation. Topical corticosteroids are used to suppress the chronic inflammatory changes seen in eczema.


Immunology_Janeway

Immunology_Janeway. A new type of allergy suppressive therapy that is beginning to gain significant use is blockade of IgE function by treatment with monoclonal anti-IgE antibodies, omalizumab being an example. This antibody binds the Fc portion of IgE at the same site that binds the FcεRI on basophils and mast cells. The portion of the Fc domain of IgE that binds to the low-affinity IgE receptor (FcεRII) that is expressed on a variety of leukocytes other than basophils and mast cells is different from the domain that binds the high-affinity FcεRI; omalizumab by steric hindrance blocks binding of IgE to the low-affinity receptor as well as to FcεRI. Prevention of binding of IgE to its receptors on basophils results in downregulation of these receptors on these cells, making them less easily activated by exposure to allergens. Omalizumab also appears to act in chronic allergic asthma to reduce IgE-mediated antigen trapping and presentation by dendritic cells, thus preventing the activation of new


Immunology_Janeway

Immunology_Janeway. by exposure to allergens. Omalizumab also appears to act in chronic allergic asthma to reduce IgE-mediated antigen trapping and presentation by dendritic cells, thus preventing the activation of new allergen-specific TH2 cells. Altogether, these actions lead to suppression of the late-phase response to allergen challenge (see Section 14-9). The antibody is administered by subcutaneous injections once every 2 to 4 weeks. This treatment has been shown to be highly effective for patients with chronic urticaria and also appears to be effective in individuals with severe chronic asthma. Of special interest is that in studies of children with moderate to severe asthma who were treated for 4 years with omalizumab, most remained symptom free without any anti-asthma treatment, suggesting that the anti-IgE therapy modified the natural history of the disease.


Immunology_Janeway

Immunology_Janeway. Another, more routinely used approach that aims to permanently eliminate the allergic response is allergen desensitization. This form of immunotherapy aims to restore the patient’s ability to tolerate exposure to the allergen. Patients are desensitized by injection with escalating doses of allergen, starting with tiny amounts. The mechanism by which desensitization occurs is not definitively established, but for most successfully desensitized patients, the procedure results in a change in the antibody response from one that is IgE predominant to one dominated by an IgG subclass. Successful desensitization appears to depend on the induction of Treg cells secreting IL-10 and/or TGF-β, which skew the response away from IgE production (see Section 14-4). For example, beekeepers exposed to repeated stings (paralleling the therapeutic desensitization process) are often naturally protected from severe allergic reactions such as anaphylaxis through a mechanism that involves IL-10-secreting T


Immunology_Janeway

Immunology_Janeway. stings (paralleling the therapeutic desensitization process) are often naturally protected from severe allergic reactions such as anaphylaxis through a mechanism that involves IL-10-secreting T cells. Similarly, specific allergen immunotherapy for sensitivity to insect venom and airborne allergens induces the increased production of IL-10 and in some cases TGF-β, as well as the production of IgG isotypes, particularly IgG4, an isotype selectively promoted by IL-10. Recent evidence shows that desensitization is also associated with a reduction in the numbers of inflammatory cells at the site of the allergic reaction. A potential complication of the desensitization approach is that in spite of starting with extremely small doses of allergen, some patients can experience an IgE-mediated allergic response, sometimes including bronchospasms. Thus, many physicians feel that allergen immunotherapy is contraindicated in patients with severe asthma. For patients who experience resolution of


Immunology_Janeway

Immunology_Janeway. response, sometimes including bronchospasms. Thus, many physicians feel that allergen immunotherapy is contraindicated in patients with severe asthma. For patients who experience resolution of their allergy symptoms during allergen immunotherapy, weekly or every other week injections are continued for 3 years, and then the therapy is discontinued. In approximately half of patients treated in this fashion, symptoms do not recur following cessation of the injections. These patients experience durable ability to tolerate the allergen without symptoms. Recent studies suggest that administration of immunotherapy via the sublingual route is equally or more effective than administration by subcutaneous injection, offering the possibility of less expensive and perhaps more effective immunotherapy in the future.


Immunology_Janeway

Immunology_Janeway. When a patient is allergic to a drug that is essential for treatment of a disease (such as an antibiotic, insulin, or a chemotherapeutic agent), it is often possible to achieve a state of temporary acute desensitization by treating the individual with progressively increasing doses of the drug, starting at a very low dose that causes no allergic symptoms and increasing the dose every half hour until the therapeutic dose is reached. It is common for individuals undergoing drug desensitization to manifest mild to moderate allergic symptoms (itching, urticaria, mild wheezing) at some time during the procedure. If this occurs, the physician reduces the dose to the previous tolerated dose and then advances the dose again. This procedure is thought to lead to subclinical activation of mast cells and basophils that have been sensitized with IgE against the drug, inducing them to gradually release their intracellular mediators at a rate that does not cause severe symptoms; eventually all of


Immunology_Janeway

Immunology_Janeway. and basophils that have been sensitized with IgE against the drug, inducing them to gradually release their intracellular mediators at a rate that does not cause severe symptoms; eventually all of the cell-bound IgE is consumed by this process, leaving insufficient IgE available to cause an allergic reaction when subsequent therapeutic doses are administered. In order to maintain the desensitized state, the patient must receive daily therapeutic doses of the drug. If treatment is interrupted, then newly formed mast cells and basophils can be charged with newly secreted drug-specific IgE and can accumulate at levels sufficient to yield a new anaphylactic reaction.


Immunology_Janeway

Immunology_Janeway. An alternative, and still experimental, immunotherapy approach is a vaccination strategy using allergen coupled to oligodeoxynucleotides rich in unmethylated CpG. The oligonucleotide mimics the CpG motifs in bacterial DNA and strongly promotes TH1 responses while suppressing TH2 responses. This appears to be useful for chronic treatment of an antigen-specific allergic response, but is not effective for acute desensitization.


Immunology_Janeway

Immunology_Janeway. A further approach to the treatment of allergic disease may be to block the recruitment of eosinophils to sites of allergic inflammation. The eotaxin receptor CCR3 is a potential target in this context. In experimental animals, the production of eosinophils in bone marrow and their exit into the circulation is reduced by blocking IL-5 action. Anti-IL-5 antibody (mepolizumab) is of benefit in treating human patients with the hypereosinophilic syndrome, in which chronic overproduction of eosinophils causes severe organ damage. Clinical trials of anti-IL-5 treatment of asthma, however, show that, in practice, any beneficial effect is likely to be limited to a small subset of asthma patients with prednisone-dependent eosinophilic asthma; in these patients, IL-5 blockade seems to reduce the number of asthma attacks when the corticosteroid dose is reduced. Summary.


Immunology_Janeway

Immunology_Janeway. The allergic response to innocuous antigens reflects the pathophysiological aspects of a defensive immune response whose physiological role is to protect against helminth parasites. It is triggered by the binding of antigen to IgE antibodies bound to the high-affinity IgE receptor FcεRI on mast cells and basophils. Mast cells are strategically distributed beneath the mucosal surfaces of the body and in connective tissue. Antigen cross-linking the IgE on the surface of mast cells causes them to release large amounts of inflammatory mediators. The resulting inflammation can be divided into early events that are characterized by short-lived mediators such as histamine, and later events that involve leukotrienes, cytokines, and chemokines, which recruit and activate eosinophils, basophils, and other leukocytes. This response can evolve into chronic inflammation, which is characterized by the presence of effector T cells and eosinophils, and is most clearly seen in chronic allergic asthma.


Immunology_Janeway

Immunology_Janeway. Non-IgE-mediated allergic diseases. In this part of the chapter we focus on immunological hypersensitivity responses involving IgG antibodies and type 1 or type 3 immune responses that involve antigen-specific TH1 or TH17 cells or CD8 T cells. These effector arms of the immune response occasionally react with noninfectious antigens to produce acute or chronic allergic reactions. Although the mechanisms initiating the various forms of hypersensitivity are different, much of the pathology is due to the same immunological effector mechanisms. in susceptible individuals occur by binding of the drug to the surface of circulating blood cells.


Immunology_Janeway

Immunology_Janeway. in susceptible individuals occur by binding of the drug to the surface of circulating blood cells. Antibody-mediated destruction of red blood cells (hemolytic anemia) or platelets (thrombocytopenia) can be caused by some drugs, including the β-lactam antibiotics penicillin and cephalosporin. In these reactions, the drug binds covalently to the cell surface and is a target for anti-drug IgG antibodies that cause destruction of the cell. The anti-drug antibodies are made in only a minority of people, and it is not clear why these individuals make them. The cell-bound antibody triggers the clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen, which bear Fcγ receptors. can follow the administration of large quantities of poorly catabolized antigens.


Immunology_Janeway

Immunology_Janeway. can follow the administration of large quantities of poorly catabolized antigens. Hypersensitivity reactions can arise following treatment with soluble antigens such as animal antisera. The pathology is caused by the deposition of antigen:antibody aggregates, or immune complexes, in particular tissues and sites. Immune complexes are generated in all antibody responses, but their pathogenic potential is determined, in part, by their size and by the amount, affinity, and isotype of the responding antibody. Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocyte system. However, the small complexes that form when antigen is in excess tend to be deposited in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury.


