Question 1

In the late 1990s, compounds that functioned as leukotriene receptor antagonists were approved for the treatment of asthma. The first such drug, zafirlukast, inhibits the actions of a major receptor for leukotrienes, known as CYSLTR1 (cysteinyl leukotriene receptor 1). One would predict that patients on this drug would show:

Accepted Answer

Leukotrienes are potent bronchoconstrictors, and leukotriene receptor antagonists inhibit their actions, resulting in reduced bronchoconstriction. Zafirlukast specifically targets CYSLTR1, which is involved in smooth muscle contraction in the airways. Therefore, patients on this drug would likely experience reduced bronchoconstriction. The other options (enhanced mucus production, enhanced vascular permeability, increased accumulation of leukocytes in the lung, and reduced mast cell activation) are not directly related to the inhibition of CYSLTR1 and are therefore unlikely to be affected by this drug.

Question 2

Fatal anaphylaxis can be induced in mice by sensitizing the mice to penicillin V (Pen V). To elicit this response, Pen V is conjugated to a protein, such as chicken ovalbumin (OVA), and mice are immunized with this conjugate by intraperitoneal (IP) injection in a T_H2-inducing adjuvant. Fourteen days later, mice are injected intravenously (IV) with Pen V conjugated to a different protein, bovine serum albumin (BSA), and examined 20 minutes later. In addition, a second set of mice received anti-IL-4 antibody injections on days 0, 2, and 4 of the sensitization phase of the response. The results in Table Q16)A were observed; (data are shown as the ratio of dead mice to total mice for each condition):as above. Twenty-four days later, serum from these mice was isolated and injected into a set of naive (unimmunized) recipient mice. Recipient mice were then sensitized by a single IP injection of Pen V-OVA in adjuvant, as above, and then 24 hours later, were given an IV injection of Pen V-BSA or BSA alone. In addition, one group of mice received serum that was depleted of specific antibodies prior to transfer into recipients. These mice develop a slightly milder disease, characterized by severe shock rather than death. Data are shown in Table Q16)B as the ratio of mice exhibiting severe shock to total mice for each condition/ Table Q16)B Which antibodies were depleted from the serum in the final experiment shown above:

Accepted Answer

The final experiment involved transferring serum from previously sensitized mice to naive recipient mice. The recipient mice were then sensitized with Pen V-OVA and given an IV injection of Pen V-BSA or BSA alone. The mice who received the serum that was depleted of specific antibodies prior to transfer into recipients developed a slightly milder disease, characterized by severe shock rather than death. This suggests that the antibodies that were depleted were crucial for the development of the severe anaphylactic response. Given that mice were sensitized with Pen V-OVA, it is likely that those crucial antibodies were IgE antibodies specific to Pen V-OVA. Therefore, the best choice is E: All IgE antibodies.

Question 3

Once an individual becomes sensitized to an allergen, such as an inhaled antigen, the allergic response can become self-amplifying upon each re-exposure to the allergen. Thus, even in the absence of CD4 T_H2 cell activation, increases in IgE secretion by mucosal-resident plasma cells can be induced by:

Accepted Answer

IL-4 secretion and CD40-ligand expression by mast cells and basophils can activate mucosal-resident plasma cells to secrete IgE upon re-exposure to an allergen, even without CD4 T cell activation. This is known as a memory response and is a self-amplifying process.

Question 4

Allergic responses to inhaled antigens occur when an individual is first sensitized to the antigen (i.e., the allergen), inducing an immune response, and then has a subsequent exposure to the same antigen. The sensitization phase is characterized by:

Accepted Answer

During the sensitization phase, the body produces IgE antibodies in response to the antigen/allergen. These IgE antibodies then bind to mast cells throughout the body, priming them for activation upon subsequent exposure to the same antigen/allergen. CD4 T cells also play a role in this phase, with the induction of a type II immune response involving Th2 cells and cytokines such as IL-4 and IL-13.

Question 5

The prevention of inflammatory immune responses to inhaled antigens in healthy individuals has mechanisms in common with those that prevent inflammatory immune responses to commensal microbes in the gut. One important component of immune regulation shared by these two situations is:

Accepted Answer

The important component of immune regulation shared by preventing inflammatory immune responses to inhaled antigens and commensal microbes in the gut is the role of CD4 regulatory T cells in suppressing inflammatory immune responses in these tissues. These regulatory T cells control the activity of other immune cells, preventing them from attacking harmless antigens and maintaining tolerance towards self-antigens.

