Immunology Exam 4

GWAS data have identified multiple genes associated with autoimmune diseases. These data indicate the presence of polymorphisms in the gene sequence among the human population, where certain alleles are increased among patients with a particular autoimmune disease. One example is the gene encoding theIL-2R chain. Interestingly, several of the polymorphisms in this gene that are found to be increased in patients with multiple sclerosis do not alter the protein coding sequence, and therefore do not result in differences in the amino acid sequence of the IL-2R chainprotein between healthy individuals and those with the disease-associated allele. Instead, it is likely that these allelic differences in the IL-2R chain locus: A. Alter the levels of expression or cell-type specificity of the IL-2R chain protein B. Are in sequences that affect a neighboring gene, rather than affecting the IL-2Rchain gene C. Are associated with healthy versus autoimmune individuals, but do not play a causal role in disease incidence D. Alter post-translational modifications of the IL-2R chain protein, rather than the amino acid sequence E. Affect the signal transduction proteins that need to associate with the IL-2R for intracellular signaling

A. Alter the levels of expression or cell-type specificity of the IL-2R chain protein

A mouse model for autoimmune hemolytic anemia can be transferred to naive mice by a single injection of anti-red blood cell IgG antibodies. However, the disease is prevented if recipient mice lack IgG-binding Fc receptors. These data indicate: A. An essential role for NK cells, neutrophils and other granulocytes, and macrophages in red blood cell destruction B. An essential role for the transport of IgG out of the blood into the tissues for red blood cell destruction C. A critical role for innate immune cells in the development of autoreactive antibody-secreting B cells D. That phagocytosis of antibody-coated red blood cells is only mechanism leading to red blood cell destruction E. Autoantibodies can traffic to the bone marrow and destroy erythroid progenitor cells

A. An essential role for NK cells, neutrophils and other granulocytes, and macrophages in red blood cell destruction

Cyclosporin A and rapamycin are each used as T cell immunosuppressants. They share the property of binding to immunophilin molecules in T cells as the initial step in their mechanisms of action. However, in the case of cyclosporin A, the drug:immunophilin complex binds to and inhibits the protein phosphatase calcineurin, whereas the rapamycin:immunophilin complex binds to and inhibitors mTOR. As a consequence, A. Cyclosporin A, but not rapamycin, blocks cytokine production by T cells. B. Both cyclosporin A and rapamycin block cytokine production by T cells. C. Rapamycin, but not cyclosporin A, blocks T cell proliferation. D. Neither rapamycin nor cyclosporin A block T cell proliferation. E. Both cyclosporin A and rapamycin inhibit co-stimulatory signaling through CD28 on T cells

A. Cyclosporin A, but not rapamycin, blocks cytokine production by T cells.

HIV-infected patients that progress to AIDS suffer from a variety of opportunistic infections that rarely cause disease in healthy individuals. In addition, manyof these patients acquire malignancies, such as B-cell lymphomas or Kaposi's sarcoma. A common feature of these two malignancies is that they are: A. Each associated with a herpesvirus infection B. Never seen in non-AIDS patients C. The only two diseases caused by herpesviruses D. Normally prevented by high affinity antibody responses E. Normally eliminated by activated NK cells

A. Each associated with a herpesvirus infection

Herpesviruses are a class of viruses that establish life-long infections in human hosts. Estimates suggest that >90% of the population is infected with severalof these viruses, including EBV, CMV, and herpes zoster, the cause of chicken pox. Oneherpesvirus, Herpes Simplex virus, causes recurrent cold sores in infected individuals. Thus, in spite of a robust anti-viral CD8 T cell response, these individuals still suffer fromperiodic virus-induced cold sores following exposure to UV light or certain hormones or other stressors. This anti-viral CD8 T cell response: A. Eliminates infected epithelial cells but not infected neurons B. Is unable to kill virus-infected cells C. Produces IFN- that has no effect on virus replication D. Is prevented from trafficking to the site of virus replication due to virus-encoded chemokine receptor antagonists E. Is inhibited by virus-encoded anti-inflammatory cytokines such as IL-10

A. Eliminates infected epithelial cells but not infected neurons

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 TH2 cell activation, increases in IgE secretion by mucosal-resident plasma cells can be induced by: A. IL-4 secretion and CD40-ligand expression by mast cells and basophils B. Inflammatory macrophages recruited to the site of allergen stimulation C. Eosinophils that are stimulated by the production of IL-4 in the mucosal tissue D. Dendritic cells that have received TLR stimulation E. The activation of the complement cascade following allergen encounter

A. IL-4 secretion and CD40-ligand expression by mast cells and basophils

Currently, the only licensed vaccine against Mycobacterium tuberculosis (Mtb) is the attenuated strain, related to Mtb, known as BCG. While BCG protects some populations against some strains of Mtb, an improved vaccine for this deadly disease is needed. One recent effort to generate a better vaccine against Mtb is to engineer BCG to have improved immunogenicity in vaccinated individuals. BCG, like Mtb, infects macrophages, replicating in the macrophage phagosomes. Both BCG and Mtb prevent phagosome acidification and fusion with lysozomes, thereby preventing macrophages from efficiently killing the ingested bacteria. In addition, antigens from the bacteria are not found in the macrophage cytosol. To alter this lifestyle, BCG was engineered to express the listeriolysin protein from Listeria monocytogenes. This enzyme lyses the phagosomal membrane allowing antigens to escape into the cytosol. In addition, a mutation was generated in this same BCG to inactivate the bacterial urease, an enzyme that prevents acidification of phagosomes carrying ingested bacteria.This modified BCG was called rBCG, for recombinant BCG. To test whether rBCG induced more potent protection than the original vaccine strain, mice were immunized with BCG or rBCG, or left unimmunized, and then challenged with virulent Mtb. Titers of Mtb (CFU/lung) were then examined over time after challenge, as shown in Figure Q16.25. Based on these data, rBCG likely induced: A. Increased cytolytic CD8 T cells capable of killing Mtb-infected macrophages B. Increased neutralizing antibody responses to Mtb C. Increased numbers of CD4 TFH cells to Mtb peptides D. Increased activation of NK cells capable of killing Mtb-infected macrophages E. A decrease in the ability of Mtb to infect macrophages in the vaccinated mice

A. Increased cytolytic CD8 T cells capable of killing Mtb-infected macrophages

A small group of HIV-infected individuals are known as 'elite controllers.' These individuals have HIV viral RNA copy numbers that persistently remain<50 copies/ml of plasma. Studies examining the immune response to the virus in these individuals would likely reveal: A. Increased numbers of virus-specific CD4 and CD8 T cells secreting IFN-compared to individuals with high viral titers B. That their T cells lacked expression of CCR5 C. Dramatically increased numbers of NK cells compared to individuals with high HIV titers D. That they were infected only with the X4 strain of the virus E. Increased levels of chemokines that bind CCR5 compared to individuals with high HIV titers

A. Increased numbers of virus-specific CD4 and CD8 T cells secreting IFN-compared to individuals with high viral titers

Within minutes after encounter with an allergen, individuals with allergic rhinitis show symptoms of nasal itching, nasal congestion, sneezing, and a runnynose. 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: A. Infiltration of eosinophils, basophils, neutrophils, T cells, and macrophages B. High concentrations of IL-22 important in repair of the damaged epithelium C. An influx of commensal microbes due to breaches in the epithelial barrier D. The absence of allergen-specific IgE on mast cells in the tissue E. Very low levels of histamine and other inflammatory mediators

A. Infiltration of eosinophils, basophils, neutrophils, T cells, and macrophages

One important feature of retroviruses such as HIV is their generation ofa provirus, a copy of the viral genome that is inserted into the host cell chromosome. In addition to providing a template for viral mRNA transcription, the proviral genome: A. Is maintained long-term and transmitted to all of the cell's progeny B. Is easily recombined out of the host cell chromosome to generate new viral genomes for packaging C. Can be cleaved by the viral proteases to generate multiple viral proteins D. Can induce DNA duplication to generate multiple viral copies in the host cell chromosome E. Can be reverse transcribed to generate viral genomes for packaging into new virus particles

