Campbell-Walsh Urology, 11th Edition

PART IV

Molecular and Cellular Biology

18

Basic Principles of Immunology and Immunotherapy in Urologic Oncology

Charles G. Drake

Questions

  1. Antigen presentation involves both uptake of foreign proteins and processing to form peptide/major histocompatibility complex (MHC) complexes. Each of the following immune-responsive cell types can carry out this function EXCEPT:
  2. granulocytes.
  3. vascular endothelial cells.
  4. monocytes.
  5. macrophages.
  6. dendritic cells.
  7. Transplants between two siblings who are histocompatibility leukocyte antigen (HLA) identical (perfect class I and II match) can be rejected. This is primarily a consequence of:
  8. direct antigen presentation.
  9. differences in complement proteins.
  10. indirect antigen presentation.
  11. differences in childhood antimicrobial vaccination.
  12. differences in numbers of circulating platelets.
  13. Lymphocyte activation depends on complex interactions among many intracellular enzymes, transcription factors, and electrolytes. The influx of which electrolyte is most important for T-cell activation?
  14. Sodium
  15. Magnesium
  16. Potassium
  17. Phosphorus
  18. Calcium
  19. Anergy describes a state of immune nonresponsiveness to antigenic stimulation. The most effective way to induce a state of anergy is by:
  20. splenic irradiation.
  21. delivery of signal 1 and signal 2.
  22. depletion of complement proteins.
  23. delivery of signal 1 without signal 2.
  24. depletion of helper CD4 + T cells.
  25. Each of the following characteristics describes the utility and adaptability of the immune system EXCEPT:
  26. memory.
  27. rapid amplification.
  28. identification of self.
  29. antigen restriction.
  30. nonspecific defense mechanisms.
  31. Innate immune responses are nonspecific and include all of the following EXCEPT:
  32. natural killer cells.
  33. antibody-dependent cell-mediated cellular cytotoxicity.
  34. complement.
  35. acute-phase proteins.
  36. physical and mucosal barriers.
  37. Which cell surface glycoprotein is commonly referred to as the “pan-T-cell marker” because of its presence on all T lymphocytes?
  38. CD3
  39. CD4
  40. CD8
  41. CD28
  42. CD45
  43. The part of an Immunoglobulin (Ig)G antibody molecule that interacts with cell surface receptors on other immune reactive cells such as natural killer (NK) cells is the:
  44. hypervariable region.
  45. disulfide bonds.
  46. amino-terminal end of the antibody.
  47. Fc fragment.
  48. Fab fragment.
  49. The family of transcription factors termed nuclear factor of activated T cells (NFAT) are essential for T-cell activation and clonal expansion through the expression of the gene for:
  50. interferon-γ (IF-γ).
  51. transferrin.
  52. tumor necrosis factor.
  53. interleukin-2 (IL-2).
  54. IL-10.
  55. The receptor on B cells that recognizes antigen and transmits signals to the nucleus for gene expression is:
  56. the T-cell receptor.
  57. the surface IgD molecule.
  58. the surface IgM molecule.
  59. CD40.
  60. CD28.
  61. The JAK/STAT signaling pathways are critical in regulating cytokine expression. Inborn deficiencies in these pathways may lead to diseases such as:
  62. Burkitt lymphoma.
  63. Wilms tumor.
  64. neuroblastoma.
  65. retinoblastoma.
  66. severe combined immunodeficiency.
  67. The initial contact of host immunoresponsive cells with foreign antigen or transplanted donor tissue takes place in the:
  68. peripheral lymph nodes.
  69. thymus gland.
  70. spleen.
  71. bursa of Fabricius.
  72. bone marrow.
  73. Programmed cell death, apoptosis, is a mechanism responsible for the elimination of aged, damaged, autoimmune, or redundant cells. Caspase proteins are responsible for executing the suicide program by:
  74. release of granzyme B.
  75. activating the alternative complement pathway.
  76. activating natural killer cells.
  77. mediating DNA fragmentation and condensation.
  78. release of perforin.
  79. Tolerance describes the absence of lymphocyte reactivity to specific antigens that have been previously encountered by the immune system. Known mechanisms of tolerance include each of the following EXCEPT:
  80. deletion of reactive T cells.
  81. deletion of reactive B cells.
  82. blocking by antigen-antibody complexes.
  83. clonal anergy by delivery of signal 1 without costimulation.
  84. suppression of immune responses by regulatory cells.
  85. Chemokines are chemoattractant cytokines that localize various cell populations to tissue sites of inflammation. Each of the following cell types respond to chemokines EXCEPT:
  86. erythrocytes.
  87. granulocytes.
  88. natural killer cells.
  89. dendritic cells.
  90. monocytes.
  91. Although most human tumors are antigenic, the immune system is often not a significant barrier to tumor growth and metastasis. A major reason for the relative weakness of the immune system to eradicate tumors is:
  92. absence of costimulation by tumors leading to anergy.
  93. tumor-induced alterations of immune function.
  94. impaired function of tumor neovasculature.
  95. rapid tumor cell proliferation.
  96. lack of tumor cell Fc receptors.
  97. Tumor cell destruction by the immune system often is weak because of tumor cell escape mechanisms, which include all of the following EXCEPT:
  98. tumor cell release of IL-2.
  99. reduced expression of MHC class I and II molecules on tumor cells.
  100. tumor cell and local release of IL-10.
  101. ligation of tumor cell FAS by the FAS ligand (FASL) to induce apoptosis of host T cells.
  102. tumor cell and local release of transforming growth factor-β (TGF-β).
  103. Immunotherapy for metastatic renal cell carcinoma in humans has included the use of cytokines such as IFN-γ and IL-2. The objective response rate (both complete and partial responses) has been demonstrated in what percentage of patients?
  104. 95%
  105. 75%
  106. 55%
  107. 35%
  108. 15%
  109. Extracellular bacteria are susceptible to killing by phagocytosis and complement, but some have developed capsules to block these mechanisms. The most effective immune countermeasure for bacterial encapsulation is the:
  110. classical complement pathway.
  111. alternative complement pathway.
  112. opsonization of bacteria by circulating antibodies.
  113. increased secretion of TGF-β in tears.
  114. increased beating of bronchial cilia.
  115. Clearance of intracellular bacteria is most dependent on which immune cell population?
  116. Macrophages.
  117. Plasma cells.
  118. Natural killer cells.
  119. Dendritic cells.
  120. Primed T lymphocytes.
  121. Passive immune therapy may be particularly useful for patients with immunodeficiency. Passive therapy is delivered by:
  122. attenuated viral organisms.
  123. lyophilized vaccines.
  124. heterologous serum.
  125. live viral organisms.
  126. cow's milk.
  127. Toll-like receptors can be engaged by all of the following EXCEPT:
  128. bacterial flagellin.
  129. bacterial lipopolysaccharides.
  130. calcium.
  131. double-stranded viral RNA.
  132. paclitaxel.
  133. Recognition of Toll-like receptors by microbial products can activate all of the following immune mechanisms EXCEPT:
  134. adaptive immunity.
  135. intracellular microbial killing.
  136. innate immunity.
  137. IgE antibody formation.
  138. expression of costimulatory molecules.
  139. DNA microarrays depend on the ability of target nucleic acid sequences to:
  140. bind to the surface of activated lymphocytes.
  141. hybridize to complementary oligonucleotides or polymerase chain reaction (PCR) products.
  142. engage the T-cell receptor (TCR).
  143. bind to antibody fixed to a glass slide.
  144. fix complement.
  145. Gene expression profiling using DNA microarrays can be used to distinguish the following characteristics of urologic cancers EXCEPT:
  146. pathologic stage of the malignancy.
  147. diagnosis and classification of the malignancy.
  148. monitoring the host response to the malignancy.
  149. discovery of targets for treatment of the malignancy.
  150. definition of the clinical prognosis of the malignancy.
  151. Which of the following events do not play a role in the initiation of TCR signaling after engagement with antigen and MHC class II molecules?
  152. TCR interaction with CD4 coreceptor
  153. TCR interaction with CD8 coreceptor
  154. Phosphorylation of TCR and CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) by LCK and FYN kinases
  155. Recruitment of ZAP-70 to TCR and its activation
  156. Activation of the adaptor molecule, linker of activation in T cells (LAT)
  157. Which of the following is a FALSE statement regarding the JANUS family of kinases?
  158. The four JAK kinases are not constitutively associated with various cytokine receptors.
  159. The JAK kinases regulate different cytokine receptors.
  160. The cytokine-receptor binding causes dimerization of receptor chains resulting in JAK activation and phosphorylation of receptors.
  161. The STATs are recruited to receptors and phosphorylated by JAK kinases.
  162. Mutation in JAK3 results in severe combined immunodeficiency.
  163. Which of the following statements is TRUE regarding programmed cell death (apoptosis)?
  164. It is a mechanism for the elimination of aged, damaged, and autoimmune cells or cells no longer needed for differentiation.
  165. It is a mechanism for inducing a primary immune response.
  166. The proteins responsible for executing apoptosis, caspases, are JAK kinases.
  167. Caspase-8 is the initiator caspase for apoptosis initiated by FAS and the T-cell receptor.
  168. BCL-2 and BCL-XL are antiapoptotic proteins that protect the nucleus from damage.
  169. The development of an effective immune response to cancer cells is dependent on appropriate antigen presentation by dendritic cells and the subsequent activation of CD4 + and CD8 + T cells. Which of the statements listed below are TRUE?
  170. Many human tumors express antigenic epitopes that can be recognized by either CD4 + T cells or by CD8 + T cells.
  171. T cells can destroy tumor cells by several mechanisms, which include the elaboration of granules containing pore-forming proteins, the upregulation of FASL that can bind FAS receptors, and the activation of macrophages.
  172. IFN-γ production by lymphocytes is necessary but not sufficient for promoting antitumor immune response.
  173. Tumors may evade T-cell detection because of a loss of MHC class I/II molecules or because of a decrease in expression of transporter proteins associated with antigen processing.
  174. All of the statements are true.