Question 6

Genome-wide association studies of large cohorts of individuals (>5000 allergic versus >10,000 controls) with IgE-mediated allergies revealed a set of genes significantly correlated with atopy. Further studies of the top ten candidate genes indicated that each gene showed allelic variations that were likely associated with differences in gene expression. One of these ten genes encodes STAT6, the transcription factor activated downstream of the IL-4 receptor. What would you predict for the allelic variant of STAT6 found more frequently in allergic individuals compared to the allele found more frequently in non-allergic controls?

Accepted Answer

The answer of Genome-wide association studies of large cohorts of...

Question 7

Individuals with peanut allergies can exhibit a variety of symptoms following exposure to the peanut allergen. These symptoms can include a runny nose, skin reactions such as hives, itching in the mouth and throat, digestive problems such as cramps, diarrhea or vomiting, and shortness of breath or wheezing. This variety of symptoms is a result of:

Accepted Answer

The answer of Individuals with peanut allergies can exhibit a...

Question 8

A relatively new form of therapy for IgE-mediated allergic diseases is the periodic injection of patients with anti-IgE antibody. This antibody binds to the Fc portion of IgE antibodies, and prevents the IgE antibodies from binding to both high affinity and low affinity IgE receptors on inflammatory cells. IgE bound to the high affinity IgE receptor on mast cells and basophils stimulates degranulation of these cells and their production of inflammatory mediators, following antigen encounter. In contrast, the low affinity IgE receptor is expressed on dendritic cells, and functions to trap allergen-IgE complexes for uptake, degradation, and presentation to T cells. Given these functions, individuals treated with this anti-IgE therapy would be expected to show:

Accepted Answer

The periodic injection of anti-IgE antibodies would block the binding of IgE to mast cells and basophils, preventing their degranulation and the release of inflammatory mediators. This would result in a reduced allergic response and no progressive worsening of the disease. However, this therapy would not cure the underlying allergy or prevent future sensitization, so rebound reactions might occur but would not cause as severe symptoms as before the therapy. The therapy would also be expected to have a beneficial effect on allergic asthma, as it involves the inflammation of the airways, but may have limited effects on food or skin allergies which involves mast cells located in the tissue instead of blood circulation. Anti-IgE therapy would not affect mucus production in the airways or GI tract, as it does not target the production of the mucus. Lastly, the therapy would not affect the response to helminthic parasite infections, as this is mediated by different types of immune cells and antibodies.

Question 9

In individuals with a peanut allergy, mild allergic responses are those that involve a single site, typically a skin reaction such as hives. More severe allergic reactions generally involve multiple tissue sites, such as the skin, oral mucosa, airway mucosa and gastrointestinal tract. Given two groups of allergic patients, one with only skin responses, and the other with 3-4 different tissue sites involved, one would expect that:

Accepted Answer

Patients with more severe allergic reactions involving multiple tissue sites are likely to have higher concentrations of allergen-specific IgE, since IgE is involved in the activation of mast cells and the release of inflammatory mediators in multiple tissue sites. Answer: B Patients with mild allergic responses may have fewer mast cells in some tissue sites, but this would not necessarily be the case in the majority of their mucosal tissues. Answer: C Patients with severe allergic responses may have allergies to several other substances in addition to peanuts, but this is not necessarily a universal finding among this group. Answer: D There is no clear evidence to suggest that antioxidant enzyme expression plays a significant role in the severity of allergic responses. Answer: E There is no clear evidence to suggest that the number of CD4+ T_reg cells (a type of regulatory T cell) is related to the severity of allergic responses.

Question 10

The 'hygiene hypothesis' has been proposed as an explanation for the rapid increase in allergies and asthma incidence in Western countries over the last half century. One line of evidence supporting this hypothesis is:

Accepted Answer

This evidence suggests that environmental factors, rather than genetic factors, contribute to the development of atopic diseases. This is because individuals of African descent have a lower incidence of atopic disease in their home countries but have an increased incidence when living in Western countries. This supports the hygiene hypothesis, which suggests that the Western lifestyle and its associated cleanliness and lack of exposure to infectious agents leads to an overactive immune system and increased allergy and asthma incidence.