A. Is maintained long-term and transmitted to all of the cell's progeny

Listeria monocytogenes is a bacterial pathogen that causes a variety of diseases including gastroenteritis, encephalitis, and sepsis. The bacterium has evolved a strategy to replicate in the cytosol of macrophages, and to spread from one macrophage to another using the host's actin machinery to facilitate direct transfer between cells, thereby avoiding the extracellular space. This unique lifestyle of L. monocytogenes is dependent on the bacteria encoding enzymes that: A. Lyse the phagocytic vesicle membrane, allowing bacterial escape into the cytoplasm B. Prevent bacterial membrane proteins from activating pattern recognition receptors expressed in the macrophage C. Block the MHC class II antigen presentation pathway D. Block the MHC class I antigen presentation pathway E. Induce the formation of granulomas that allow the bacteria to persist indefinitely in the host

A. Lyse the phagocytic vesicle membrane, allowing bacterial escape into the cytoplasm

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: A. Patients with the severe allergic responses would have higher concentrations of allergen-specific IgE. B. Patients with mild allergic responses would have fewer mast cells in the majority of their mucosal tissues. C. Patients with severe allergic responses would also have allergies to several othersubstances, such as bee venom or pollen. D. Patients with severe allergic responses would have reduced expression of antioxidant enzymes, such as glutathione-S-transferases. E. Patients with mild allergic responses would have higher numbers of CD4+ Tregcells

A. Patients with the severe allergic responses would have higher concentrations of allergen-specific IgE.

In 2015, the US FDA approved the use of secukinumab for the treatment of psoriasis, a disease caused by chronic inflammation in the skin. Secukinumab is fully human monoclonal antibody against IL-17A. Clinical trials of this treatment indicated an increased rate of infections in patients on secukinumab, the majority of which were upper respiratory tract infections caused by viral or bacterial pathogens. For many of these infections, this side effect of secukinumab can be explained by: A. Poor recruitment of neutrophils to infected airways B. Lack of mucus production by airway epithelial cells C. Poor recruitment of eosinophils to infected airways D. Enhanced production of antimicrobial peptides by airway epithelial cells E. Loss of tight junctions between airway epithelial cells

A. Poor recruitment of neutrophils to infected airways

Due to its multiple roles in promoting inflammatory responses, the complement system has been a target for the development of compounds that interfere with the complement system as a means of treating chronic autoimmune diseases. While some compounds inhibit the formation of the membrane attack complex, others are aimed at inhibiting earlier steps in the complement cascade. One such compound is an inhibitor of the C5a receptor, a receptor expressed on macrophages, dendritic cells, and granulocytes. The C5a receptor inhibitor would function to: A. Prevent the recruitment of macrophages and neutrophils to the sites of autoantibody binding B. Prevent cell lysis by the membrane attack complex C. Prevent cell uptake by phagocytic cells bearing complement receptors D. Enhance the binding of IVIG to the low affinity Fc receptor on phagocytes E. Prevent the binding of autoantibodies to activating Fc receptors

A. Prevent the recruitment of macrophages and neutrophils to the sites of autoantibody binding

The vitamin D3 metabolite 1,25(OH)2D3 binds to the vitamin D receptor(VDR). This complex then functions as a transcriptional regulator. The activation of VDR following treatment of cells with 1,25(OH)2D3 has been found to modulate the activity of antigen-presenting dendritic cells. In one study, dendritic cells were isolated from wild-type mice and activated in vitro by stimulation with LPS plus IFN- in the presence or absence of 1,25(OH)2D3 for 24 hours. These activated dendritic cells were then pulsed with a peptide from the chicken ovalbumin protein (OVA) that binds to MHC class II and is recognized by OT-II CD4 T cells. The peptide-pulsed dendritic cells and T cells were incubated together for 3 days, and then IL-2 levels in the supernatants were measured, as shown in Figure Q6.12 Based on these data, dendritic cells activated in the presence of 1,25(OH)2D3 are likely to show: A. Reduced MHC class II and reduced B7 expression compared to controls B. Enhanced expression of IL-12 compared to controls C. Reduced expression of IL-6 and TNF- compared to controls D. Increased expression of MHC class I and class II expression compared to controls E. Reduced expression of proteins involved in antigen presentation compared to controls

A. Reduced MHC class II and reduced B7 expression compared to controls

. 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: A. Reduced symptoms upon allergen encounter and no progressive worsening of disease B. Reduced symptoms upon allergen encounter, but rebound to severe disease if therapy is discontinued C. Beneficial effects for allergic asthma, but no effect on food or skin allergies D. No reduction in mucus production in the airways or GI tract E. A normal response to helminthic parasite infections

A. Reduced symptoms upon allergen encounter and no progressive worsening of disease

Individuals with defects in ubiquitously expressed DNA repair proteins have a form of SCID known as RS-SCID (radiation-sensitive SCID). Studies have shownthat, in addition to immune deficiencies, these patients have an increased rate of cancer.Yet, in general, they are diagnosed first based on their immunodeficiency disease, not on their susceptibility to getting cancer. This is due to the fact that: A. The immune response to infections is required almost immediately after birth B. Cells other than lymphocytes have additional redundant DNA repair pathways. C. More people have immunodeficiency diseases than have cancer. D. Cancer only occurs in older individuals. E. If treated for their immunodeficiency disease, the increased cancer incidence goes away.

A. The immune response to infections is required almost immediately after birth

Immunotoxin therapy as an anticancer treatment is a focus of current efforts to develop new anticancer drugs. An alternative strategy, known as radioimmunotherapy, involves the conjugation of a tumor-antigen specific antibody to a radioisotope, rather than to a bacterial toxin. One advantage of radioimmunotherapy over that of immunotoxin therapy is that the radioisotope: A. Will damage neighboring tumor cells in addition to the cell binding the drug B. Has a finite half-life and will spontaneously lose activity in the patient C. Is less likely to cause collateral damage to healthy tissues than the toxin D. Will not cause inflammation due to recognition by PRRs in innate immune cells, but the toxin will E. Is unable to bind to Fc receptors on phagocytic cells, so will have increased longevity in patients

A. Will damage neighboring tumor cells in addition to the cell binding the drug

Treg cells that express FoxP3 are generally thought to have T-cell receptors that recognize self-peptides bound to MHC class II molecules. In the skin, keratin and filaggrin are among the self-antigens expressed. FoxP3+ Treg cells found in skin and skin-draining lymph nodes might be specific for the self-antigen, filaggrin. These FoxP3+ filaggrin-specific Treg cells: A. Would inhibit the activation of naive filaggrin-specific and keratin-specific CD4 T cells B. Would only inhibit the activation of naive filaggrin-specific CD4 T cells C. Would inhibit the activation of all naive T cells in skin-draining lymph nodes following an infection D. Would not inhibit naive T cells specific for antigens expressed by commensal microbes but not by host cells E. Are the only subset of autoreactive cells expressing TGF- receptors

A. Would inhibit the activation of naive filaggrin-specific and keratin-specific CD4 T cells

A variety of genetic defects can result in patients exhibiting SCID. For many of these diseases, infants with the disease are given bone marrow transplants from healthy donors to restore normal immune function. Yet, some diseases causing T cell deficiencies cannot be treated by bone marrow transplantation. Which of the diseases below is treatable by giving patients hematopoietic stem cells from a healthy donor? A. XSCID B. Di George syndrome C. FOXN1 deficiency D. MHC class II deficiency E. MHC class I deficiency

A. XSCID

AIRE is a transcriptional regulator that promotes the expression of some 'tissue-specific' proteins in thymic stromal cells. This provides a means to induce central tolerance of developing T cells to these antigens. Patients with inactivating mutations in AIRE (a disease known as APECED) develop a range of symptoms, several of which involve autoimmune attack of exocrine glands. However, analysis of many patients with APECED reveals that some organs in the body are never attacked byautoimmune T cells in individuals with this syndrome, whereas other organs are commonly found to be destroyed in these patients. This targeted autoimmune response against a subset of tissues in APECED patients indicates: A. Some tissues in the body cannot be targeted by autoimmune mechanisms. B. AIRE likely regulates genes expressed in this subset of tissues, but not genes in other tissues. C. Central tolerance is more efficient in deleting T cells reactive to some tissues in the body than others D. Central tolerance is only important for deleting auto-reactive T cells recognizing self-antigens expressed in exocrine glands. E. Exocrine glands express much higher levels of self-antigens than other tissues do