Answers

  1. a. Granulocytes. Macrophages, monocytes, some B cells, Langerhans cells of the skin, dendritic reticulum cells, and vascular endothelial cells can process and present antigen.
  2. c. Indirect antigen presentation.The evidence for an indirect recognition pathway for alloantigens comes from observations that rejection can take place even if donor and recipient share most, if not all, MHC antigens.
  3. e. Calcium.This event also leads to the opening of the calcium channels in the plasma membrane, which further increases Ca2 + levels. Elevated intracellular Ca2 + results in the activation of the enzyme calcineurin, which is a cytosolic serine/threonine protein phosphatase that regulates the activation of a family of transcription factors termed nuclear factor of activated T cells (NFAT).
  4. d. Delivery of signal 1 without signal 2.In fact, stimulation by signal 1 alone leads to a state of anergy, whereby the T cell becomes unresponsive to further stimulation by antigen.
  5. d. Antigen restriction.Unique characteristics that help explain the utility and adaptability of the immune system against many different foreign invaders include (1) the ability to identify self from nonself, (2) specificity, (3) memory, and (4) rapid amplification.
  6. b. Antibody-dependent cell-mediated cellular cytotoxicity.Innate defense mechanisms represent nonspecific barriers to invaders, which rely primarily on physical barriers, phagocytic cells, natural killer cells, complement, acute phase proteins, lysozyme, and the interferons.
  7. a. CD3.Each T-cell precursor retains the pan-T-cell CD3 marker, which is the signal-transducing complex closely linked to the T-cell receptor.
  8. d. Fc fragment.The Fc fragment does not bind antibody but is responsible for fixation to complement and attachment of the molecule to the cell surface.
  9. d. Interleukin-2.NFAT along with other transcription factors plays a critical role in T-cell activation and clonal expansion through activation of the IL-2 gene.
  10. b. The surface IgD molecule.The receptor on B cells that recognizes antigen and transmits signals to the nucleus for gene expression is composed of a cell surface immunoglobulin containing heavy and light chains with variable regions.
  11. e. Severe combined immunodeficiency.The biologic importance of different JAKs and STATs has been revealed by deficiencies of these proteins both in human and animal models. Mutations in JAK3 have resulted in patients having severe combined immunodeficiency (SCID) that is similar to X-linked SCID, which occurs because of a mutation in the common cytokine receptor chain.
  12. a. Peripheral lymph nodes. Activation of specific T cells and the generation of an immune response require transport of antigenic components to the lymphoid tissue. For the induction of most T-cell–mediated immune responses, the crucial antigen-presenting cell is the dendritic cell, which is interspersed throughout peripheral tissues.
  13. d. Mediating DNA fragmentation and condensation. The proteins responsible for executing the suicide program, the caspases,are essentially common to all the stimuli and pathways and mediate the nuclear and cytoplasmic alterations characteristic of apoptotic cell death. The specific roles of each member of the caspase cascade are gradually becoming defined, whereby caspases 3, 6, and 7 have been identified as the terminal effectors mediating DNA fragmentation and chromatin condensation.
  14. c. Blocking by antigen-antibody complexes.An important mechanism mediating tolerance to self-proteins is the deletion of self-reactive T cells and B cells during maturation. Clonal anergy of T cells is induced by T-cell receptor engagement of peptide/MHC complexes in the absence of costimulatory signals. An active mechanism of tolerance mediated by T cells with suppressive or downregulatory activities may also be induced to inhibit immune responses to self and exogenous antigens.
  15. a. Erythrocytes.Cytokines with chemoattractant properties, chemokines, are also crucial in mediating localization and trafficking of leukocytes to tissue sites during physiologic processes, including inflammation and homeostasis.
  16. b. Tumor-induced alterations of immune function.Tumor-induced alterations in the functional status of immune cells may be responsible for the poor development of antitumor immunity in many cancer patients.
