Exam 14: Allergy and Allergic Diseases

Celiac disease occurs when an individual makes an aberrant immune response to a protein in gluten, such as $\alpha$ -gliadin. Evidence suggests that very few proteins are able to elicit the immune response that causes celiac disease. A key piece of this evidence is that:

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.

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:

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:

IL-33 is a cytokine known as an 'alarmin'. Following stimulation by pathogens or allergens, or in response to damage, epithelial cells in the skin, lungs, and gastrointestinal tract will release IL-33. This cytokine binds to its receptor, which is expressed on several cell types important in type 2 immune responses. When mice are injected with recombinant IL-33 once per day for 7 days (or saline as a control), specific cytokines are found elevated in multiple tissues and in their serum. An example of data from lung is shown in Figure Q26)A, with cytokine mRNA being measured by RT-PCR. Other cytokines, such as IL-2, IL-4, IL-6, IL-10, IL-12, TNF- $\alpha$ , and IFN- $\gamma$ were not altered by IL-33 injection. a) Name three cell types that are likely to express IL-33 receptors. These experiments were repeated using Rag-deficient mice, in comparison to wild-type controls. When cytokines were analyzed after IL-33 treatment of Rag-deficient mice, similar amounts of the same cytokines were observed as seen in wild-type controls. b) Do these data affect your answer to part (a) above? Why or why not? When IL-33-deficient mice were compared to wild-type controls in a mouse model of chronic airway inflammation, disease symptoms were reduced in IL33^-/- mice. In this model, chicken ovalbumin protein (OVA) is mixed with a TH2-inducing adjuvant, and used to sensitize mice by intraperitoneal injection. Four weeks later, mice are challenged intranasally with OVA or saline alone on days 28, 29, and 30. The number of cells in the bronchiolar lavage fluid is then assessed, as shown in Figure . c) Given these data, as well as the cytokine data above, what are two important functions of IL-33? Leukocytes are isolated from the lung epithelium of wild-type mice in which chronic airway inflammation has been induced to OVA. The cells are separated into two subsets: lymphocytes and non-lymphocytes. Then each population is stimulated in vitro with IL-33 in the presence or absence of OVA protein, and 48 hours later the cytokines in the supernatants are assessed by ELISA. The results are shown in Figure for one cytokine. Similar data were obtained for IL-9 and IL-13. d) What are the likely cell types responding in each isolated population?

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:

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:

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:

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:

The response of most individuals to contact with poison ivy includes the development of redness, swelling, blistering (edema fluid accumulation between the dermis and the epidermis), and itching. If one intended to transfer this response from a sensitized to a naive individual, one would transfer:

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

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:

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?

On occasion, individuals on antibiotics such as Minomycin have an allergic response to the antibiotic. Symptoms often include an urticarial rash on the skin, and swelling (edema) of the legs and ankles. When this occurs, patients are advised to stop taking the antibiotic, and are treated with corticosteroids. During follow-up visits to their physician, patients are often given a skin test for hypersensitivity to the drug. This skin test involves intradermal injection of a small amount of Minomycin, and 15 minutes later the site of injection is examined for redness and swelling. In cases where this skin test is negative, the patient most likely generated:

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?

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:

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:

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:

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:

Hypersensitivity responses to divalent cations such as nickel are relatively common. Individuals sensitized to these metals will develop a skin rash within 15 minutes of putting on a bracelet or ring containing that metal.