B. AIRE likely regulates genes expressed in this subset of tissues, but not genes in other tissues.

A mutant mouse line (Mutant-X) is discovered that is defective in generating IgG or IgA antibody responses to immunization with the inactivated influenza A virus vaccine. As a first step in determining the gene responsible for the immunodeficiency, T lymphocytes and B lymphocytes are separately isolated from wild-type or Mutant-X mice and mixtures of cells are transferred into Rag-deficient recipients, which are then immunized with the Influenza A vaccine as shown in Figure Q13.10A. Fourteen days later, serum from the immunized mice is collected, and tested for anti-influenza IgG and IgA antibody titers. The results are shown in Figure Q13.10BFigure Q13.10AFigure Q13.10BGiven these data, the most likely identity for the gene that is defective in Mutant-X mice is: A. NEMO B. CD40-ligand C. CD40 D. AID E. TACI

B. CD40-ligand

Studies have shown that secondary lymphoid tissues are a major reservoir of HIV in infected individuals. In part, this is due to the high numbers of viral target cells expressing CD4, such as T cells, macrophages, and dendritic cells. Surprisingly, secondary lymphoid tissues were also found to contain large numbers of infectious virus particles in the form of immune complexes. A comparison of the viral species found in these immune complexes indicates that they include virus particles that have been retained for over a year. The cells responsible for this reservoir of infectious HIV are A. HIV-specific B cells B. Follicular dendritic cells C. CD4 T cells D. Subcapsular sinus macrophages E. CD4+ dendritic cells

B. Follicular dendritic cells

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: A. Airway epithelial cells B. ILC2 cells C. Eosinophils D. TH2 cells E. Macrophages

B. ILC2 cells

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: A. IgE antibodies to the Minomycin B. IgG antibodies to the Minomycin C. CD4 TH2 cells specific to Minomycin-modified red blood cells D. CD4 TH1 cells specific to Minomycin-modified self proteins E. Activated macrophages that produce IL-1 and TNF-

B. IgG antibodies to the Minomycin

A small subset of patients taking antibiotics such as minocycline develop symptoms resembling those of systemic lupus erythematosis (SLE). These symptoms include a severe skin rash that may cover the legs and trunk, arthritic joint pain, and swelling of the lower limbs, as well as the face, lips, ears, and tongue. These symptoms subside once the antibiotic is discontinued. In these individuals, a skin test forhypersensitivity to minocycline within 15 minutes of intradermal injection of the drug is negative. Analysis of the peripheral blood from these patients would likely reveal: A. IgE antibodies to the minocycline antibiotic B. IgG antibodies to the minocycline antibiotic C. Effector TH2 CD4 T cells specific for a minocycline-modified protein D. Red blood cells coated with antibodies and complement components E. A substantial increase in the numbers of circulating neutrophils and eosinophils

B. IgG antibodies to the minocycline antibiotic

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: A. Individuals living in Western countries have fewer CD4 Treg cells in their mucosal tissues. B. Individuals of African descent have much higher incidence of atopic disease when living in Western countries. C. Individuals that are infected with RSV as infants are protected from developing allergies and asthma later in life. D. Individuals that are infected with Hepatitis A virus are more likely to develop allergies and asthma. E. Persistent exposure with helminthic parasites predisposes individuals to developing atopic diseases due to increased Type II immune responses.

B. Individuals of African descent have much higher incidence of atopic disease when living in Western countries.

Studies performed in mice have revealed one important component affecting the altered immune response in individuals undergoing malnutrition or starvation. In these studies, mice were placed on a starvation diet for several days, and then immunized with a protein antigen in an adjuvant. One group of starved mice were given injections of 'compound X' for 48 hours, starting at the time of immunization. Seven days later, draining lymph nodes were isolated, and T cell responses were measured in vitro following stimulation with antigen. The results are shown in Figure Q13.19. Compound X' is most likely: A. IL-1 B. Leptin C. TNF- D. IL-10 E. Double-stranded RNA

B. Leptin

A mouse model for type 1 diabetes, the NOD mouse, has a well-described sex bias in the incidence and rate of diabetes onset. Female NOD mice are about twofold more likely to become diabetic, and do so on average about six-weeks earlier than male NOD mice. Recent studies have shown that a large component of this sex bias is due to differences in the intestinal microbiota between male and female NOD mice. In fact, colonization of young female NOD mice with male microbiota reduced the incidence and time to onset of diabetes in the transplanted mice, resulting in a disease course resembling that of the typical male NOD mice. These data indicate that: A. Male mice are genetically resistant to type 1 diabetes. B. Sex-based differences in microbiota have a substantial impact on immune system regulation. C. Differences in microbiota between male and female mice affect the regulation of pancreatic insulin-producing cells. D. Environmental factors are more important than genetic factors in determining which individuals acquire an autoimmune disease. E. Antibiotic treatment to eliminate intestinal microbiota would be a useful treatment for most autoimmune diseases

B. Sex-based differences in microbiota have a substantial impact on immune system regulation.

An area of cancer immunotherapy that is undergoing rapid development is the use of agents that function as checkpoint blockaders. These agents work by interfering with receptors on T cells that normally induce inhibitory signals that suppress T cell responses. For example, one clinical trial tested the effects of a drug known as ipilimumab, which is a human monoclonal antibody that binds to and inhibits CTLA-4, on patients with metastatic melanoma, a deadly form of skin cancer. A simplified version of these data are shown in Figure Q16.20. In this case, one group of patients received a peptide vaccine, comprised of a mixture of HLA class I-binding peptides derived from the melanoma antigen, gp100. A second group of patients received ipilimumab, and a third group received the gp100 peptide vaccine + ipilimumab. While mean survival times between the treatments were not that remarkable (~10 months for the two groups receiving ipilimumab versus ~6 months for the gp100 peptide vaccine alone), the remarkable finding was the durable long-term survival of ~20% of thepatients receiving ipilimumab. However, based on the similarity in the data for the group of patients receiving ipilimumab plus the gp100 peptide vaccine versus those receiving ipilimumab alone, the most likely affect of the ipilimumab is: A. That it promotes the development of effector T cells from tumor-specific naive T cells B. That it allows T cells already present in the patient to kill tumor cells more effectively C. That it promotes the activation of CD4 instead of CD8 T cells specific for the tumor D. To prevent the immunosuppressive environment of the tumor from killing T cells E. To act directly on the tumor cells, similar to a cytotoxic chemotherapeutic drug

B. That it allows T cells already present in the patient to kill tumor cells more effectively

Most vaccines currently administered are delivered by intramuscular injection. Yet the pathogenic organisms these vaccines aim to protect against usually enter the body by a different route. For instance, many viruses infect us via the respiratory tract, and many bacterial pathogens infect via the gastrointestinal tract. One major advantage of delivering vaccines against these organisms via their normal route ofinfection would be: A. That the vaccines would no longer require the incorporation of an adjuvant in their composition B. That the vaccines would elicit IgA antibodies in addition to IgG antibodies C. That the vaccines would no longer require several boosters to elicit protective responses D. That the vaccines would be more stable and not require refrigeration E. That the vaccines would be safer and have fewer side effects than injected vaccines

B. That the vaccines would elicit IgA antibodies in addition to IgG antibodies

Some forms of SCID are due to defects in common 'housekeeping' enzymes, such as enzymes involved in nucleotide biosynthesis pathways, that are present in all cells of the body. These genetic deficiencies cause SCID because: A. The enzymes responsible are normally expressed more highly in lymphocytes than in other cells of the body. B. The absence of these enzymes causes build-up of intermediates in the pathway that are toxic to developing lymphocytes. C. The absence of these enzymes deprives lymphocytes of purine nucleotides that are needed for their development. D. The absence of these enzymes impairs the extensive proliferation of developing lymphocytes needed to generate the large number of circulating B and T cells. E. The enzymes involved in these nucleotide biosynthesis pathways cannot be compensated for by redundant pathways in the cells

B. The absence of these enzymes causes build-up of intermediates in the pathway that are toxic to developing lymphocytes.

Unlike defects in antibodies or T cell functions, defects in complement components often lead to autoimmune-like symptoms, rather than to increased susceptibility to infections. This is because: A. Complement components do not require antibodies to attack microbial pathogens. B. The complement pathway normally functions to clear immune complexes from the circulation. C. Complement inhibitory proteins are up-regulated by complement activation. D. The complement pathway is part of the innate, rather than the adaptive immune response. E. Partial activation of the complement cascade promotes phagocytosis of host cells.