Immunology_Janeway

Immunology_Janeway. A local hypersensitivity reaction called an Arthus reaction (Fig. 14.17) can be triggered in the skin of sensitized individuals who possess IgG antibodies against the sensitizing antigen. When antigen is injected into the skin, circulating IgG antibody that has diffused into the skin forms immune complexes locally. The immune complexes bind Fc receptors such as FcγRIII on mast cells and other leukocytes, generating a local inflammatory response and increased vascular permeability. Fluid and cells, especially polymorphonuclear leukocytes, then enter the site of inflammation from local blood vessels. The immune complexes also activate complement, leading to the production


Immunology_Janeway

Immunology_Janeway. C5a Local in˜ammation, increased ˜uid and protein release, phagocytosis, and blood vessel occlusion 1–2 hours Locally injected antigen in immune individual with IgG antibody Activation of Fc˜RIII on mast cells induces their degranulation Local immune-complex formation activates complement. C5a binds to and sensitizes the mast cell to respond to immune complexes


Immunology_Janeway

Immunology_Janeway. Fig. 14.17 The deposition of immune complexes in tissues activation of complement, and the complement component C5a causes a local inflammatory response known as an Arthus contributes to sensitizing the mast cell to respond to immune reaction. In individuals who have already made IgG antibody against complexes. As a result of mast-cell activation, inflammatory cells an antigen, the same antigen injected into the skin forms immune invade the site, and blood vessel permeability and blood flow are complexes with IgG antibody that has diffused out of the capillaries. increased. Platelets also accumulate inside the vessel at the site, Because the dose of antigen is low, the immune complexes are ultimately leading to vessel occlusion. If the reaction is severe, all formed only close to the site of injection, where they activate mast these changes can lead to tissue necrosis. cells bearing Fcγ receptors (FcγRIII). The immune complex induces of the complement fragment C5a. This is a key


Immunology_Janeway

Immunology_Janeway. site of injection, where they activate mast these changes can lead to tissue necrosis. cells bearing Fcγ receptors (FcγRIII). The immune complex induces of the complement fragment C5a. This is a key participant in the inflammatory reaction because it interacts with C5a receptors on leukocytes to activate these cells and attract them to the site of inflammation (see Section 2-5). Both C5a and FcγRIII have been shown to be required for the experimental induction of an Arthus reaction in the lung by macrophages in the walls of the alveoli, and they are probably required for the same reaction induced by mast cells in the skin and the synovial linings of joints. Recruitment and activation of C5a receptor-bearing leukocytes leads to tissue injury, sometimes resulting in frank necrosis.


Immunology_Janeway

Immunology_Janeway. A systemic reaction known as serum sickness can result from the injection of large quantities of a poorly catabolized foreign antigen. This illness was so named because it frequently followed the administration of therapeutic horse antiserum. In the pre-antibiotic era, antiserum made by immunizing horses with Streptococcus pneumoniae was often used to treat pneumococcal pneumonia; the specific anti-pneumococcal antibodies in the horse serum would help the patient to clear the infection. In much the same way, antivenin (serum from horses immunized with snake venoms) is still used today as a source of neutralizing antibodies to treat people suffering from the bites of poisonous snakes. Serum sickness occurs 7–10 days after the injection of horse serum, an inter Drug-induced Serum val that corresponds to the time required to mount an IgG-switched primary


Immunology_Janeway

Immunology_Janeway. Serum sickness occurs 7–10 days after the injection of horse serum, an inter Drug-induced Serum val that corresponds to the time required to mount an IgG-switched primary Sickness immune response against the foreign horse serum antigens. The clinical features of serum sickness are chills, fever, rash, arthritis, and sometimes glomerulonephritis (inflammation of the glomeruli of the kidneys). Urticaria is a prominent feature of the rash, implying a role for histamine derived from mast-cell degranulation. In this case, the mast-cell degranulation is triggered by the ligation of cell-surface FcγRIII by IgG-containing immune complexes and by the anaphylatoxins C3a and C5a released due to complement activation by these complexes. fever, vasculitis, arthritis, nephritisforeign serum injectionLevelinplasmaTime (days) foreign serum proteins antigen:antibody complexes antibody against foreign serum proteins


Immunology_Janeway

Immunology_Janeway. fever, vasculitis, arthritis, nephritisforeign serum injectionLevelinplasmaTime (days) foreign serum proteins antigen:antibody complexes antibody against foreign serum proteins Fig. 14.18 Serum sickness is a classic example of a transient immune complex-mediated syndrome. An injection of a foreign protein, such as horse antitoxin, leads to an anti-horse serum antibody response. These antibodies form immune complexes with the circulating foreign proteins. The complexes are deposited in small blood vessels and activate complement and phagocytes, inducing fever and inflammatory lesions in blood vessels in the skin and connective tissues (vasculitis), in the kidney (nephritis), and in joints (arthritis). All these effects are transient and resolve when the foreign protein is cleared.


Immunology_Janeway

Immunology_Janeway. The course of serum sickness is illustrated in Fig. 14.18. The onset of disease coincides with the development of antibodies against the abundant soluble proteins in the foreign serum; these antibodies form immune complexes with their antigens throughout the body. The immune complexes fix complement and can bind to and activate leukocytes bearing Fc and complement receptors; these leukocytes in turn cause widespread tissue damage. The formation of immune complexes causes clearance of the foreign antigen, so serum sickness is usually a self-limiting disease. Serum sickness after a second dose of antigen follows the kinetics of a secondary antibody response (see Section 10-14), with symptoms typically appearing within a day or two.


Immunology_Janeway

Immunology_Janeway. With the increasing clinical use of humanized monoclonal antibodies (such as anti-TNF-α used for the treatment of rheumatoid arthritis), cases of serum sickness are observed, fortunately rarely, in settings where the attempt to humanize the monoclonal antibody was not successful for selected patients because they produce uncommon Ig allotypes. In these individuals, symptoms are generally mild, and one of the most significant features of the anti-monoclonal antibody response is more rapid clearance of the antibody from the circulation, leading to reduction of its therapeutic effects.


Immunology_Janeway

Immunology_Janeway. Pathological immune-complex deposition is seen in other situations in which antigen persists. One is when an adaptive antibody response fails to clear the infecting pathogen, as occurs in subacute bacterial endocarditis or chronic viral hepatitis. In these situations, the replicating pathogen is continuously generating new antigen in the presence of a persistent antibody response, with the consequent formation of abundant immune complexes. These are deposited within small blood vessels and result in injury in many tissues and organs, including the skin, kidneys, and nerves.


Immunology_Janeway

Immunology_Janeway. Immune-complex disease also occurs when inhaled allergens provoke IgG rather than IgE antibody responses, perhaps because they are present at relatively high levels in the air. When a person is reexposed to high doses of such allergens, immune complexes form in the walls of alveoli in the lungs. This leads to the accumulation of fluid, protein, and cells in the alveolar wall, slowing blood:air exchange of O2 and CO2, compromising lung function. This type of reaction is more likely to occur in occupations such as farming, in which there is repeated exposure to hay dust or mold spores, and the resulting disease is known as farmer’s lung. If exposure to antigen is sustained, the lining of the lungs can be permanently damaged. 14-16 Hypersensitivity reactions can be mediated by TH1 cells and CD8 cytotoxic T cells.


Immunology_Janeway

Immunology_Janeway. Unlike the immediate hypersensitivity reactions, which are mediated by antibodies, cellular hypersensitivity reactions such as delayed-type hypersensitivity reactions are mediated by antigen-specific effector T cells. We have already seen the involvement of TH2 effector cells and the cytokines they produce in the chronic response of IgE-initiated allergic reactions. Here we consider the hypersensitivity diseases caused by TH1 and CD8 cytotoxic T cells (Fig. 14.19). These cells function in hypersensitivity in essentially the same way as when they respond to a pathogen (described in Chapter 9), and the responses can be transferred between experimental animals by purified T cells or cloned T-cell lines. Much of the chronic inflammation seen in some of the allergic diseases described earlier is due to cellular hypersensitivity reactions mediated by antigen-specific TH1 cells acting in concert with TH2 cells.


Immunology_Janeway

Immunology_Janeway. The prototypic delayed-type hypersensitivity reaction is the Mantoux test— the standard tuberculin test that is used to determine whether an individual has previously been infected with Mycobacterium tuberculosis. In the Mantoux test, small amounts of tuberculin—a complex extract of peptides and carbohydrates derived from M. tuberculosis—are injected intradermally. In people who have been exposed to the bacterium, either by infection or by immunization with the BCG vaccine (an attenuated form of M. tuberculosis), a local T-cell-mediated inflammatory reaction evolves over 24–72 hours. The response is caused by TH1 cells, which enter the site of antigen injection, recognize complexes of peptide:MHC class II molecules on antigen-presenting cells, and release inflammatory cytokines such as IFN-γ, TNF-α, and lymphotoxin. These stimulate the expression of adhesion molecules on endothelium and increase local blood vessel permeability, allowing plasma and accessory cells to enter the site,


Immunology_Janeway

Immunology_Janeway. IFN-γ, TNF-α, and lymphotoxin. These stimulate the expression of adhesion molecules on endothelium and increase local blood vessel permeability, allowing plasma and accessory cells to enter the site, thus causing a visible swelling (Fig. 14.20). Each of these phases takes several hours and so the fully developed response only appears 24–48 hours after challenge. The cytokines produced by the activated TH1 cells and their actions are shown in Fig. 14.21.