Question 11

NRF2 is a transcription factor that is required to induce anti-oxidant genes, such as glutathione-S-transferase genes, in response to reactive oxygen and reactive nitrogen species released by inflammatory cells in the airways following phagocytosis of inhaled particles. Mice deficient in Nrf2 were tested for their allergic airway response to inhaled allergens in comparison to wild-type controls. Compared to wild type mice, the Nrf2^-/- mice would be expected to show:

Accepted Answer

Nrf2 is involved in the induction of antioxidant genes that protect against oxidative stress. Mice deficient in Nrf2 would have impaired antioxidant defenses, leading to increased damage and inflammation in response to allergens. This would likely result in an enhanced Th2 immune response, characterized by increased levels of IL-4 and IL-13, which are key cytokines in the allergic response.

Question 12

Within minutes after encounter with an allergen, individuals with allergic rhinitis show symptoms of nasal itching, nasal congestion, sneezing, and a runny nose. These symptoms generally subside within 30 minutes, but reappear several hours later. Analysis of the nasal epithelium in such an individual 6 hours after allergen encounter would show:

Accepted Answer

The symptoms of allergic rhinitis are caused by an allergic response, which is characterized by the infiltration of inflammatory cells such as eosinophils, basophils, neutrophils, T cells, and macrophages into the nasal epithelium. Six hours after allergen encounter, the inflammatory response would still be ongoing, and these cells would be present in the nasal epithelium.

Question 13

Studies using mouse models of allergic asthma have provided information about the cell types and soluble mediators that contribute to this disease. One common experimental model uses airway exposure to protease allergens, such as papain from papaya or the house dust mite allergen. Interestingly, papain is able to induce allergic lung inflammation even in RAG-deficient mice. In this system, the type 2 cytokines, IL-5, IL-9, and IL-13, are likely coming from:

Accepted Answer

Type 2 cytokines IL-5, IL-9, and IL-13 are predominantly produced by ILC2 cells in mouse models of allergic asthma, including those induced by protease allergens like papain. These cytokines are key mediators of airway inflammation, mucus production, and bronchoconstriction. Other cell types, such as airway epithelial cells, eosinophils, and macrophages, also play important roles in asthma pathogenesis, but they are not the main sources of type 2 cytokines. The T_H2 cells mentioned in the answer choices are not a known cell type in the context of allergic asthma.

Question 14

Allergen-induced airway remodeling in mice is used as a model for human allergic asthma. This disease is induced by first sensitizing mice to the protein antigen, chicken ovalbumin (OVA) by intraperitoneal immunization with OVA in a T_H2-inducing adjuvant. Three weeks later, mice are challenged by inhalation of aerosolized OVA (or saline alone, as a control) daily for the following three weeks. At the end of the entire six week period, the lungs of the mice are examined for leukocyte numbers in the bronchial alveolar lavage fluid (BALF) and for tissue remodeling as assessed by measuring fibrotic areas in the lung tissue. To determine the cell type most likely responsible for the tissue damage in this disease, IL-5 receptor-deficient mice (IL5R^-/-) are compared to wild-type, as shown in Figure Q13). airway remodeling disease model is:

Accepted Answer

Eosinophils are the cell type most likely responsible for tissue damage in allergen-induced airway remodeling in mice, which is used as a model for human allergic asthma. This is supported by the fact that IL-5 receptor-deficient mice (IL5R^-/-), which are unable to support eosinophil survival, have reduced tissue remodeling compared to wild-type mice.

Question 15

Common allergens that trigger atopic responses in humans share several features. For example, nearly all allergens are proteases.

Accepted Answer

This statement is false. While some allergens are proteases, not all allergens share this feature. There are many other types of molecules that can trigger an allergic response, including proteins, glycoproteins, and carbohydrates.

Question 16

Genetic studies have identified more than 40 genes that show allelic variations associated with the development of allergic asthma and atopic dermatitis, as well as the predisposition to develop allergies to particular antigens. Among these genes are several that implicate CD4 T cell responses in the development of these allergic diseases. Name two genes (or gene clusters) associated with atopic diseases that indicate a central role for CD4 T cells in these diseases.