B. The complement pathway normally functions to clear immune complexes from the circulation.

A subset of patients with imbalances in glucose metabolism are found to have autoantibodies to the insulin receptor. These patients, as well as patients with myasthenia gravis, may be treated with a procedure known as plasmapheresis. During plasmapheresis for these disorders, blood is removed from the patient, and then separated into two fractions, one containing cells, and the other containing the plasma. The plasma is then treated to deplete it of antibodies, and then the cells plus the antibody-depleted plasma are returned to the patient. This cumbersome treatment may be necessary because, for these diseases: A. The disease symptoms are an indirect effect of inflammation induced by the autoantibodies. B. The disease symptoms are a direct effect of autoantibody binding to its target receptor on cells. C. Treatment with anti-inflammatory drugs makes the disease symptoms worsen D. The depletion of antibodies from the patient's plasma also eliminates all the complement components. E. The leukocytes in the blood are required to bind to antibody-coated target cells, so must be returned to the patient

B. The disease symptoms are a direct effect of autoantibody binding to its target receptor on cells.

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 ascramps, diarrhea or vomiting, and shortness of breath or wheezing. This variety of symptoms is a result of: A. Systemic production of inflammatory mediators causing responses in many tissues B. The presence of mast cells with pre-bound IgE in all mucosal tissues C. The simultaneous exposure of skin, oral mucosa, throat, and gastrointestinal tract to an ingested allergen D. The high concentrations of histamine present in pre-stored mast cell granules E. The presence of high concentrations of monomeric IgE in the circulation

B. The presence of mast cells with pre-bound IgE in all mucosal tissues

Mycophenolate mofetil is a cytotoxic drug that is commonly used in patients receiving kidney transplants, as part of a combination therapy with other immunosuppressive drugs. Studies have been performed to assess whether reductions in mycophenolate mofetil dose given to transplant patients starting around 4 months post-transplant have deleterious effects on the transplanted kidney function or on episodes of graft rejection. The motivation for this type of study is: A. The high expense of combination therapies that require multiple different drugs B. The side effects of the cytotoxic drug on healthy dividing cells in the body C. The convenience to the transplant patient of fewer medications to take on a daily basis D. The off-target effects of mycophenolate mofetil on non-dividing cells E. The possibility that transplant patients develop an allergic reaction to the mycophenolate mofetil

B. The side effects of the cytotoxic drug on healthy dividing cells in the body

In some cases, a transient autoimmune process can occur as a result of an infection. This may be due to molecular mimicry between the pathogen and a self-antigen, or to the release of normally sequestered self-antigens due to tissue damage from the infection. An important factor leading to these autoreactive immune responses is the activation of dendritic cells by the infection-induced inflammation. Once the infection is resolved, this inflammation will also subside. As a consequence, autoreactiveT cells may no longer receive sufficient signals to promote their activation, causing a remission in the autoimmune symptoms. One important change in antigen-presenting dendritic cells during an infection that would contribute to the activation of normally self-tolerant self-reactive T cells is: A. The down-regulation of phagocytic activity by activated dendritic cells B. The up-regulation of MHC class I and class II molecules on activated dendritic cells C. The increased production of Type I interferons by activated dendritic cells D. The increased expression of cytoplasmic nucleic acid sensors by activated dendritic cells E. The down-regulation of anti-inflammatory cytokines, such as IL-10, by activated dendritic cells

B. The up-regulation of MHC class I and class II molecules on activated dendritic cells

In the case of HIV infection by sexual transmission, a key step in the establishment of disseminated HIV infection is the replication of the virus in regional lymph nodes draining the mucosal site of initial virus entry. The ability of the virus to spread from the mucosa to the regional lymph node is made possible by: A. The high viral titers generated by the initial replication in the mucosal tissue B. The virus' ability to infect migratory cells that carry it from the mucosa to the lymph node C. The ability of infected CD4 T cells from the transmitting individual to proliferate and spread in the recipient's GALT D. The extremely high titers of HIV required for transmission from one individual to the next E. The resistance of virus in the mucosal tissue to elimination by antiretroviral drugs

B. The virus' ability to infect migratory cells that carry it from the mucosa to the lymph node

Effective vaccines have been developed against a number of deadly diseases, including viral diseases such as measles, mumps, polio, and smallpox, as wellas several bacterial infections. However, there remain several important infectious diseases for which vaccines are currently lacking. One important aspect of developing effective vaccines against these pathogens is: A. The discovery of an attenuated form of the pathogenic organism B. The purification of surface components of the pathogen C. A clear understanding of the immune mechanisms required to eliminate the infection D. The purification of toxins made by the pathogen E. The development of more effective adjuvants to include in the vaccine

C. A clear understanding of the immune mechanisms required to eliminate the infection

Based on these data, FcRIII is most likely: A. An Fc receptor that transports IgG from the blood into tissues B. An Fc receptor that transports antibodies across epithelial surfaces into the gut lumen C. An activating Fc receptor that stimulates phagocytic uptake and NK cell killing D. An inhibitory Fc receptor that inhibits macrophage phagocytic uptake via activating Fc receptors E. An activating Fc receptor that stimulates mast cell and basophil degranulation

C. An activating Fc receptor that stimulates phagocytic uptake and NK cell killing

Immune responses to tumors have been studied extensively in mice, using transplantable tumors injected into syngeneic mice. The basis for many of these studies is the assumption that the process of tumorigenesis generates mutations in genes encoding self-antigens that would allow the immune system to see these mutant proteins as 'foreign'. In this scenario, the dominant immune response targeting the tumorcells would be mediated by: A. Antibodies B. CD4 TH1 cells C. CD8 T cells D. NK cells E. FcR+ phagocytic cells

C. CD8 T cells

Patients with Wiskott-Aldrich syndrome show severely impaired responses to vaccines such as the tetanus vaccine, which is composed of the inactivated tetanus toxin (i.e., tetanus toxoid). Yet, these patients can generate normal antibody responses to bacterial polysaccharide antigens. This selective defect in antibody responses in Wiskott-Aldrich syndrome patients is due to: A. Defective antigen presentation by dendritic cells B. Impaired phagocytic function of macrophages and dendritic cells C. Defective polarized secretion of cytokines by CD4 T cells D. Impaired B cell activation to monovalent, rather than polyvalent antigens E. Impaired migration of B cells to germinal centers

C. Defective polarized secretion of cytokines by CD4 T cells

Multiple autoimmune diseases are associated with particular alleles of MHC class II molecules. For example, individuals expressing HLA-DR2 are nearly 16 times more likely to develop Goodpasture's syndrome than individuals expressing other HLA-DR alleles. The evidence to date indicate that these associations between MHC class II alleles and specific autoimmune diseases are due to: A. Enhanced negative selection in the thymus mediated by disease-associated HLAalleles B. Allelic variations in non-MHC class II genes encoded in the HLA locus C. Differences in the peptide-binding properties of different MHC class II alleles D. Differences in the autoantigens expressed in males versus females with disease-associated alleles E. Differences in the development of FoxP3+ regulatory CD4 T cells in individuals expressing different alleles

C. Differences in the peptide-binding properties of different MHC class II alleles

Abatacept is a biologic drug that is a fusion protein formed from the B7-binding domain of CTLA-4 fused to the human IgG1 constant region. In patients suffering from rheumatoid arthritis (RA), high levels of granzyme B in the synovial fluid ofinflamed joints is thought to contribute to joint erosion. When treated with abatacept, a subset of patients shows significant improvement in their RA symptoms together with decreased levels of granzyme B in their affected joints. These data indicate that the granzyme B found in RA patients' inflamed joints is predominantly made by: A. Antigen-presenting cells such as dendritic cells B. Activated macrophages C. Effector T cells D. FoxP3+ Treg cells E. Neutrophils

C. Effector T cells

A common misconception is that our immune system fails to make a productive immune response to HIV infection, thereby leading to chronic infection. In fact, following a primary HIV infection, our immune system: A. Generates a response, but it is an inappropriate Type II instead of a Type I response B. Generates a response characterized by a cytokine storm that is poor at controlling virus replication C. Generates a response that efficiently controls viral replication D. Generates immunity at the mucosal surfaces, but does not control the systemic infection E. Generates a T cell but not an antibody response to the virus

C. Generates a response that efficiently controls viral replication

HAART therapy is widely used in the US to treat HIV-infected individuals. This treatment is quite effective at inhibiting HIV replication, thereby preventing the progression to AIDS. However, HAART treatment is unable to completely eradicate all viral stores; consequently, patients must remain on this treatment indefinitely, as cessation of treatment leads to a rapid rebound in viral replication. One additional important side benefit of HAART treatment is its ability to: A. Block HIV binding to CD4 B. Block HIV binding to CCR5 C. Greatly reduce HIV transmission D. Stimulate CD4 T cell development in the thymus E. Block viral reactivation from latency

C. Greatly reduce HIV transmission

In the late 1990s, a group of individuals was discovered that remained uninfected with HIV, in spite of multiple exposures to the virus. Analysis indicated that these HIV-resistant individuals had a homozygous deficiency caused by a 32-bp deletionin a single gene, and furthermore, that this mutation was present at a frequency of ~10%(in heterozygous form) in individuals of European descent. These data provided clear evidence indicating that: A. Healthy individuals can have a genetic deficiency in the expression of CD4. B. Testing for HIV by seroconversion does not identify all infected individuals. C. HIV infection requires a co-receptor in addition to CD4. D. Some individuals can be infected with HIV but not develop AIDS. E. Both R5 and X4 variants of HIV are equally important in HIV transmission.