Immunology_Janeway

Immunology_Janeway. Very similar reactions are observed in allergic contact dermatitis (also called contact hypersensitivity), which is an immune-mediated local inflammatory reaction in the skin caused by direct skin contact with certain antigens. It is important to note that not all contact dermatitis is immune-mediated and allergic in nature; it can also be caused by direct damage to the skin by irritant or toxic chemicals. 24–72 hours A TH1 effector cell recognizes antigen and releases cytokines, which act on vascular endothelium Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion Antigen is injected into subcutaneous tissue and processed by local antigen-presenting cells


Immunology_Janeway

Immunology_Janeway. Fig. 14.19 Cellular hypersensitivity reactions. These responses are mediated by T cells and require 3–5 days or more to develop. They can be grouped into three syndromes, according to the route by which antigen passes into the body. In delayed-type hypersensitivity the antigen is injected into the skin; in contact hypersensitivity it is absorbed into the skin; and in gluten-sensitive enteropathy it is absorbed by the gut. In contact hypersensitivity, vesicles commonly form. They represent accumulations of fluid in small blister-like lesions at the level of the basement membrane between the dermis and epidermis. Their formation at this location is probably the result of antigen penetrating the epidermis, accumulating at the basement membrane, and inducing a local inflammatory response with edema fluid. DNFB (dinitrofluorobenzene) is a sensitizing agent that can cause contact hypersensitivity. MOVIE 14.1


Immunology_Janeway

Immunology_Janeway. MOVIE 14.1 Fig. 14.20 The stages of a delayed-type hypersensitivity reaction. The first phase involves uptake, processing, and presentation of the antigen by local antigen-presenting cells. In the second phase, TH1 cells that have been primed by a previous exposure to the antigen migrate into the site of injection and become activated. Because these specific cells are rare, and because there is little inflammation to attract cells into the site, it can take several hours for a T cell of the correct specificity to arrive. These cells release mediators that activate local endothelial cells, which recruit an inflammatory cell infiltrate dominated by macrophages and cause the accumulation of fluid, serum proteins, and more leukocytes, thus producing a visible lesion.


Immunology_Janeway

Immunology_Janeway. Antigen in the local tissues is internalized and processed by antigen-presenting cells and presented on MHC class II molecules. Antigen-specific TH1 cells that recognize the antigen:MHC complexes locally at the site of antigen injection release chemokines and cytokines that recruit macrophages and other leukocytes to the site. Antigen presentation by the newly recruited macrophages then amplifies the response. T cells can also affect local blood vessels through the release of TNF-α and lymphotoxin (LT), and stimulate the production of macrophages through the release of IL-3 and GM-CSF. TH1 cells activate macrophages through the release of IFN-γ and TNF-α, and kill macrophages and other sensitive cells through the cell-surface expression of the Fas ligand. Contact Sensitivity to Poison Ivy Fig. 14.21 The delayed-type hypersensitivity response is directed by chemokines and cytokines released by antigen-stimulated TH1 cells.


Immunology_Janeway

Immunology_Janeway. Contact Sensitivity to Poison Ivy Fig. 14.21 The delayed-type hypersensitivity response is directed by chemokines and cytokines released by antigen-stimulated TH1 cells. TNF-˜ and LT Chemokines lL-3/GM-CSFIFN-˛ Stimulate monocyte production by bone marrow stem cells Recruit macrophages and other leukocytes to site of antigen deposition Induces expression of vascular adhesion molecules. Activates macrophages, increasing release of infammatory mediators Cause local tissue destruction. Cooperate with IFN-˜to increase expression of adhesion molecules on local blood vessels Antigen is processed by tissue macrophages and stimulates TH1 cells cytokines cytotoxins chemokines TH1


Immunology_Janeway

Immunology_Janeway. Allergic contact dermatitis can be caused by the activation of CD4 or CD8 T cells, depending on the pathway by which the antigen is processed. Typical antigens that cause allergic contact dermatitis are highly reactive small molecules that can easily penetrate intact skin, especially if they cause itching that leads to scratching and its consequent injury to the skin barrier. These chemicals then react with self proteins, creating haptenated proteins that can be proteolytically processed in antigen-presenting cells to haptenated peptides capable of being presented by MHC molecules and recognized by T cells as foreign antigens. As with other allergic responses, there are two phases to a cutaneous allergic response: sensitization and elicitation. During the sensitization phase, Langerhans cells in the epidermis and dendritic cells in the dermis take up and process antigen, and migrate to regional lymph nodes, where they activate T cells (see Fig. 9.13) with the consequent production of


Immunology_Janeway

Immunology_Janeway. in the epidermis and dendritic cells in the dermis take up and process antigen, and migrate to regional lymph nodes, where they activate T cells (see Fig. 9.13) with the consequent production of memory T cells, which localize in the dermis. In the elicitation phase, a subsequent exposure to the sensitizing chemical leads to antigen presentation to memory T cells in the dermis, with the release of T-cell cytokines such as IFN-γ and IL-17. This stimulates the keratinocytes of the epidermis to release IL-1, IL-6, TNF-α, GM-CSF, the chemokine CXCL8, and the interferon-inducible chemokines CXCL11 (IP-9), CXCL10 (IP-10), and CXCL9 (Mig, a monokine induced by IFN-γ). These cytokines and chemokines enhance the inflammatory response by inducing the migration of monocytes into the lesion and their maturation into macrophages, and by attracting more T cells (Fig. 14.22).


Immunology_Janeway

Immunology_Janeway. The rash produced by contact with the poison ivy plant (Fig. 14.23) is a common example of allergic contact dermatitis in the United States and is caused by a CD8 T-cell response to urushiol oil (a mixture of pentadecacatechols) in the plant. These chemicals are lipid-soluble and so can cross the cell membrane and attach to intracellular proteins. The modified proteins are recognized by the immunoproteasome, and following cleavage, they are translocated into the endoplasmic reticulum and delivered to the cell surface bound to MHC class I molecules. CD8 T cells recognizing the peptides cause damage either by killing the eliciting cell or by secreting cytokines such as IFN-γ.


Immunology_Janeway

Immunology_Janeway. Fig. 14.22 Elicitation of a delayed-type hypersensitivity TH1 cells (which were primed in lymph nodes as a result of prior response to a contact-sensitizing agent. A contact-sensitizing antigen exposure). The activated TH1 cells then secrete cytokines agent is a small, highly reactive molecule that can penetrate intact such as IFN-γ that stimulate keratinocytes to secrete additional skin. It binds covalently as a hapten to a variety of endogenous cytokines and chemokines, which in turn attract monocytes and proteins, altering their structures so they become antigenic. These induce their maturation into activated tissue macrophages, further modified proteins are internalized, processed by Langerhans cells contributing to inflammatory lesions like those caused by poison ivy (the major antigen-presenting cells of skin), and presented to effector (see Fig. 14.23). NO, nitric oxide.


Immunology_Janeway

Immunology_Janeway. The ability of CD4 T cells to mediate contact hypersensitivity responses is established by experimental exposure to the strong sensitizing chemical picryl chloride. Picryl chloride modifies extracellular self proteins by haptenation. These haptenated proteins can then be proteolytically processed by APCs, yielding haptenated peptides that bind to self-MHC class II molecules and are recognized by TH1 cells. When sensitized TH1 cells recognize these complexes, they produce extensive inflammation by activating macrophages (see Fig. 14.22). Common clinical features of allergic contact hypersensitivity responses are erythema of the affected skin; development of a dermal and epidermal infiltrate consisting of monocytes, macrophages, lymphocytes, scant neutrophils, and mast cells; formation of intraepidermal abscesses; and vesicles (blisterlike collections of edema fluid between the dermis and epidermis).


Immunology_Janeway

Immunology_Janeway. Some insect proteins also elicit a delayed-type hypersensitivity response. One example of this in the skin is a severe reaction to mosquito bites. Instead of a small itchy bump, people allergic to proteins in mosquito saliva can develop an immediate hypersensitivity reaction such as urticaria and swelling or, much more rarely, anaphylactic shock (see Section 14-10). Some allergic individuals subsequently develop a delayed reaction (consisting of a late-phase response) that can include profound swelling that can involve an entire limb.


Immunology_Janeway

Immunology_Janeway. Contact hypersensitivity responses to divalent cations such as nickel have also been observed. These divalent cations can alter the conformation or the peptide binding of MHC class II molecules, and thus provoke a T-cell response. In humans, nickel can also bind to the receptor TLR-4 and produce a pro-inflammatory signal. Sensitization to nickel is widespread as a result of prolonged contact with nickel-containing items such as jewelry, buttons, and clothing fasteners, but some countries now have standards that specify that such products must have non-nickel coatings, and this is reducing the prevalence of nickel allergy in those countries.


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Immunology_Janeway. Finally, although this section has focused on the role of TH1 and cytotoxic T cells in inducing cellular hypersensitivity reactions, there is evidence that antibody and complement might also have a role. Mice deficient in B cells, antibody, or complement show impaired contact hypersensitivity reactions. In particular, IgM antibodies (produced in part by B1 cells), which activate the complement cascade, facilitate the initiation of these reactions. Fig. 14.23 Blistering skin lesions on the hand of a patient with allergic contact dermatitis caused by poison ivy. Photograph courtesy of R. Geha.


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Immunology_Janeway. Photograph courtesy of R. Geha. Fig. 14.24 The pathological features of celiac disease. Left: the surface of the normal small intestine is folded into fingerlike villi, which provide an extensive surface for nutrient absorption. Right: the local immune response against the food protein α-gliadin, a prominent component of wheat, oat, and barley gluten, leads to massive infiltration of the lamina propria (in the deeper, inner portion of the villi) with CD4 T cells, plasma cells, macrophages, and smaller numbers of other leukocytes, ultimately leading to destruction of the villi. In parallel, there is lengthening and increased mitotic activity in the underlying crypts, where new epithelial cells are produced. Because the villi contain all the mature epithelial cells that digest and absorb foodstuffs, their loss can result in life-threatening malabsorption and diarrhea. Photographs courtesy of Allan Mowat. 14-17 Celiac disease has features of both an allergic response and autoimmunity.