  17. a. Tumor cell release of IL-2.Natural killer cells can recognize and destroy some tumors, particularly those of lymphoid origin, without any exogenous activation. Reduction in or loss of MHC class I and class II expression by tumors, including renal cell carcinoma, has been well documented. In some tumors, there is also decreased expression of transporter proteins associated with antigen processing (TAP proteins). Among the best studied immunosuppressive molecules overexpressed in the tumor microenvironment is the Th2 cytokine IL-10. TGF-β is also thought to contribute to the suppression of tumor immunity. Evidence suggests that the downregulation of antitumor immunity may be due in part to the induction of the FAS apoptotic pathway in T cells.
  18. e. 15%.It is clear from these and other studies that a subset of individuals with metastatic renal cancer does respond favorably to cytokine therapy; however, they represent a minority of patients (< 15% response rate).
  19. c. Opsonization of bacteria by circulating antibodies.Many of these bacterial mechanisms can be overridden by host antibodies, which are soluble or secreted on external mucosal surfaces. Circulating antibodies can directly bind to bacterial exotoxins and "neutralize" them. They can also bind to the encapsulated bacteria, which will permit ingestion by polymorphs and macrophages.
  20. e. Primed T lymphocytes.Clearance of these intracellular microbes depends directly on T cells, which in turn must activate the infected macrophages. Specifically primed T cells react with processed antigen derived from the intracellular bacteria in association with MHC class II molecules on the macrophage surface.
  21. c. Heterologous serum.Protection against a specific infection can be passively transferred from one individual to another by serum containing preformed antibodies. This type of passive immunity is generally short-lived, because the half-life of immunoglobulins is 1 to 2 weeks. Patients with immunodeficiency diseases may actually be sustained by regular treatments with pooled nonspecific human immune globulin treatments.
  22. c. Calcium.Toll-like receptors are cell surface glycoproteins that need physical contact with other macromolecules such as bacterial flagellins, lipopolysaccharides, phytins, or nucleic acids. Minerals such as calcium are too small.
  23. d. IgE antibody formation.Engagement of Toll-like receptors activates various cellular immune responses. IgE antibody on the surface of mast cells promotes degranulation and allergy. IgE antibody is constitutively expressed on basophils/mast cells.
  24. b. Hybridize to complementary oligonucleotides or PCR products.DNA microarrays or gene chips are tests performed in a laboratory. They depend on the natural ability of two complementary strands of nucleic acids to hybridize to each other. The others are in vivo biologic processes.
  25. a. Pathologic stage of the malignancy. DNA microarrays can identify a unique molecular signature of a cancer, which represents the sum of genes upregulated or downregulated by the tumor.This can help classify the specific cancer, aid in identifying potential molecular targets for therapy, or possibly predict the outcome of therapy. The pathologic stage of the cancer is a description of its extent in the host. It is usually defined clinically, often aided by radiologic and histologic evaluation.
  26. b. TCR interaction with CD8 coreceptor.The interaction of the TCR and class II HLA antigens requires the stabilization of CD4 on T cells. Class I antigen would be required to engage the CD8 molecules. The initiation of further downstream intracellular events is dependent on the cell surface engagement of class II antigen and CD4.
  27. a. The 4 JAK kinases are not constitutively associated with various cytokine receptors.The JANUS family of kinases are constitutively expressed and are associated with various cell surface cytokine receptors. Once these receptors are engaged, the JAK kinases become activated and promote cytokine gene expression.
  28. a. It is a mechanism for the elimination of aged, damaged, and autoimmune cells or cells no longer needed for differentiation.The proteins responsible for executing the suicide program are the caspases, and they can be triggered by a number of mechanisms such as FAS and TNFR but not the T-cell receptor or JAK kinases.
  29. e. All of the statements are true.