C. HIV infection requires a co-receptor in addition to CD4.

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: A. Reduced recruitment of eosinophils to the airway mucosa B. Enhanced production of IL-17 and IL-22 required to repair damaged epithelium C. Increased levels of IL-4 and IL-13 in the airway D. Increased numbers of CD4 Treg cells in the airway epithelium E. Reduced levels of allergen-specific IgE

C. Increased levels of IL-4 and IL-13 in the airway

Yersinia pestis, the causative agent of the bubonic plague, has multiple mechanisms of immune evasion. This Gram-negative bacterium is transmitted from fleas (body temperature, 26°C) to humans (body temperature, 37°C) by flea bites. Studies have shown that the lipopolysaccharide (LPS) produced by Y. pestis grown at 37°C is about 10-fold less potent at stimulating TLR4 signaling than is the Y. pestis LPS from bacteria grown at 26°C. When these two forms of Y. pestis LPS are compared for their abilities to induce responses from human macrophages, one would expect that the 26°C Y. pestis LPS would result in: A. Increased production of antimicrobial peptides B. Reduced production of IL-10 C. Increased production of TNF- and IL-6 D. Reduced production of Type I interferons E. Increased activation of the inflammasome

C. Increased production of TNF- and IL-6

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 hasa subsequent exposure to the same antigen. The sensitization phase is characterized by: A. Induction of IgA antibodies against the allergen B. Activation of tissue-resident ILC3 cells following stimulation by the allergen C. Induction of a CD4 T cell type II immune response D. Production of high concentrations of IL-12 and IL-23 by tissue-resident dendritic cells E. Recruitment of large numbers of neutrophils to the site of allergen entry

C. Induction of a CD4 T cell type II immune response

A mouse model for multiple sclerosis is induced by immunizing mice with murine central nervous system proteins mixed with Complete Freund's adjuvant. This adjuvant contains components that stimulate both TLR2 and TLR4. The adjuvant is essential to the development of autoimmunity because: A. It induces copious amounts of type I interferons. B. It prevents the differentiation of CD4 TH2 effector cells. C. It activates dendritic cells to up-regulate co-stimulatory molecules. D. It promotes tissue damage that mimics a central nervous system viral infection. E.It prevents the production of TGF- by astrocytes in the central nervous system.

C. It activates dendritic cells to up-regulate co-stimulatory molecules.

Genetic linkage studies have identified numerous genes in which certain polymorphisms are associated with a predisposition to autoimmune disease. Yet in most cases, the effects of individual genetic polymorphisms are very small, with each one being linked to a very modest effect on disease incidence. This indicates that: A. The genetic data are not providing useful information about genes involved in immune regulation. B. Autoimmune diseases can be caused by many different single gene defects. C. Many different environmental factors are determining which predisposed individuals develop autoimmunity. D. It is unlikely that autoimmune disease incidences would be increased in particularfamilies. E. Individuals with particular genetic backgrounds would have the same likelihood ofautoimmunity regardless of where they reside in the world

C. Many different environmental factors are determining which predisposed individuals develop autoimmunity.

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: A. Activation of the complement cascade leading to red blood cell lysis B. Trapping of red blood cells on large endothelial vessels C. Phagocytosis by Fc-receptor expressing macrophages in the spleen D. Stimulation of CD4 T cells recognizing modified red blood cell surface proteins formed by the binding of the drug E. Stimulation of CD8 cytotoxic T cells that recognize drug-self protein conjugates and are triggered to kill the red blood cells

C. Phagocytosis by Fc-receptor expressing macrophages in the spleen

A disease resembling systemic lupus erythematosis (SLE) can be induced in mice. A key characteristic of this disease is the production of autoantibodies with specificity for double-stranded DNA (dsDNA), nucleosomes, and ribonucleotide-protein complexes (RNPs). When these mice are treated with a small molecule TLR7 and TLR9 inhibitor, twice a week starting at 4 months of age, the data in Figure Q15.4are obtainedIn this system, the TLR7/TLR9 inhibitor: A. Prevents B cell activation by bacterial DNA from microbes in the environment B. Prevents B cell activation by DNA from commensal microbes in the gut C. Prevents B cell activation due to uptake of chromatin from apoptotic host cells D. Prevents B cell activation by IgG present in immune complexes E. Prevents B cell activation following low affinity antigens stimulating the B-cell receptor

C. Prevents B cell activation due to uptake of chromatin from apoptotic host cells

One group of immune deficiency diseases is caused by an inability of CD8 effector T cells to kill virus-infected target cells, due to defects in cytotoxic vesicle exocytosis. Because of the inflammatory response that accompanies a normal virus infection, together with the prolongation of this response due to the inability to control theinfection, patients with these disorders suffer from tissue damage caused by the infiltration of effector CD8 cells and activated macrophages into multiple organs. In addition, a subset of these patients also show increased susceptibility to extracellular and intracellular bacterial infections. This is because: A. CD8 T cells are required to kill extracellular bacteria B. CD8 T cells in these patients are defective in producing IFN-. C. Some proteins required for cytotoxic vesicle exocytosis are required for phagosome-lysosome fusion. D. Inflammatory cytokines in these patients are inducing macrophages to phagocytose red and white blood cells. E. Persistent uncontrolled herpesvirus infections cause immunosuppressive effects on bacterial clearance mechanisms

C. Some proteins required for cytotoxic vesicle exocytosis are required for phagosome-lysosome fusion.

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: A. Mast cells with their pre-bound IgE from the sensitized to the naive individual B. Purified IgG antibody from the serum of the sensitized to the naive individual C. T cells from the skin-draining lymph nodes of the sensitized to the naive individual D. Dendritic cells from the skin of the sensitized to the naive individual E. Fc-receptor positive phagocytes from the skin of the sensitized to the naive individua

C. T cells from the skin-draining lymph nodes of the sensitized to the naive individual

In the first few days following organ transplantation, patients are often treated with several doses of an antibody mixture known as anti-thymocyte globulin. Theanti-thymocyte globulin is generated by immunizing rabbits or horses with human T cells,to generate antibodies against the human T cell surface molecules. Following the anti-thymocyte globulin treatment, patients are generally put on a sustained regimen of cyclosporin A or other small-molecule immunosuppressive drugs. The immediate post-operative treatment with anti-thymocyte globulin is likely used to: A. Activate the patient's T cells in vivo to prevent infections B. Enhance the binding of the T-cell receptor to peptide:MHC on the graft C. Temporarily deplete the patient's T cells D. Allow the clinicians to monitor the patient's T cell numbers by flow cytometry E. Stimulate the development of FoxP3+ Treg cells

C. Temporarily deplete the patient's T cells

CAR T cells have shown remarkable efficacy in treating hematological malignancies (e.g., leukemias). More recently efforts have been underway to design CAR T cells to target solid tumors. One example currently in trials is a CAR T cell therapy for tumors expressing the protein mesothelin, a tumor associated-antigen found on many pancreatic cancers, ovarian cancers, and some lung cancers. A design of a CAR to target mesothelin is shown in Figure Q16.17. I n this cartoon, the component of the CAR indicated by the arrow is composed of: A. A T-cell receptor specific for mesothelin B. The ligand that normally binds to mesothelin C. The Fab fragment of an anti-mesothelin antibody D. A co-stimulatory receptor signaling domain E. The CD3 signaling components of the T-cell receptor