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Immunology_Janeway. Celiac disease is a chronic condition of the upper small intestine caused by an immune response directed at gluten, a complex of proteins present in wheat, oats, and barley. Elimination of gluten from the diet restores normal gut function, but to date no approach for desensitization to gluten has been developed, so gluten ingestion must be avoided throughout life. The pathology of celiac disease is characterized by the loss of the slender, fingerlike villi formed by the intestinal epithelium (a condition termed villous atrophy), together with an increase in the size of the sites in which epithelial cells are renewed (crypt hyperplasia) (Fig. 14.24). These pathological changes result in the loss of the mature epithelial cells that cover the villi and normally absorb and digest food, and are accompanied by severe inflammation of the intestinal wall, with increased numbers of T cells, macrophages, and plasma cells in the lamina propria, as well as increased numbers of lymphocytes in the


Immunology_Janeway

Immunology_Janeway. accompanied by severe inflammation of the intestinal wall, with increased numbers of T cells, macrophages, and plasma cells in the lamina propria, as well as increased numbers of lymphocytes in the epithelial layer. Gluten seems to be the only food component that provokes intestinal inflammation in this way, a property that reflects gluten’s ability to stimulate both innate and specific immune responses in genetically susceptible individuals. The incidence of celiac disease has increased fourfold in the past 60 years, correlating with changes in baking practice that include adding large amounts of extra gluten to dough to decrease the time required for the dough to rise and to improve the texture.


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Immunology_Janeway. Celiac disease shows an extremely strong genetic predisposition, with more than 95% of patients expressing the HLA-DQ2 class II MHC allele. In mono-zygotic twins, if one twin develops it, there is an 80% probability that the other will, but only a 10% concordance is observed in dizygotic twins. Nevertheless, most individuals expressing HLA-DQ2 do not develop celiac disease despite the almost universal presence of gluten in the Western diet. Thus, other genetic or environmental factors must make important contributions to susceptibility.


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Immunology_Janeway. Peptides naturally produced from gluten do not bind to MHC class II molecules FasIFN-˜An enzyme, tissue transglutaminase (tTG), modiÿes the peptides so they now can be processed and bind to the MHC class II molecules The bound peptide activates gluten-speciÿc CD4 T cells FasLtTGThe activated T cells can kill mucosal epithelial cells by binding Fas. They also secrete IFN-˜, which activates the epithelial cell to produce cytokines and chemokines that recruit other in°ammatory cells Fig. 14.25 Molecular basis of immune recognition of gluten in celiac disease. After the digestion of gluten by gut digestive enzymes, deamidation of epitopes by tissue transglutaminase renders the gluten more susceptible to being readily processed by local antigen-presenting cells, ultimately leading to its binding to HLA-DQ molecules and priming of the immune system.


Immunology_Janeway

Immunology_Janeway. Most evidence indicates that celiac disease requires the aberrant priming of IFN-γ-producing CD4 T cells by antigenic peptides present in α-gliadin, one of the major proteins in gluten. It is generally accepted that only a limited number of peptides can provoke an immune response leading to celiac disease. This is likely due to the unique structure of the peptide-binding groove of the HLA-DQ2 molecule. The key step in the immune recognition of α-gliadin is the deamidation of its peptides by the enzyme tissue transglutaminase (tTG), which converts selected glutamine residues to negatively charged glutamic acid. Only peptides containing negatively charged residues in certain positions bind strongly to HLA-DQ2, and thus the transamination reaction promotes the formation of peptide:HLA-DQ2 complexes, which can activate antigen-specific CD4 T cells (Fig. 14.25). Activated gliadin-specific CD4 T cells accumulate in the lamina propria, producing IFN-γ, a cytokine that when present in this


Immunology_Janeway

Immunology_Janeway. complexes, which can activate antigen-specific CD4 T cells (Fig. 14.25). Activated gliadin-specific CD4 T cells accumulate in the lamina propria, producing IFN-γ, a cytokine that when present in this location leads to intestinal inflammation.


Immunology_Janeway

Immunology_Janeway. Celiac disease is entirely dependent on the presence of the foreign antigen, gluten. It is not associated with a specific immune response against self antigens in the tissue—the intestinal epithelium—that is damaged during the immune response. Thus, celiac disease is not a classical autoimmune disease. But it does have some features of autoimmunity. Autoantibodies against tissue transglutaminase are found in all patients with celiac disease; indeed, the presence of serum IgA antibodies against this enzyme is used as a sensitive and specific test for the disease. Interestingly, no tTG-specific T cells have been found, and it has been proposed that gluten-reactive T cells provide help to B cells that are reactive to tissue transglutaminase. In support of this hypothesis, gluten can complex with the enzyme and therefore could be taken up and presented by tTG-reactive B cells (Fig. 14.26). There is no evidence, however, that these autoantibodies contribute directly to tissue damage.


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Immunology_Janeway. Fig. 14.26 A hypothesis to explain antibody production against tissue transglutaminase (tTG) in the absence of T cells specific for tTG in celiac patients. tTG-reactive B cells endocytose gluten–tTG complexes and present gluten peptides to the gluten-specific T cells. The stimulated T cells can now provide help to these B cells, which produce autoantibodies against tTG. Gluten peptides activate mucosal epithelial cells to express MIC molecules MIC IL1R IL1 NKG2D CD8 T cell (IEL) Intraepithelial lymphocytes (IELs) express NKG2D, which binds to MIC molecules and activates the IELs to kill the epithelial cell


Immunology_Janeway

Immunology_Janeway. Fig. 14.27 The activation of cytotoxic T cells by the innate immune system in celiac disease. Gluten peptides can induce the expression of the MHC class Ib molecules MIC-A and MIC-B on gut epithelial cells and the synthesis and release of IL-1 from these cells. Intraepithelial lymphocytes (IELs), many of which are CD8 cytotoxic T cells, recognize the MIC proteins via the receptor NKG2D, which, together with the co-stimulator IL-1, activates the IELs to kill the MIC-bearing cells, leading to destruction of the gut epithelium.


Immunology_Janeway

Immunology_Janeway. Chronic T-cell responses against food proteins are normally prevented by the development of oral tolerance (see Section 12-18). Why this breaks down in patients with celiac disease is unknown. The properties of the HLA-DQ2 molecule provide a partial explanation, but there must be additional factors because most HLA-DQ2-positive individuals do not develop celiac disease, and the high concordance rates in monozygotic twins indicate a role for additional genetic factors. The incidence of celiac disease is especially high in individuals with trisomy 21 (Down syndrome), approximately sixfold higher than in the normal population, underscoring the impact of genetic factors on disease prevalence. Polymorphisms in the gene for CTLA-4 or in other immunoregulatory genes have been suggested to be associated with susceptibility. There could also be differences in how individuals digest gliadin in the intestine, so that differing amounts survive for deamidation and presentation to T cells.


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Immunology_Janeway. The gluten protein also seems to have several properties that contribute to pathogenesis. As well as its relative resistance to digestion, there is mounting evidence that some gliadin-derived peptides stimulate the innate immune system by inducing the release of IL-15 by intestinal epithelial cells. This process is antigen-nonspecific and involves peptides that cannot be bound by HLA-DQ2 molecules or recognized by CD4 T cells. IL-15 release leads to the activation of dendritic cells in the lamina propria, as well as the upregulation of MIC-A expression by epithelial cells. CD8 T cells in the mucosal epithelium can be activated via their NKG2D receptors, which recognize MIC-A, and they can kill MIC-A-expressing epithelial cells via these same NKG2D receptors (Fig. 14.27). Triggering of these innate immune responses by α-gliadin may create some intestinal damage on its own and also induce some of the co-stimulatory events necessary for initiating an antigen-specific CD4 T-cell response


Immunology_Janeway

Immunology_Janeway. innate immune responses by α-gliadin may create some intestinal damage on its own and also induce some of the co-stimulatory events necessary for initiating an antigen-specific CD4 T-cell response to other parts of the α-gliadin molecule. The ability of gluten to stimulate both innate and adaptive immune responses may thus explain its unique ability to induce celiac disease.


Immunology_Janeway

Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Non-IgE-mediated immunological hypersensitivity reflects normal immune mechanisms that are inappropriately directed against innocuous antigens or inflammatory stimuli. It comprises both immediate-type and delayed-type reactions. Immediate-type reactions are due to the binding of specific IgG antibodies to allergen-modified cell surfaces, as in drug-induced hemolytic anemia, or to the formation of immune complexes of antibodies bound to poorly catabolized antigens, as occurs in serum sickness. Cellular hypersensitivity reactions mediated by TH1 cells and cytotoxic T cells develop more slowly than immediate-type reactions. The TH1-mediated hypersensitivity reaction in the skin provoked by mycobacterial tuberculin is used to diagnose previous exposure to Mycobacterium tuberculosis. The allergic reaction to poison ivy is due to the recognition and destruction by cytotoxic T cells of skin cells modified by a plant molecule, and to cytotoxic T-cell cytokines. These T-cell-mediated responses


Immunology_Janeway

Immunology_Janeway. reaction to poison ivy is due to the recognition and destruction by cytotoxic T cells of skin cells modified by a plant molecule, and to cytotoxic T-cell cytokines. These T-cell-mediated responses require the induced synthesis of effector molecules and develop over 1–10 days.


Immunology_Janeway

Summary to Chapter 14.

Immunology_Janeway. Summary to Chapter 14.


Immunology_Janeway

Immunology_Janeway. In susceptible individuals, immune responses to otherwise innocuous antigens can produce allergic reactions upon reexposure to the same antigen. Most allergic reactions involve the production of IgE antibody against common environmental allergens. Some people are intrinsically prone to making IgE antibodies against many allergens, and such people are said to be atopic. IgE production is driven by antigen-specific TH2 cells; the response is skewed toward TH2 by an array of chemokines and cytokines that engage specific signaling pathways, including signals that activate ILC2 cells in submucosal tissues at sites of antigen entry. The IgE produced binds to the high-affinity IgE receptor FcεRI on mast cells and basophils. Specific effector T cells, mast cells, and eosinophils, in combination with TH1 and TH2 cytokines and chemokines, orchestrate chronic allergic inflammation, which is the major cause of the chronic morbidity of asthma. Failure to regulate these responses can occur at many


Immunology_Janeway

Immunology_Janeway. TH1 and TH2 cytokines and chemokines, orchestrate chronic allergic inflammation, which is the major cause of the chronic morbidity of asthma. Failure to regulate these responses can occur at many levels of the immune system, including defects in regulatory T cells. Increasingly successful processes for suppressing allergic responses and reestablishing the ability to tolerate the sensitizing antigen are being developed, raising the hope of reducing the prevalence of allergic disorders. Antibodies of certain isotypes and various antigen-specific effector T cells contribute to allergic hypersensitivity to other antigens.