Accepted Answer

One set of genes identified as associated to the development of atopic diseases encodes the TIM family (for T cell, immunoglobulin domain, and mucin domain). The genes in this set encode three T-cell-surface proteins (Tim-1, 2, and 3) and one protein expressed primarily on antigen-presenting cells (Tim-4). Mouse strains that carry different variants of the Tim genes differ both in their susceptibility to allergic inflammation of the airways and in the production of IL-4 and IL-13 by their T cells. In humans, inherited variation in the three human TIM genes has been correlated with airway hyperreactivity or hyperresponsiveness. A second type of inherited variation in IgE responses is linked to the HLA class II region (the human MHC class II region), and it affects responses to specific allergens, rather than a general susceptibility to atopy. IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular peptide:MHC combinations might favor a strong T_H2 response; for example, IgE responses to several ragweed pollen allergens are associated with haplotypes containing the HLA class II allele DRB1 *1501. Many people are therefore generally predisposed to make T_H2 responses and are specifically predisposed to respond to some allergens more than others. A third possible answer to this question would be the Type II cytokine locus, encoding IL-4, IL-5, IL-9, IL-13, and GM-CSF. This is a less direct indicator of CD4 T cells, as other cell types are known to produce these cytokines in addition to T_H2 cells.

Question 17

Genetic variations in proteins involved in immune and inflammatory responses have been shown to be associated with the development of atopic dermatitis and other allergic diseases. However, several genes associated with these conditions do not affect the immune system directly. For example, among this latter group are genes that:

Accepted Answer

Genes that regulate barrier function by airway and skin epithelial cells have been shown to be associated with the development of atopic dermatitis and other allergic diseases. These genes influence skin and airway barrier function and their alterations can leave individuals susceptible to allergen sensitization.

Answer: E 
 Some genes are common to atopic diseases and autoimmune diseases, showing shared genetic susceptibility. These genes affect immune system function and may explain the similar clinical and histological features observed between these diseases.

Question 18

Red blood cells are common targets of drug-induced anemia, a disorder that occurs when some drugs bind to the surface of red blood cells and trigger the development of IgG antibodies that bind to the drug-coated red blood cell and promote red blood cell destruction. Since the drug binding to the red blood cell surface does not actually harm the red blood cell, the anemia resulting in this disorder is caused by:

Accepted Answer

Drug-induced anemia occurs when drugs bind to the surface of red blood cells and trigger the development of IgG antibodies that bind to the drug-coated red blood cell and promote red blood cell destruction. The destruction of red blood cells in this disorder is primarily caused by phagocytosis by Fc receptor-expressing macrophages in the spleen. The other choices listed do not accurately describe the mechanism of anemia in drug-induced anemia.

Question 19

Individuals with allergic responses to inhaled antigens show an immediate (within minutes) response to encounter with the allergen, resulting in bronchial smooth muscle constriction and edema that makes breathing difficult. Which over-the-counter medication that might be taken to prevent or reduce this response, and how does it act?

Accepted Answer

The answer of Individuals with allergic responses to inhaled antigens...

Question 20

In mice, an allergic response in the airways can be induced by systemic immunization with a protein antigen (chicken ovalbumin) in an adjuvant that promotes Type II immune responses, followed by several exposures to aerosolized ovalbumin administered via the airways. Mice that have a genetic deficiency in expression of the receptor c-kit are resistant to this disease because:

Accepted Answer

Mast cells are an important effector cell in allergic responses, as they release histamine and other mediators that cause airway inflammation and bronchoconstriction. Mice that lack mast cells because of a c-kit deficiency are therefore resistant to the development of allergic airway disease.

Quiz 14: Allergy and Allergic Diseases

Allergic responses to inhaled antigens occur when an individual is first sensitized to the antigen (i.e., the allergen) , inducing an immune response, and then has a subsequent exposure to the same antigen. The sensitization phase is characterized by:

The prevention of inflammatory immune responses to inhaled antigens in healthy individuals has mechanisms in common with those that prevent inflammatory immune responses to commensal microbes in the gut. One important component of immune regulation shared by these two situations is:

The 'hygiene hypothesis' has been proposed as an explanation for the rapid increase in allergies and asthma incidence in Western countries over the last half century. One line of evidence supporting this hypothesis is:

Common allergens that trigger atopic responses in humans share several features. For example, nearly all allergens are proteases.