C. The Fab fragment of an anti-mesothelin antibody

Patients with X-linked lymphoproliferative syndrome type 1 (XLP1) have mutations in the SLAM-family adapter protein, SAP. These patients suffer from an inability to control infections of the herpesvirus Epstein-Barr virus (EBV) that infects B cells. Studies have been done using peripheral blood T cells from these patients to examine their response to EBV in comparison to the responses of normal individuals (EBV-infected) as controls. These data were obtained by ELISPOT analysis, to quantify the numbers of IFN--producing CD8 T cells per million peripheral blood leukocytes in response to several EBV peptides, indicated as peptide 1, 2, 3, or 4 (note: the patients and controls were matched for HLA class I molecules; Figure Q13.13) These results indicate that: A. XLP patients have a defect in priming CD8 T cell responses following EBV infection. B. XLP patients require IFN- production to kill EBV-infected B cells. C. XLP patients have normal CD8 effector cell priming following EBV infection. D. XLP patients have a defect in cytotoxicity by NK cells rather than by CD8 T cells. E. XLP patients have no defect in cytotoxicity by CD8 T cells

C. XLP patients have normal CD8 effector cell priming following EBV infection.

Viruses utilize many different strategies to evade the immune responseafter infection. One strategy, illustrated in Figure Q13.25, is an effect on virus-infected cells. The virus used in this experiment is most likely: A. An RNA virus with a segmented genome B. A retrovirus C. A negatively stranded RNA virus D. A large DNA virus E. A virus that establishes latency in the host

D. A large DNA virus

Safety concerns in the latter part of the twentieth century prompted thedevelopment of an acellular formulation of a vaccine directed against Bordetella pertussis, the causative agent of whooping cough. This acellular vaccine, made from a mixture of four B. pertussis proteins, was designed to replace the whole-cell B. pertussisvaccine, made from inactivated intact bacteria. Subsequent studies showed that the mechanisms of protection varied between the whole-cell and the acellular B. pertussisvaccines. One major difference was that the B. pertussis LPS present in the whole-cell vaccine stimulated dendritic cells to produce IL-23. As a result, the whole-cell B. pertussis vaccine, rather than the acellular vaccine, likely induced: A. A robust antibody response comprised primarily of IgA B. A robust systemic antibody response comprised primarily of IgG C. A strong inflammatory response leading to septic shock D. A robust cellular response comprised primarily of TH17 cells E. A robust cellular response comprised primarily of TFH cell

D. A robust cellular response comprised primarily of TH17 cells

Based on these data, FcRII is most likely: A. An Fc receptor that transports IgG from the blood into tissues B. An Fc receptor that transports antibodies across epithelial surfaces into the gut lumen C. An activating Fc receptor that stimulates phagocytic uptake and NK cell killing D. An inhibitory Fc receptor that inhibits macrophage phagocytic uptake via activating Fc receptors E. An activating Fc receptor that stimulates mast cell and basophil degranulation

D. An inhibitory Fc receptor that inhibits macrophage phagocytic uptake via activating Fc receptors

Rheumatoid arthritis is often classified as a T-cell-mediated autoimmune disease, where disease symptoms are caused by chronic inflammation in the joints. Yet approximately 50% of rheumatoid arthritis patients that were treated with aB-cell depleting antibody (rituximab, anti-CD20 antibody) showed significant improvement in their disease symptoms. This improvement following rituximab treatmentis due to: A. Off-target effects of rituximab that lead to inhibition of T cells B. Loss of T cell function after depletion of B cells C. Elimination of epitope spreading from B cells to T cells that prevents disease progression D. Elimination of autoreactive B cells and antibodies that contribute to disease symptoms E. Misdiagnosis of patients' disease as rheumatoid arthritis, when it is actually a different disease

D. Elimination of autoreactive B cells and antibodies that contribute to disease symptoms

Immune privileged sites, such as the brain, the eye, and the testis, are often the targets of autoimmune attack. Thus, once effector T cells are generated that have specificity for autoantigens expressed in these tissues, the effector cells can gain entry to the tissue and cause tissue damage. However, under normal circumstances, thepriming and differentiation of effector cells specific for antigens found in the brain, for example, is generally prevented. This is because 'immune privileged' sites: A. Express antigens that never leave the tissue where they are produced B. Are surrounded by tissue barriers that block all lymphocyte trafficking C. Express the cell death receptor, Fas D. Express the cytokine, TGF- E. Promote the differentiation of TH17 cells

D. Express the cytokine, TGF-

. The first drug treatment for HIV licensed in the US was zidovudine (AZT), a reverse transcriptase inhibitor. However, AZT has now been completely replaced by HAART as the recommended treatment for HIV-infected individuals. The use of HAART, rather than AZT, is preferred because: A. HAART includes a reverse transcriptase inhibitor that is more potent than AZT. B. HAART only needs to be taken once per week compared to daily AZT treatment. C. HAART has fewer side effects than AZT. D. HAART is a combination therapy that reduces the possibility of viral escape mutants. E. HAART is less expensive than AZT.

D. HAART is a combination therapy that reduces the possibility of viral escape mutants.

In 1918, a worldwide epidemic of influenza A resulted in the deaths of 40-50 million people. This strain of influenza A, known as H1N1—referring to the genotypes of the viral surface proteins, hemagglutinin (H) and neuraminidase (N)—was shown to be derived from an avian virus that adapted to infect and grow in human cells. Interestingly, by 1957, the H1N1 strains of Influenza A had completely disappeared from the human population, to be replaced by new strains (H2N2) that contained three gene segments from avian origin. The most likely explanation for the disappearance of the early twentieth century form of H1N1 Influenza A virus is: A. The replacement by a more pathogenic strain of Influenza A in 1957 B. The slow accumulation of mutations in the 1918 Influenza A virus that impaired its infectivity in humans C. The changes in human living conditions leading to spread of Influenza A from pigs into humans, rather than from birds D. High levels of existing immunity in the human population to the H1N1 surface antigens E. The greater mobility of the human population due to the rapid increase in airplane travel

D. High levels of existing immunity in the human population to the H1N1 surface antigens

The first JAK kinase inhibitor to be developed, tofacitinib, inhibits JAK1and JAK3. These two JAK kinases are required for the signaling pathways induced by multiple cytokines, including all of the receptors that share the cytokine receptor common gamma chain (c; includes the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), all of the receptors that share gp130 (includes the receptor for IL-6), the receptors for GM-CSF, IL-12, and IL-23, and both type I and type II (i.e., IFN-) interferon receptors. Tofacitinib has recently been shown to be effective in the treatment of severe rheumatoid arthritis, an autoimmune disease characterized by inflammation of the joints with prominent inflammatory cell infiltrates, autoantibodies, and eventual cartilage and bone destruction. A likely explanation for the therapeutic benefits of tofacitinib in this disease is: A. Its ability to inhibit the T cell functions that eventually lead to other disease symptoms B. Its ability to prevent T cell help for B cells producing autoantibodies C. Its ability to block migration of inflammatory cells into joints D. Its ability to block innate as well as adaptive immune responses E. Its ability to prevent T cell proliferation by blocking IL-2 receptor signaling

D. Its ability to block innate as well as adaptive immune responses

Celiac disease occurs when an individual makes an aberrant immune response to a protein in gluten, such as -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: A. All patients with celiac disease make IgA antibodies to transglutaminase. B. Gliadin-derived peptides stimulate epithelial cells to produce IL-15. C. Innate immune responses to gluten induce up-regulation of MIC-A on epithelial cells. D. More than 95% of patients express the MHC class II DQ2 allele. E. Monozygotic twins show an 80% concordance for developing celiac disease

D. More than 95% of patients express the MHC class II DQ2 allele.

Individuals that lack all T cells have the most severe form of immunodeficiency (SCID) and will not survive past their first birthday without a bone marrow transplant from a healthy donor. These individuals fail to make antibody responses to the normal childhood vaccines because: A. They generally lack all B cells B. SCID causes a defect in B-cell receptor signaling C. SCID patients lack AID, so their B cells cannot undergo class switching D. Most antibody responses require T cell help for the B cells E. Persistent infections in SCID infants disrupts hematopoiesis

D. Most antibody responses require T cell help for the B cells

Immunotherapies aimed at promoting anti-tumor immune responses are being developed for tumors of many different tissue or cell-type origins. Interestingly,some of these approaches, when tested in clinical trials, were found to also cause patients to develop autoimmune symptoms related to their tumor type. For instance, in patients with malignant skin cancer (melanoma), immunotherapy treatment can develop an autoimmune disorder known as vitiligo, in which T cells attack and destroy melanocytes in the skin, causing depigmentation. These findings indicate that, in some individuals the melanoma-specific anti-tumor T cell responses are directed at: A. Tumor-specific mutated oncogenes B. Transcription factors not normally expressed in melanocytes C. Oncogenic proteins encoded by viruses D. Proteins normally expressed in melanocytes E. Neoantigens created from expression of abnormally spliced mRNAs