Immunology_Janeway

Immunology_Janeway. Questions. 14.1 True or False: Only TH2 cells can initiate the chain of signals needed to induce B cells to class-switch to IgE. 14.2 Multiple Choice: Which of the following has not been associated with genetic susceptibility to both allergic asthma and atopic eczema? A. β subunit of FcεRI B. GM-CSF C. IL-3 D. IL-4 E. IFN-γ 14.3 Different factors affect our susceptibility to allergic diseases. Which of the following is a false statement? A. Environmental factors rarely contribute to the development of allergic disease. B. The prevalence of atopy has been steadily increasing in the developed world. C. Individuals with variant alleles of GSTP1 and GSTM1 have higher susceptibility to increased airway hyperactivity. D. Children less than 6 months old who are exposed to other children in day care appear to be partially protected against asthma. 14.4 True or False: Like other antibodies, IgE is mainly found in body fluids.


Immunology_Janeway

Immunology_Janeway. 14.4 True or False: Like other antibodies, IgE is mainly found in body fluids. 14.5 Matching: Match the following options with the best 14.6 Which of the following statements is true? A. Connective tissue mast cells do not participate in the initiation of an anaphylactic reaction. B. Epinephrine should be avoided in patients suffering from anaphylactic shock as it may worsen the patient’s condition. C. During anaphylactic shock, blood vessels lose permeability, and high blood pressure leads to death. D. Penicillin can modify self proteins, causing an immune response with IgE production in some individuals that can lead to anaphylaxis upon re-encountering the drug. 14.7 Multiple Choice: Hypersensitivity reactions can cause pathology through the deposition of immune complexes. Which of the following is a mechanism by which immune complexes can be pathogenic? (More than one may apply.) ___ A. Immune complexes deposit in blood vessel walls.


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Immunology_Janeway. ___ B. IgE is cross-linked on the surface of mast cells and basophils, leading to activation. ___ C. Fc receptor ligation leads to leukocyte activation and tissue injury. ___ D. The complement system is activated, leading to the production of anaphylatoxin C5a. ___ E. CD8+ T cells are stimulated to secrete IL-4. 14.8 Fill-in-the-Blanks: There are two phases to a cutaneous allergic response: ______ and ______. The first phase is characterized by activation of T cells by skin antigen-presenting cells called _________, while the second phase invokes release of chemokines and cytokines by __________ upon subsequent antigen exposure. 14.9 Matching: Match each allergic reaction with the corresponding immune process.


Immunology_Janeway

Immunology_Janeway. 14.9 Matching: Match each allergic reaction with the corresponding immune process. ___ A. Arthus reaction i. Formation of local immune complexes caused by IgG antibodies acting against an antigen in previously sensitized individuals ___ B. Poison ivy rash ii. Systemic reaction to injection of large quantities of foreign antigen, primarily IgG-mediated 14.10 Multiple Choice: Which of the following is a false statement? A. The tuberculin test illustrates the prototypic delayed-type hypersensitivity reaction. B. TH1 cells are not directly involved in delayed-type hypersensitivity reactions. General references. Fahy, J.V.: Type 2 inflammation in asthma – present in most, absent in many. Nat. Rev. Immunol. 2015, 15:57–65. Holgate, S.T.: Innate and adaptive immune responses in asthma. Nat. Med. 2012, 18:673–683.


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Immunology_Janeway. Holgate, S.T.: Innate and adaptive immune responses in asthma. Nat. Med. 2012, 18:673–683. Johansson, S.G., Bieber, T., Dahl, R., Friedmann, P.S., Lanier, B.Q., Lockey, R.F., Motala, C., Ortega Martell, J.A., Platts-Mills, T.A., Ring, J., et al.: Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 2004, 113:832–836. Kay, A.B.: Allergy and allergic diseases. First of two parts. N. Engl. J. Med. 2001, 344:30–37. Kay, A.B.: Allergy and allergic diseases. Second of two parts. N. Engl. J. Med. 2001, 344:109–113. Valenta, R., Hochwallner, H., Linhart, B., and Pahr, S.: Food Allergies: the basics. Gastroenterology 2015, 148:1120-1131. Section references. 14-1 Sensitization involves class switching to IgE production on first contact with an allergen.


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Immunology_Janeway. Section references. 14-1 Sensitization involves class switching to IgE production on first contact with an allergen. Akuthota, P., Wang, H., and Weller, P.F.: Eosinophils as antigen-presenting cells in allergic upper airway disease. Curr. Opin. Allergy Clin. Immunol. 2010, 10:14–19. Berkowska, M.A., Heeringa, J.J., Hajdarbegovic, E., van der Burg, M., Thio, H.B., van Gahen, P.M., Boon, L., Orfao, A., van Dongen, J.J.M, and van Zelm, M.C.: Human IgE+B cells are derived from T cell-dependent and T cell-independent pathways. J. Allergy Clin. Immunol. 2014, 134:688–697. Bieber T: The pro-and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (FcεRI). Immunobiology 2007, 212:499–503.


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Immunology_Janeway. Bieber T: The pro-and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (FcεRI). Immunobiology 2007, 212:499–503. Gold, M.J., Antignano, F., Halim, T.Y.F., Hirota, J.A., Blanchet, M.-R., Zaph, C., Takei, F., and McNagny, K.M.: Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J. Allergy Clin. Immunol. 2014, 133:1142–1148. He, J.S., Narayanan, S., Subramaniam, S., Ho, W.Q., Lafaille, J.J., and Curotto de Lafaille, M.A.: Biology of IgE production: IgE cell differentiation and the memory of IgE responses. Curr. Opin. Microbiol. Immunol. 2015, 388:1–19. Kumar, V.: Innate lymphoid cells: new paradigm in immunology of inflammation. Immunol. Lett. 2014, 157:23–37. C. Allergic contact dermatitis can be mediated by CD4 or CD8 T cells. D. Mice deficient in B cells or complement have impaired contact hypersensitivity reactions.


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Immunology_Janeway. C. Allergic contact dermatitis can be mediated by CD4 or CD8 T cells. D. Mice deficient in B cells or complement have impaired contact hypersensitivity reactions. 14.11 Short Answer: Describe the perceived need for the endotyping system for asthma. 14.12 True or False: Allergic asthma can be triggered by factors other than the initial specific allergen. Mikhak, Z., and Luster, A.D.: The emergence of basophils as antigen-presenting cells in Th2 inflammatory responses. J. Mol. Cell Biol. 2009, 1:69–71. Mirchandani, A.S., Salmond, R.J., and Liew, F.Y.: Interleukin-33 and the function of innate lymphoid cells. Trends Immunol. 2012, 33:389–396. Platzer, B., Baker, K., Vera, M.P., Singer, K., Panduro, M., Lexmond, W.S., Turner, D., Vargas, S. O., Kinet, J.-P., Maurer, D., et al.: Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites. Mucosal Immunol. 2015, 8:516–532.


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Immunology_Janeway. Spencer, L.A., and Weller, P.F.: Eosinophils and Th2 immunity: contemporary insights. Immunol. Cell Biol. 2010, 88:250–256. Wu, L.C., and Zarrin, A.A.: The production and regulation of IgE by the immune system. Nat. Rev. Immunol. 2014, 14:247-259. 14-2 Although many types of antigens can cause allergic sensitization, proteases are common sensitizing agents. Alvarez, D., Arkinson, J.L., Sun, J., Fattouh, R., Walker, T., and Jordana, M.: TH2 differentiation in distinct lymph nodes influences the site of mucosal TH2 immune-inflammatory responses. J. Immunol. 2007, 179:3287–3296. Brown, S.J., and McLean, W.H.I.: One remarkable molecule: Filaggrin. J. Invest. Dermatol. 2012, 132:751–762. Grunstein, M.M., Veler, H., Shan, X., Larson, J., Grunstein, J.S., and Chuang, S.: Proasthmatic effects and mechanisms of action of the dust mite allergen, Der p 1, in airway smooth muscle. J. Allergy Clin. Immunol. 2005, 116:94–101.


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Immunology_Janeway. Lambrecht, B.N., and Hammad, H.: Allergens and the airway epithelium response: gateway to allergic sensitization. J. Allergy Clin. Immunol. 2014, 134:499–507. Nordlee, J.A., Taylor, S.L., Townsend, J.A., Thomas, L.A., and Bush, R.K.: Identification of a Brazil-nut allergen in transgenic soybeans. N. Engl. J. Med. 1996, 334:688–692. Papzian, D., Wagtmann, V.R., Hansen, S., and Wurtzen, P.A.: Direct contact between dendritic cells and bronchial epithelial cells inhibits T cell recall responses towards mite and pollen allergen extracts in vitro. Clin. Exp. Immunol. 2015, 181:207–218. Sehgal, N., Custovic, A., and Woodcock, A.: Potential roles in rhinitis for protease and other enzymatic activities of allergens. Curr. Allergy Asthma Rep. 2005, 5:221–226.