Chapter review

  1. The immune response is divided into innate immunity and adaptive immunity.
  2. Innate immunity is nonspecific and involves polymorphonuclear leukocytes, macrophages, natural killer cells, complement, acute-phase proteins, interferons, and lysosomes, among others.
  3. Adaptive immunity is specific and involves lymphocytes, antibodies, and cytokines.
  4. Natural killer cells do not require prior contact with the antigen and are not MHC restricted.
  5. Immune responses may be either humoral or cellular. The humoral response involves antibodies, whereas the cellular response involves macrophages, T cells, dendritic cells, etc.
  6. The thymus is responsible for the selection and education of T cells; the bone marrow is responsible for the education of B cells, which produce antibody.
  7. Dendritic cells process antigen and present it to the T cells. T cells present antigen to B cells. B cells make antibody.
  8. The MHC markers (HLA) are divided into class I and class II.
  9. All nucleated cells express HLA class I antigens, whereas class II antigens are primarily found on B cells, monocytes, macrophages, and antigen-presenting cells.
  10. The major histocompatibility complex (MHC) is located on chromosome 6. Current tissue typing checks for three class I antigens—HLA-A, HLA-B, and HLA-C—and two class II antigens—HLA-DR and HLA-DQ. A six-antigen match refers to HLA-A, HLA-B, and HLA-DR.
  11. The T-cell receptor, or TCR, is responsible for the initial step in T-cell activation on encounter with an antigen. During antigen priming, CD4 + T cells produce cytokines.
  12. Chemokine production is primarily regulated by the cytokine environment. Chemokines attract leukocytes to the area in which they are located.
  13. T lymphocytes are central to the generation of an effective tumor immune response.
  14. Activation of CD8 + T cells that recognize tumor-associated antigens presented by MHC class I molecules and CD4 + T cells that respond to tumor-associated antigens presented by MHC class II molecules represents the most effective tumor immune response.
  15. There are five classes of antibodies: IgA, IgG, IgM, IgD, and IgE. They are produced by plasma cells (B cells).
  16. Immune responses to cancer are restrained by a specific set of molecules expressed on CD4 and CD8 tumor infiltrating lymphocytes. These "checkpoint" molecules are critically important in restraining the antitumor response.
  17. Interferons render cells more sensitive to attack.
  18. The major goal of cancer vaccines is to activate antigen-specific CD8 T cells.
  19. Inflammation has a role in the development of bladder cancer and possibly prostate cancer.
  20. DNA microarrays can identify a unique molecular signature of a cancer, which represents the sum of genes upregulated or downregulated by the tumor.