D. Proteins normally expressed in melanocytes

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 donot affect the immune system directly. For example, among this latter group are genes that A. Regulate the recruitment of inflammatory cells to the airways or other mucosa B. Function in cytokine receptor signaling pathways C. Encode proteins expressed in airway epithelial cells D. Regulate barrier function by airway and skin epithelial cells E. Are common to atopic diseases and to autoimmune diseases

D. Regulate barrier function by airway and skin epithelial cells

Bone marrow transplantation is currently used to treat many immunodeficiency diseases resulting from defects in hematopoietic cells, such aslymphocytes or myeloid cells. Often, the donor of the bone marrow is a healthy relative of the patient, such as a sibling or a parent (Table Q13.18). Which of the individual relatives above would not be a potential donor for the patient's bone marrow transplant? A. Mother B. Father C. Grandmother D. Sibling 1 E. Sibling 2

D. Sibling 1

All-trans retinoic acid (tRA) is a metabolite generated from vitamin A in the diet, and is a key component in generating an appropriate balance of FoxP3+ regulatory CD4 T cells versus TH17 effector CD4 T cells in mucosal tissues. Patients withsome autoimmune diseases, such as psoriasis, derive benefit from oral synthetic retinoidtreatment for their condition. This indicates: A. A possible role for genetic defects in retinol dehydrogenase, an enzyme required to covert vitamin A into tRA, in autoimmunity B. That TH17 cells play a role in all autoimmune diseases C. That tRA likely has systemic actions unrelated to the immune system D. That environmental factors such as diet can impact the onset of autoimmunity E. A likely role for tRNA in the development of effector CD4 T cells in the skin

D. That environmental factors such as diet can impact the onset of autoimmunity

Systemic lupus erythematosis (SLE) is an autoimmune disease characterized by the development of autoantibodies specific for DNA and other nuclear antigens. Patients with SLE show a wide variety of symptoms that include anemia, skin rashes, joint and muscle pain, heart problems, and kidney damage. This is considered a systemic autoimmune disease because: A. Different patients have different symptoms. B. All patients have damage to more than one organ. C. The majority of patients have kidney damage D. The autoantigen targeted by the immune system is not-tissue specific. E. Multiple different tissue-specific autoantigens are recognized in a single patient.

D. The autoantigen targeted by the immune system is not-tissue specific.

Large clinical trials have been performed to compare the vaccine efficacy of the live-attenuated influenza virus vaccine with that of the inactivated virus vaccine. In all, data from over 25,000 children aged 6-71 months were analyzed. The conclusion was that the children who received the live-attenuated vaccine reported 50% fewer cases of influenza than those who received the inactivated vaccine. One difference in the immune response elicited by the live-attenuated versus the inactivated vaccine is: A. The live-attenuated vaccine elicits higher antibody titers than the inactivated vaccine. B. The live-attenuated vaccine elicits antibodies with higher affinities than the inactivated vaccine. C. The live-attenuated vaccine elicits increased numbers of CD4 TFH cells than the inactivated vaccine. D. The live-attenuated vaccine elicits antiviral CD8 effector responses but the inactivated vaccine does not. E. The live-attenuated vaccine induces antibodies of the IgA isotype, but the inactivated vaccine does not.

D. The live-attenuated vaccine elicits antiviral CD8 effector responses but the inactivated vaccine does not.

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: A. They are unable to generate an IgE antibody response to ovalbumin. B. They lack expression of the high affinity IgE receptor. C. Their inflammatory cells do not respond to chemokine receptor stimulation. D. They lack mast cells. E. They lack B cells

D. They lack mast cells.

While relatively rare, individuals with a homozygous deficiency in complement C1 activity have been identified, and >90% of them developed a lupus-like illness at a very young age. These individuals had significant kidney damage and damage to blood vessels in the central nervous system, both of which were associated with severe inflammation. A reasonable hypothesis to explain the development of the lupus-like disease in these patients is: A. Immune complex-mediated activation of the classical complement pathway B. Trapping of immune complexes in small blood vessels that block blood flow, leading to necrosis C. A non-immune function of C1 that is unrelated to the complement pathway D. A failure of immune complexes lacking complement deposition on them to bind to phagocyte Fc receptors E. A role for the complement pathway in clearing apoptotic cells from the circulation

E. A role for the complement pathway in clearing apoptotic cells from the circulation

One HIV vaccine trial provided some small measure of hope for the development of an effective HIV vaccine. This vaccine, known as RV144, was administered to a high risk population in Thailand, and reduced new infections by ~30%. To address the mechanism of immune protection correlating with vaccine efficacy, a series of studies were performed. In one study, total IgG antibodies from four non-infected vaccinees were isolated and were mixed with HIV-infected cells plus peripheral blood lymphocytes from healthy unrelated donors. As a control, IgG antibodies were purified from four donors receiving the placebo, rather than the RV144 vaccine. Six hours later, lysis of the HIV-infected target cells was assessed, as shown in Figure Q13.40 The immune mechanism that correlates with protection based on these data is: A. CD8-dependent target cell lysis B. Complement-dependent cell lysis C. Induction of apoptosis by TNF-R stimulation D. Target cell apoptosis induced by Fas-ligand stimulation E. ADCC induced by NK cells

E. ADCC induced by NK cells

Malaria is caused by protozoan parasites, Plasmodium falciparum andPlasmodium vivax. These pathogens are transmitted when an individual is bitten by a Plasmodium-infected mosquito. This route of transmission: A. Allows the parasite to directly infect the red blood cells of the human host B. Allows the infected blood cells of the mosquito to replicate and spread in the human host C. Allows the parasite to replicate in the blood and rapidly spread all over the body D. Prevents the parasite from being eliminated by the adaptive immune response E. Allows the parasite to avoid the normal mechanisms blocking infections at barriersurfaces

E. Allows the parasite to avoid the normal mechanisms blocking infections at barriersurfaces

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 TH2-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 Q14.13. The cell type most likely responsible for the tissue damage in this allergen-induced airway remodeling disease model is: A. Neutrophils B. Macrophages C. Mast cells D. TH2 cells E. Eosinophils

E. Eosinophils

A recent strategy showing some promise for the treatment of IgE-mediated allergies is a form of allergen immunotherapy, in which allergic individuals are given 3-4 intradermal injections of soluble peptides. For example, in one study, allergic individuals were injected with a set of 13-17 amino acid long peptides derived from the house dust mite protein antigen; these peptides were selected based on predictions for sequences likely to be MHC class II binding epitopes. Following the treatment, individuals were found to have increased numbers of antigen-specific IL-10-producing CD4 T cells, a finding that correlated with reduced allergic responses to allergen challenge. One of the goals of this therapy might also be to: A. Reduce the levels of IgE antibodies specific for the allergen B. Induce type 1 or type 3 immune responses that might inhibit the type 2 allergic responses C. Induce CD8 T cell responses that would kill allergen specific TH2 cells D. Induce IgG and IgA antibodies to the allergen E. Induce apoptosis of allergen-specific effector CD4 T cells

E. Induce apoptosis of allergen-specific effector CD4 T cells

HIV encodes several proteins that function to promote viral replication, packaging, and budding from host CD4 T cells. In addition to inhibiting cell-intrinsic antiviral mechanisms and down-regulating surface expression of MHC class I and class II molecules, these proteins function to: A. Induce constitutive activation of NF-B B. Promote nuclear localization of NFAT C. Block nuclear export of unspliced viral RNA D. Up-regulate surface expression of CD4 E. Induce robust, sustained CD4 T cell activation

E. Induce robust, sustained CD4 T cell activation

One of the first biologics developed was a drug known as etanercept (common name, Enbrel) that is a fusion protein formed from the cytokine binding domainof the TNF-receptor fused to the human IgG1 constant region, as shown in Figure Q16.6. This biologic is used to treat patients with inflammatory diseases such as rheumatoid arthritis, psoriasis, and others. Etanercept was developed to avoid injecting patients with the mouse monoclonal antibody to TNF-, which was available at the time. Etanercept was preferred because: A. It had a higher affinity for TNF- than the antibody B. It had a higher valency of binding to TNF- than the antibody C. It had a longer in vivo half-life than the anti-TNF- antibody D. It was easier and cheaper to produce than the antibody E. It would not elicit an anti-drug antibody response