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Immunology_Janeway. Sehgal, N., Custovic, A., and Woodcock, A.: Potential roles in rhinitis for protease and other enzymatic activities of allergens. Curr. Allergy Asthma Rep. 2005, 5:221–226. Sprecher, E., Tesfaye-Kedjela, A., Ratajczak, P., Bergman, R., and Richard, G.: Deleterious mutations in SPINK5 in a patient with congenital ichthyosiform erythroderma: molecular testing as a helpful diagnostic tool for Netherton syndrome. Clin. Exp. Dermatol. 2004, 29:513–517. Wan, H., Winton, H.L., Soeller, C., Tovey, E.R., Gruenert, D.C., Thompson, P.J., Stewart, G.A., Taylor, G.W., Garrod, D.R., Cannell, M.B., et al.: Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Invest. 1999, 104:123–133. 14-3 Genetic factors contribute to the development of IgE-mediated allergic disease. Cookson, W.: The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat. Rev. Immunol. 2004, 4:978–988.


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Immunology_Janeway. Cookson, W.: The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat. Rev. Immunol. 2004, 4:978–988. Illing, P.R., Vivian, J.P., Purcell, A.W., Rossjohn, J., and McCluskey J.: Human leukocyte antigen-associated drug hypersensitivity. Curr. Opin. Immunol. 2013, 25:81–89. Li, Z., Hawkins, G.A., Ampleford, E.J., Moore, W.C., Li, H., Hastie, A.T., Howard, T.D., Boushey H.A., Busse, W.W., Calhoun, W.J., et al.: Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. J. Allergy Clin. Immunol. 2013, 132:313–320. Peiser, M.: Role of TH17 cells in skin inflammation of allergic contact dermatitis. Clin. Dev. Immunol. 2013, doi:10.1155/2013/261037.


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Immunology_Janeway. Peiser, M.: Role of TH17 cells in skin inflammation of allergic contact dermatitis. Clin. Dev. Immunol. 2013, doi:10.1155/2013/261037. Thyssen, J.P., Carlsen, B.C., Menné, T., Linneberg, A., Nielsen, N.H., Meldgaard, M., Szecsi, P.B., Stender, S., and Johansen, J.D.: Filaggrin null-mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study. Br. J. Dermatol. 2010, 163:115–120. Van den Oord, R.A.H.M., and Sheikh, A.: Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 2009, 339:b2433. Van Eerdewegh, P., Little, R.D., Dupuis, J., Del Mastro, R.G., Falls, K., Simon, J., Torrey, D., Pandit, S., McKenny, J., Braunschweiger, K., et al.: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002, 418:426–430.


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Immunology_Janeway. Weiss, S.T., Raby, B.A., and Rogers, A.: Asthma genetics and genomics. Curr. Opin. Genet. Dev. 2009, 19:279–282. 14-4 Environmental factors may interact with genetic susceptibility to cause allergic disease. Culley, F.J., Pollott, J., and Openshaw, P.J.: Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J. Exp. Med. 2002, 196:1381–1386. Deshane, J., Zmijewski, J.W., Luther, R., Gaggar, A., Deshane, R., Lai, J.F., Xu, X., Spell, M., Estell, K., Weaver, C.T., et al.: Free radical-producing myeloid-derived regulatory cells: potent activators and suppressors of lung inflammation and airway hyperresponsiveness. Mucosal Immunol. 2011, 4:503–518. Fuchs, C., and von Mutius, E.: Prenatal and childhood infections: implications for the development and treatment of childhood asthma. Lancet Respir. Med. 2013, 1:743–754. Harb, H., and Renz, H.: Update on epigenetics in allergic disease. J. Allergy Clin. Immunol. 2015, 135:15–24.


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Immunology_Janeway. Harb, H., and Renz, H.: Update on epigenetics in allergic disease. J. Allergy Clin. Immunol. 2015, 135:15–24. Huang, L., Baban, B., Johnson, B.A. 3rd, and Mellor, A.L.: Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int. Rev. Immunol. 2010, 29:133–155. Meyers, D.A., Bleecker, E.R., Holloway, J.W., and Holgate, S.T.: Asthma genetics and personalized medicine. Lancet Respir. Med. 2014, 2:405–415. Minelli, C., Granell, R., Newson, R., Rose-Zerilli, M.-J., Torrent, M., Ring, S.M., Holloway, J.W., Shaheen, S.O., and Henderson, J.A.: Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data. Int. J. Epidemiol. 2010, 39:539–562. Morahan, G., Huang, D., Wu, M., Holt, B.J., White, G.P., Kendall, G.E., Sly, P.D., and Holt, P.G.: Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 2002, 360:455–459.


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Immunology_Janeway. Romieu, I., Ramirez-Aguilar, M., Sienra-Monge, J.J., Moreno-Macías, H., del Rio-Navarro, B.E., David, G., Marzec, J., Hernández-Avila, M., and London, S.: GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur. Respir. J. 2006, 28:953–959. Saxon, A., and Diaz-Sanchez, D.: Air pollution and allergy: you are what you breathe. Nat. Immunol. 2005, 6:223–226. von Mutius, E.: Allergies, infections and the hygiene hypothesis -the epidemiologic evidence. Immunobiology 2007, 212:433-439. 14-5 Regulatory T cells can control allergic responses. Bohm, L., Meyer-Martin, H., Reuter, S., Finotto, S., Klein, M., Schild, H., Schmitt, E., Bopp, T., and Taube, C.: IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma. J. Immunol. 2015, 194:887–897. Duan, W., and Croft, M.: Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann. Am. Thorac. Soc. 2014, 11 Suppl 5:S305–S313.


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Immunology_Janeway. Duan, W., and Croft, M.: Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann. Am. Thorac. Soc. 2014, 11 Suppl 5:S305–S313. Hawrylowicz, C.M.: Regulatory T cells and IL-10 in allergic inflammation. J. Exp. Med. 2005, 202:1459–1463. Lin, W., Truong, N., Grossman, W.J., Haribhai, D., Williams, C.B., Wang, J., Martin, M.G., and Chatila, T.A.: Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J. Allergy Clin. Immunol. 2005, 116:1106–1115. Mellor, A.L., and Munn, D.H.: IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 2004, 4:762–774. 14-6 Most IgE is cell-bound and engages effector mechanisms of the immune system by pathways different from those of other antibody isotypes. Conner, E.R., and Saini, S.S.: The immunoglobulin E receptor: expression and regulation. Curr. Allergy Asthma Rep. 2005, 5:191–196.


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Immunology_Janeway. Conner, E.R., and Saini, S.S.: The immunoglobulin E receptor: expression and regulation. Curr. Allergy Asthma Rep. 2005, 5:191–196. Gilfillan, A.M., and Tkaczyk, C.: Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol. 2006, 6:218–230. Mcglashan, D.W., Jr.: IgE-dependent signalling as a therapeutic target for allergies. Trends Pharmacol. Sci. 2012, 33:502–509. Suzuki, R., Scheffel, J., and Rivera, J.: New insights on the signalling and function of the high-affinity receptor for IgE. Curr. Top. Microbiol.Immunol. 2015, 388:63–90. 14-7 Mast cells reside in tissues and orchestrate allergic reactions. Eckman, J.A., Sterba, P.M., Kelly, D., Alexander, V., Liu, M.C., Bochner, B.S., MacGlashan, D.W., and Saini, S.S.: Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J. Allergy Clin. Immunol. 2010, 125:889–895.


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Immunology_Janeway. Galli, S.J., Nakae, S., and Tsai, M.: Mast cells in the development of adaptive immune responses. Nat. Immunol. 2005, 6:135–142. Gonzalez-Espinosa, C., Odom, S., Olivera, A., Hobson, J.P., Martinez, M.E., Oliveira-Dos-Santos, A., Barra, L., Spiegel, S., Penninger, J.M., and Rivera, J.: Preferential signaling and induction of allergy-promoting lymphokines upon weak stimulation of the high affinity IgE receptor on mast cells. J. Exp. Med. 2003, 197:1453–1465. Islam, S.A., and Luster, A.D.: T cell homing to epithelial barriers in allergic disease. Nat. Med. 2012, 18:705-715. Kitamura, Y., Oboki, K., and Ito, A.: Development of mast cells. Proc. Jpn Acad, Ser. B 2007, 83:164–174. Kulka, M., Sheen, C.H., Tancowny, B.P., Grammer, L.C., and Schleimer, R.P.: Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2007, 123:398–410. Metcalfe, D.: Mast cells and mastocytosis. Blood 2007, 112:946–956.


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Immunology_Janeway. Bousquet, J., Jeffery, P.K., Busse, W.W., Johnson, M., and Vignola, A.M.: Asthma. From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2000, 161:1720–1745. Boxall, C., Holgate, S.T., and Davies, D.E.: The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma. Eur. Respir. J. 2006, 27:208–229. Dakhama, A., Park, J.W., Taube, C., Joetham, A., Balhorn, A., Miyahara, N., Takeda, K., and Gelfand, E.W.: The enhancement or prevention of airway hyper-responsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production. J. Immunol. 2005, 175:1876–1883. Finotto, S., Neurath, M.F., Glickman, J.N., Qin, S., Lehr, H.A., Green, F.H., Ackerman, K., Haley, K., Galle, P.R., Szabo, S.J., et al.: Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 2002, 295:336–338.


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Immunology_Janeway. George, B.J., Reif, D.M., Gallagher, J.E., Williams-DeVane, C.R., Heidenfelder, B.L., Hudgens, E.E., Jones, W., Neas, L., Cohen Hubal, E.A., and Edwards, S.W.: Data-driven asthma endotypes defined from blood biomarker and gene expression data. PLoS ONE 2015, 10:e0117445. Gour, N., and Wills-Karp, M.: IL-4 and IL-13 signaling in allergic airway disease. Cytokine 2015, 75:68-78. Haselden, B.M., Kay, A.B., and Larche, M.: Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J. Exp. Med. 1999, 189:1885–1894. Kuperman, D.A., Huang, X., Koth, L.L., Chang, G.H., Dolganov, G.M., Zhu, Z., Elias, J.A., Sheppard, D., and Erle, D.J.: Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 2002, 8:885–889.