E. It would not elicit an anti-drug antibody response

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: A. Enhanced mucus production B. Enhanced vascular permeability C. Increased accumulation of leukocytes in the lung D. Reduced mast cell activation E. Reduced bronchoconstriction

E. Reduced bronchoconstriction

Polymorphisms in the IL-2R chain gene are associated with multiple autoimmune diseases, including type 1 diabetes, vitiligo, multiple sclerosis, Crohn's disease, autoimmune thyroiditis, and juvenile arthritis. One hypothesis for this striking listof disease associations with polymorphisms in the IL-2R chain gene is that these alterations affect the function of FoxP3+ regulatory CD4 T cells. If this was the case, onewould expect that disease-associated alleles of the IL-2R chain gene would: A. Result in enhanced IL-2 production by FoxP3+ regulatory CD4 T cells B. Result in enhanced proliferation of FoxP3+ regulatory CD4 T cells C. Lead to reduced IL-2 production by FoxP3+ regulatory CD4 T cells D. Lead to enhanced development of FoxP3+ regulatory CD4 T cells in the thymus E. Result in reduced responsiveness of FoxP3+ regulatory CD4 T cells to IL-2

E. Result in reduced responsiveness of FoxP3+ regulatory CD4 T cells to IL-2

Some early studies aimed at deciphering the mechanisms involved in immunological tolerance, and its breakdown in cases of autoimmune disease, were based on generating transgenic mice that constitutively expressed a viral protein in the -islet cells of the pancreas. These mice were crossed to transgenic mice expressing a T-cell receptor specific for MHC class I bound to a peptide of this viral protein. The double transgenic mice generated large numbers of CD8 T cells capable of recognizing this viral antigen on -islet cells, yet the mice never spontaneously developed type I diabetes, a disease in which -islet cells are destroyed by T cells. This lack of response most likely reflects: A. The deletion of all the antigen-specific T cells by central tolerance mechanisms inthe thymus B. The fact that -islet cells in the pancreas are few in number, and therefore unableto generate enough antigen to prime T cell responses C . The absence of CD4 T cells that recognize the same viral antigen D. The fact that the pancreas is an immune privileged site E. The absence of infection or tissue damage needed to trigger the priming of effector T cell responses

E. The absence of infection or tissue damage needed to trigger the priming of effector T cell responses

The prevention of inflammatory immune responses to inhaled antigensin 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: A. The presence of tissue-resident dendritic cells that produce IL-23 when activated B. The presence of tissue-resident mast cells that bind IgE through the high affinity IgE receptor C. The high levels of constitutive IL-10 present in the mucosal surfaces of both the airway and the gastrointestinal tract D. The induction of increased numbers of IFN--producing T cells and ILCs in the airway and gastrointestinal epithelium E. The important role for CD4 regulatory T cells in suppressing inflammatory immune responses in these tissues

E. The important role for CD4 regulatory T cells in suppressing inflammatory immune responses in these tissues

Individuals with a complete absence of B cells and antibodies, such as patients with XLA, show a limited range of susceptibilities to infection rather than a global immunodeficiency to all categories of pathogens. For example, XLA patients showincreased susceptibility to pyogenic bacterial infections, as antibody binding to these microbes is critical for their uptake and destruction by phagocytes. Clinicians caring for these patients are advised regarding their vaccinations, some of which could be highly dangerous to the antibody-deficient patient. In particular, XLA patients should never receive: A. The tetanus toxoid vaccine composed of the inactivated toxin protein B. The pneumococcal vaccine composed of polysaccharide antigens from 9 strains of Streptococcus pneumoniae C. The influenza vaccine, composed of inactivated influenza virus D. The Hib vaccine, composed of Haemophilus influenzae type b polysaccharides conjugated to the tetanus toxoid protein E. The live oral polio vaccine, composed of an attenuated strain of the enteric poliovirus

E. The live oral polio vaccine, composed of an attenuated strain of the enteric poliovirus

The US Department of Health and Human Services has a stated goal for the seasonal influenza vaccine of vaccinating 80% of healthy (i.e., low-risk) individuals. This vaccine is formulated each year from the serotypes of influenza likely tobe circulating in the population during the coming flu season. The reason this goal is not 100% of individuals is because: A. It is not feasible to expect 100% of healthy individuals to get the flu vaccine everyyear. B. Individuals who had the flu vaccine the year before will already be protected. C. Individuals who are healthy need not be too concerned about getting infected with flu. D. Healthy individuals are unlikely to spread the virus to others. E. Unvaccinated individuals are protected when 80% of people around them are vaccinated.

E. Unvaccinated individuals are protected when 80% of people around them are vaccinated.

A mouse model of an immunodeficiency disease affecting the innateimmune response was generated by knocking out a single gene. Studies of these mice, performed in the 1990s, showed that they were highly susceptible to infections of pyogenic bacteria, such as Staphylococcus and Lactobacillus species, and to infections of fungal pathogens, such as Paecilomyces. In fact, without deliberately infecting the mice, the researchers performing these studies found that the knockout mice were spontaneously succumbing to these infections while housed in their vivarium (animal facility), as shown in Figure Q13.16A. To determine the potential mechanism leading to the immune deficiency, a series of additional studies were performed. In one study, peripheral blood leukocytes from the mice were mixed with Staphylococcus aureus bacteria, and the ability of the cells to kill the bacteria was assessed. In a second study, the compound thioglycolate was injected into the peritoneal cavity of the mice, and five hours later the numbers of white blood cells were measured. This compound elicits a robust inflammatory response in the peritoneum, including the production of several inflammatory cytokines, such as TNF, IL-1, and IL-6, as well as a number of chemokines known to recruit neutrophils and monocytes from the blood to the site of inflammation. The results of these studies are shown in Figure Q13.16B. Given these data, a likely candidate for the gene that was targeted in these knockout mice is: A. IRAK4 B. CD18, the integrin chain C. TLR3 D. G6PC3, the glucose-6-phosphatase catalytic subunit 3 E. p47, a component of NADPH oxidase

E. p47, a component of NADPH oxidase

Important information can be learned by studying the immune system of female carriers of the XLA disease gene. These individuals, identified as mothers of boys with XLA, show non-random X chromosome inactivation in their B cells, butrandom X chromosome inactivation in all of their other cells, including their T cells and macrophages. This finding indicates that: A. The BTK protein is expressed by bone marrow stromal cells that support B cell development. B. The BTK protein is required in hematopoietic stem cells. C. The BTK protein is required for mature B cells to enter lymphoid follicles. D. B cells and T cells do not share a common progenitor. E.B cells require the BTK protein for normal development

E.B cells require the BTK protein for normal development

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

False

True/False: 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.

False

True/False: Multiple mechanisms provide a series of checkpoints that function to maintain immunological self-tolerance. A breakdown in any one of these mechanisms is likely to lead to autoimmunity

False

True/False: The majority of monogenic defects in humans that cause autoimmune diseases are in genes that regulate T cell responses. These include the AIRE, CTLA4, FOXP3, and FAS genes. These findings indicate that B cells and innate immune cells are not important in autoimmunity

False

True/False: The population of HIV viral variants circulating in the human population is extremely diverse, a phenomenon that contributes to the difficulties in generating an HIVvaccine. However, within a given individual, all HIV viruses are genetically identical

False

True/False: All autoreactive CD4 T cells are not necessarily able to cause autoimmune diseases. Depending on the target tissue expressing the antigen recognized by the effector CD4 T cells, and the cytokines made by these effector T cells, autoimmune tissue damage may or may not occur

True

True/False: Defects in components of the complement pathway do not lead to recurrent or persistent virus infections.

True

True/False: Epidemiological evidence has indicated that exposure to particular infections can predispose individuals to specific autoimmune diseases. An example is the data linking Coxsackie virus infections with subsequent development of type 1 diabetes. In many cases, there is no indication of cross-reactive antigens between the pathogen and the autoantigens targeted by the autoimmune disease.

True

True/False: Evidence indicates that HIV-1 and HIV-2 originated in non-human primates, and only made the jump to infecting humans in the early twentieth century. As a consequence, these viruses are not well adapted to co-exist in equilibrium with their human hosts

True