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Immunology_Janeway. Lambrecht, B.N., and Hammad, H.: The role of dendritic and epithelial cells as master regulators of allergic airway inflammation. Lancet 2010, 376:835–843. Lloyd, C.M., and Hawrylowicz, C.M.: Regulatory T cells in asthma. Immunity 2009, 31:438–449. Lotvall, J., Akdis, C.A., Bacharier, L.B., Bjermer, L., Casale, T.B., Custovic, A., Lemanske, R.F., Jr., Wardlaw, A.J., Wenzel, S.E., and Greenberger, P.A.: Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 2011, 127:355–360. Meyer, E.H., DeKruyff, R.H., and Umetsu, D.T.: T cells and NKT cells in the pathogenesis of asthma. Annu. Rev. Med. 2008, 59:281–292. Newcomb, D.C., and Peebles, R.S., Jr.: Th17-mediated inflammation in asthma. Curr. Opin. Immunol. 2013, 25:755-760. Peebles, R.S. Jr.: The emergence of group 2 innate lymphoid cells in human disease. J. Leukoc. Biol. 2015, 97:469–475.


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Immunology_Janeway. Peebles, R.S. Jr.: The emergence of group 2 innate lymphoid cells in human disease. J. Leukoc. Biol. 2015, 97:469–475. Robinson, D.S.: Regulatory T cells and asthma. Clin. Exp. Allergy 2009, 39:1314–1323. Yan, X., Chu, J.-H., Gomez, J., Koenigs, M., Holm, C., He, X., Perez, M.F., Zhao, H., Mane, S., Martinez, F.D., et al.: Non-invasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma. Am. J. Respir. Crit. Care Med. 2015, 191:1116–1125. 14-12 Allergy to particular foods causes systemic reactions as well as symptoms limited to the gut. Du Toit, G., Robert, G., Sayre, P.H., Bahnson, H.T., Radulovic, S., Santos, A.D., Brough, H.A., Phippard, D., Basting, M., Feeney, M., et al.: Randomized trial of peanut consumption in infants at risk for peanut allergy. N. Engl. J. Med. 2015, 372:803–813. Lee, L.A., and Burks, A.W.: Food allergies: prevalence, molecular characterization, and treatment/prevention strategies. Annu. Rev. Nutr. 2006, 26:539–565.


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Immunology_Janeway. Lee, L.A., and Burks, A.W.: Food allergies: prevalence, molecular characterization, and treatment/prevention strategies. Annu. Rev. Nutr. 2006, 26:539–565. 14-13 IgE-mediated allergic disease can be treated by inhibiting the effector pathways that lead to symptoms or by desensitization techniques that aim at restoring biological tolerance to the allergen. Akdis, C.A., and Akdis, M.: Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ. J. 2015, 8:17. Bryan, S.A., O’Connor, B.J., Matti, S., Leckie, M.J., Kanabar, V., Khan, J., Warrington, S.J., Renzetti, L., Rames, A., Bock, J.A., et al.: Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000, 356:2149–2153. Dunn, R.M., and Wechsler, M.E.: Anti-interleukin therapy in asthma. Clin. Pharmacol. Ther. 2015, 97:55–65.


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Immunology_Janeway. Dunn, R.M., and Wechsler, M.E.: Anti-interleukin therapy in asthma. Clin. Pharmacol. Ther. 2015, 97:55–65. Haldar, P., Brightling, C.E., Hargadon, B., Gupta, S., Monteiro, W., Sousa, A., Marshall, R.P., Bradding, P., Green, R.H., Wardlaw A.J., et al.: Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 2009, 360:973–984. Lai, T., Wang, S., Xu, Z., Zhang, C., Zhao, Y., Hu, Y., Cao, C., Ying, S., Chen, Z., Li, W., et al: Long-term efficacy and safety of omalizumab in patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis. Sci. Rep. 2015, 5:8191. Larche, M.: Mechanisms of peptide immunotherapy in allergic airways disease. Ann. Am. Thorac. Soc. 2014, 11:S292-S296. Nair, P., Pizzichini, M.M.M., Kjarsgaard, M., Inman, M.D., Efthimiadis, A., Pizzichini, E., Hargreave, F.E., and O’Byrne, P.M.: Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 2009, 360:985–993.


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Immunology_Janeway. Peters-Golden, M., and Henderson, W.R., Jr: The role of leukotrienes in allergic rhinitis. Ann. Allergy Asthma Immunol. 2005, 94:609–618. Roberts, G., Hurley, C., Turcanu, V., and Lack, G.: Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma. J. Allergy Clin. Immunol. 2006, 117:263–268. Shamji, M.H., and Durham, S.R.: Mechanisms of immunotherapy to aeroallergens. Clin. Exp.. Allergy 2011, 41:1235–1246. Zhu, D., Kepley, C.L., Zhang, K., Terada, T., Yamada, T., and Saxon, A.: A chimeric human–cat fusion protein blocks cat-induced allergy. Nat. Med. 2005, 11:446–449. susceptible individuals occur by binding of the drug to the surface of circulating blood cells. Arndt, P.A.: Drug-induced immune hemolytic anemia: the last 30 years of changes. Immunohematology 2014, 30:44–54.


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Immunology_Janeway. Arndt, P.A.: Drug-induced immune hemolytic anemia: the last 30 years of changes. Immunohematology 2014, 30:44–54. Greinacher, A., Potzsch, B., Amiral, J., Dummel, V., Eichner, A., and Mueller Eckhardt, C.: Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4–heparin complex as the major antigen. Thromb. Haemost. 1994, 71:247–251. Semple, J.W., and Freedman, J.: Autoimmune pathogenesis and autoimmune hemolytic anemia. Semin. Hematol. 2005, 42:122–130. 14-15 Systemic disease caused by immune-complex formation can follow the administration of large quantities of poorly catabolized antigens. Bielory, L., Gascon, P., Lawley, T.J., Young, N.S., and Frank, M.M.: Human serum sickness: a prospective analysis of 35 patients treated with equine anti-thymocyte globulin for bone marrow failure. Medicine (Baltimore) 1988, 67:40–57.


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Immunology_Janeway. Davies, K.A., Mathieson, P., Winearls, C.G., Rees, A.J., and Walport, M.J.: Serum sickness and acute renal failure after streptokinase therapy for myocardial infarction. Clin. Exp. Immunol. 1990, 80:83–88. Hansel, T.T., Kropshofer, H., Singer, T., Mitchell, J.A., and George, A.J.: The safety and side effects of monoclonal antibodies. Nat. Rev. Drug Discov. 2010, 9:325–338. Schifferli, J.A., Ng, Y.C., and Peters, D.K.: The role of complement and its receptor in the elimination of immune complexes. N. Engl. J. Med. 1986, 315:488–495. Schmidt, R.E., and Gessner, J.E.: Fc receptors and their interaction with complement in autoimmunity. Immunol. Lett. 2005, 100:56–67. Skokowa, J., Ali, S.R., Felda, O., Kumar, V., Konrad, S., Shushakova, N., Schmidt, R.E., Piekorz, R.P., Nurnberg, B., Spicher, K., et al.: Macrophages induce the inflammatory response in the pulmonary Arthus reaction through Gαi2 activation that controls C5aR and Fc receptor cooperation. J. Immunol. 2005, 174:3041–3050.


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Immunology_Janeway. 14-16 Hypersensitivity reactions can be mediated by TH1 cells and CD8 cytotoxic T cells. Fyhrquist, N., Lehto, E., and Lauerma, A.: New findings in allergic contact dermatitis. Curr. Opin. Allergy Clin. Immunol. 2014, 14:430–435. Kalish, R.S., Wood, J.A., and LaPorte, A.: Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro. J. Clin. Invest. 1994, 93:2039–2047. Mark, B.J., and Slavin, R.G.: Allergic contact dermatitis. Med. Clin. North Am. 2006, 90:169–185. Muller, G., Saloga, J., Germann, T., Schuler, G., Knop, J., and Enk, A.H.: IL-12 as mediator and adjuvant for the induction of contact sensitivity in vivo. J. Immunol. 1995, 155:4661–4668. Schmidt, M., Raghavan, B., Müller, V., Vogl, T., Fejer, G., Tchaptchet, S., Keck, S., Kalis, C., Nielsen, P.J., Galanos, C., et al.: Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat. Immunol. 2010, 11:814–819.


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Immunology_Janeway. Vollmer, J., Weltzien, H.U., and Moulon, C.: TCR reactivity in human nickel allergy indicates contacts with complementarity-determining region 3 but excludes superantigen-like recognition. J. Immunol. 1999, 163:2723–2731. 14-17 Celiac disease has features of both an allergic response and autoimmunity. Ciccocioppo, R., Di Sabatino, A., and Corazza, G.R.: The immune recognition of gluten in celiac disease. Clin. Exp. Immunol. 2005, 140:408–416. Green, P.H.R., Lebwohl, B., and Greywoode, R.: Celiac disease. J. Allergy Clin. Immunol. 2015, 135:1099–1106. Koning, F.: Celiac disease: caught between a rock and a hard place. Gastroenterology 2005, 129:1294–1301. Shan, L., Molberg, O., Parrot, I., Hausch, F., Filiz, F., Gray, G.M., Sollid, L.M., and Khosla, C.: Structural basis for gluten intolerance in celiac sprue. Science 2002, 297:2275–2279.


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Immunology_Janeway. Shan, L., Molberg, O., Parrot, I., Hausch, F., Filiz, F., Gray, G.M., Sollid, L.M., and Khosla, C.: Structural basis for gluten intolerance in celiac sprue. Science 2002, 297:2275–2279. van Bergen, J., Mulder, C.J., Mearin, M.L., and Koning, F.: Local communication among mucosal immune cells in patients with celiac disease. Gastroenterology 2015, 148:1187–1194.


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Immunology_Janeway. We have already seen how undesirable adaptive immune responses can be elicited by environmental antigens, and how this can cause serious disease in the form of allergic and atopic reactions (see Chapter 14). In this chapter, we examine responses to other medically important categories of antigens—those expressed by the body’s own cells and tissues, by the commensal microbiota, or by transplanted organs. The responses to self antigens or antigens associated with the microbiota that lead to tissue damage and disease are broadly referred to as autoimmunity—although, strictly speaking, disease-causing immune responses to the commensal microbiota are a form of xenoimmunity because the organisms from which the antigens derive are foreign and are not encoded by the human genome. Nevertheless, here we will consider immune-mediated disease directed against the commensal microbiota to be part of the extended spectrum of autoimmune diseases, because the microbiota can be regarded as being part


Immunology_Janeway

Immunology_Janeway. we will consider immune-mediated disease directed against the commensal microbiota to be part of the extended spectrum of autoimmune diseases, because the microbiota can be regarded as being part of a ‘superorganism’ made up of host and commensal microbiota together. The response to nonself antigens on transplanted organs is called allograft rejection.


Immunology_Janeway

Immunology_Janeway. The gene rearrangements that occur during lymphocyte development in the central lymphoid organs inevitably result in the generation of some lymphocytes with affinity for self antigens. Such lymphocytes are normally removed from the repertoire or held in check by a variety of mechanisms. These generate a state of self-tolerance in which an individual’s immune system does not attack the normal tissues of the body. Autoimmunity represents a breakdown or failure of the mechanisms of self-tolerance. Therefore, we first revisit the mechanisms that keep the lymphocyte repertoire self-tolerant and see how these may fail. We then discuss a selection of autoimmune diseases that illustrate the various pathogenic mechanisms by which autoimmunity can damage the body. How genetic and environmental factors predispose to or trigger autoimmunity are then considered. In the remaining part of the chapter, we discuss the adaptive immune responses to nonself tissue antigens that cause transplant


Immunology_Janeway

Immunology_Janeway. factors predispose to or trigger autoimmunity are then considered. In the remaining part of the chapter, we discuss the adaptive immune responses to nonself tissue antigens that cause transplant rejection.


Immunology_Janeway

Immunology_Janeway. The making and breaking of self-tolerance. As we learned in Chapter 8, the immune system takes advantage of surrogate markers of self and nonself to identify and delete potentially self-reactive lymphocytes. Despite this, some self-reactive lymphocytes escape elimination and can subsequently be activated to cause autoimmunity. In addition, many lymphocytes with some degree of self-reactivity can also respond to foreign antigens; therefore, if all weakly self-reactive lymphocytes were eliminated, the function of the immune system would be impaired. 15-1 A critical function of the immune system is to discriminate self from nonself. The immune system has very powerful effector mechanisms that can eliminate a variety of pathogens. Early in the study of immunity it was realized that these could, if turned against the host, cause severe tissue damage. The concept The making and breaking of self‑tolerance. Autoimmune diseases and pathogenic mechanisms.


Immunology_Janeway

Immunology_Janeway. The making and breaking of self‑tolerance. Autoimmune diseases and pathogenic mechanisms. The genetic and environmental basis of autoimmunity. Responses to alloantigens and transplant rejection. Fig. 15.1 Some common autoimmune diseases. The diseases listed are among the most common autoimmune diseases and will be used as examples in this part of the chapter. They are listed in order of prevalence.


Immunology_Janeway

Immunology_Janeway. of autoimmunity was first presented at the beginning of the 20th century by Paul Ehrlich, who described it as ‘horror autotoxicus.’ Autoimmune responses resemble normal immune responses to pathogens in that they are specifically activated by antigens—in this case self antigens, or autoantigens—and give rise to autoreactive effector cells and antibodies, called autoantibodies, against the self antigen. When dysregulated reactions to self tissues occur they cause a variety of chronic syndromes called autoimmune diseases. These syndromes are quite varied in their severity, their tissue distribution, and effector mechanisms that are critical in causing tissue damage (Fig. 15.1).


Immunology_Janeway

Immunology_Janeway. Collectively, autoimmune disorders affect approximately 5% of the populations of Western countries, and their incidence is on the rise. Nevertheless, their relative individual rarity indicates that the immune system has evolved multiple mechanisms to prevent self-injury. The most fundamental principle underlying these mechanisms is the discrimination of self from nonself, but this discrimination is not easy to achieve. B cells recognize the three-dimensional shape of an epitope, but an epitope presented by a pathogen can be indistinguishable from one originating in humans. Similarly, short peptides derived from the processing of pathogen antigens can be identical to self peptides. So how does a lymphocyte know what ‘self’ really is if there are no unique molecular signatures of self?


Immunology_Janeway

Immunology_Janeway. The first mechanism proposed for distinguishing between self and nonself was that recognition of antigen by an immature lymphocyte leads to a negative signal causing lymphocyte death or inactivation. Thus, ‘self’ was thought to comprise molecules recognized by a lymphocyte shortly after it began to express its antigen receptor. Indeed, this is an important mechanism of inducing self-tolerance in lymphocytes developing in the thymus and bone marrow. The tolerance induced at this stage is known as central tolerance (see Chapter 8). Newly formed lymphocytes are especially sensitive to inactivation by strong signals through their antigen receptor, whereas the same signals activate mature lymphocytes in the periphery. The making and breaking of self‑tolerance.


Immunology_Janeway

Immunology_Janeway. Tolerance induced to antigens recognized after lymphocytes have left the central or primary lymphoid organs is known as peripheral tolerance. An antigenic quality that correlates with self in the periphery is recognition in the absence of ‘danger’ signals that are produced by the innate immune system as a result of tissue damage or infection. Nearly all cells in the body become senescent and die, and many cells routinely undergo turnover at steady state (for example, hematopoietic cells and epithelial cells of the intestines and skin). Typically, this occurs by programmed cell death, or apoptosis. In contrast to cell death that results from physical or microbial injury, which generate damageor microbe-associated molecular patterns (DAMPs and MAMPs, respectively), death of senescent cells by apoptosis releases signals to tissue phagocytes that generally promote an anti-inflammatory response and repress presentation of antigens in an activating form. Thus, self antigens recognized in


Immunology_Janeway

Immunology_Janeway. by apoptosis releases signals to tissue phagocytes that generally promote an anti-inflammatory response and repress presentation of antigens in an activating form. Thus, self antigens recognized in the context of normal, or physiologic, cellular turnover fail to induce pro-inflammatory cytokines (for example, IL-6 or IL-12) and co-stimulatory molecules (for example, B7.1) that would otherwise induce naive T cells to undergo effector differentiation. In these circumstances, the encounter of a naive lymphocyte with a self antigen may lead to no signal at all, or such an encounter can promote the development of regulatory lymphocytes that suppress the development of damaging effector responses. The removal of apoptotic cells by phagocytes is thus important for maintaining tissue homeostasis and activating programs in antigen-presenting cells that promote immunological tolerance. Some of the same mechanisms appear to be involved in the induction of tolerance to antigens of the commensal


Immunology_Janeway

Immunology_Janeway. and activating programs in antigen-presenting cells that promote immunological tolerance. Some of the same mechanisms appear to be involved in the induction of tolerance to antigens of the commensal microbiota in the intestines, where recognition of bacterial antigens typically does not generate inflammation unless there is associated tissue damage.


Immunology_Janeway

Immunology_Janeway. Thus, several clues are used to distinguish self from nonself ligands: encounter with the ligand when the lymphocyte is immature, recognition of antigen in the context of antigen-presenting cells that have received tolerizing signals from recognition of homeostatic cell turnover signals, and binding of ligand in the absence of inflammatory cytokines or co-stimulatory signals. All of these mechanisms are error-prone because none of them distinguishes a self ligand from a foreign one at the molecular level. The immune system therefore has several additional mechanisms for controlling autoimmune responses should they start. 15-2 Multiple tolerance mechanisms normally prevent autoimmunity.


Immunology_Janeway

Immunology_Janeway. The mechanisms that normally prevent autoimmunity may be thought of as a succession of checkpoints. Each checkpoint is partially effective in preventing antiself responses, and together the checkpoints act synergistically to provide efficient protection against autoimmunity without inhibiting the ability of the immune system to mount effective responses to pathogens. Central tolerance mechanisms eliminate newly formed, strongly autoreactive lymphocytes. On the other hand, mature self-reactive lymphocytes that do not sense self strongly in the central lymphoid organs—because their cognate self antigens are not expressed there, for example—may be killed or inactivated in the periphery. The principal mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression by T cells, induction of T cell development instead of effector T-cell development (functional deviation), and deletion of lymphocytes from the repertoire due to activation-induced cell death. In


Immunology_Janeway

Immunology_Janeway. by T cells, induction of T cell development instead of effector T-cell development (functional deviation), and deletion of lymphocytes from the repertoire due to activation-induced cell death. In addition, some antigens are sequestered in organs that are not normally accessible to the immune system (Fig. 15.2).


Immunology_Janeway

Immunology_Janeway. Each checkpoint strikes a balance between preventing autoimmunity and not impairing immunity too greatly, and in combination, all the checkpoints provide an effective overall defense against autoimmune disease. It is relatively The different ways in which the immune system prevents activation of and damage caused by autoreactive lymphocytes are listed, along with the specific mechanism and where such tolerance predominantly occurs. Autoimmunity Immune dysregulation Genetic factors Infection and environmental exposure Fig. 15.3 Requirements for the development of autoimmune disease. In genetically predisposed individuals, autoimmunity may be triggered as a result of the failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection.