Allergy and Immunology Review Corner: Chapter 19 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD.

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1 Allergy and Immunology Review Corner: Chapter 19 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD. Chapter 19: Tolerance, Autoimmunity, and Autoinflammation Prepared by Meagan W. Shepherd, MD, Ohio State University 1. Which of the following terms refers to a specific immunological unresponsiveness to an antigen resulting from a previous exposure to the same antigen? A. Antigenicity B. Tolerance C. Allergenicity D. Immunodeficiency 2. Anergy refers to which of the following? A. T cell clones that are unable to respond to an antigenic stimulus B. B cells that are unable to produce immunoglobulin C. Induction of double negative T cells upon exposure to stimulus D. Activation of the Fas pathway 3. Which of the following molecules has the highest affinity when binding with CD80/86? A. MHC-I B. MHC-II C. CD28 D. CTLA-4 4. Which of the following diseases can be caused by a mutation to the Fas or Fas ligand gene? A. X-linked lymphoproliferative syndrome B. Severe combined immunodeficiency (SCID) C. Autoimmune lymphoproliferative syndrome (ALPS) D. Wiskott-Aldrich syndrome 5. Which of the following cytokines are the most important in suppressing the immune response? A. IL-3 and IL-5 B. IFN-gamma and IL-1 C. IL-2 and IL-4 D. TNF-β and IL Autoimmune Polyglandular Syndrome Type I (APS-1) is caused by a mutation or absence of which of the following? A. Autoimmune regulator (AIRE) B. Fas C. WASp protein

2 D. STAT 3 7. Which of the following is the proposed self-antigen in Wegener s granulomatosis? A. Thyrotropin receptor B. Nuclear antigens (SSA, SSB) C. Proteinase 3 (c-anca) D. Citrulinated peptides in the joint, IgG 8. Which of the following MHC-associations is found with multiple sclerosis? A. HLA-B27 B. HLA-DR2 C. HLA-DR4 D. HLA-B13 9. Which of the following drugs is not implicated in causing high rates of drug-induced lupus erythematosus? A. Hydralazine B. Amoxicillin C. Procainamide D. Isoniazid 10. True or False: B cells that bear receptors capable of recognizing self-antigens are all eliminated in the bone marrow? Answers 1. B, page 769 One of the most important immunologic principles required for an understanding of autoimmunity and autoimmune disease is the concept of tolerance, which refers to specific immunological unresponsiveness to an antigen resulting from a previous exposure to the same antigen. 2. A, page 773 One of the major mechanisms that the human body uses to inactivate self-reactive T cell clones that have escaped central and peripheral clonal deletion is anergy. By definition, anergy refers to T cell clones that are unable to respond to an antigenic stimulus. 3. D, page 774 CTLA-4, a homologue of CD28, also binds the CD80/86 ligands, but with greater affinity than CD28, resulting in the inhibition and negative regulation of T cell activation. MHC molecules do not bind with CD80/ C, page 773 There is another rare human disease called autoimmune lymphoproliferative syndrome (ALPS) that is caused by mutations similar to the lpr mouse mutations in either the Fas or Fas ligand gene (termed ALPS 1a and 1b respectively). Patient with these mutations have significant lymphadenopathy and also produce an array of autoantibodies.

3 5. D, page 775 The reactivity of T cells is under the influence of immunoregulatory cells either through direct cell-cell interaction or through the secretion of cytokines, e.g. transforming growth factor (TGF)-β and IL A, page 770 T cells that recognize autoantigens on the surface of the thymic epithelial cells undergo apoptosis, thus preventing peripheral autoimmunity. These autoantigens are proteins derived from a diversity of tissues and organs and are expressed on the thymic epithelial cells at least partly under the regulation of the transcription factor autoimmune regulator (AIRE). 7. C, page 779, Table 19-2 Wegener s granulomatosis is thought to be caused by self-antigens to proteinase 3 (c- ANCA). 8. B, page 781, Table 19-4 Multiple sclerosis is associated with HLA-DR2. 9. B, page 782 Of the thirty medications known to cause drug-induced lupus, the three that most commonly cause the condition are hydralazine, procainamide, and isoniazid. 10. False, page 777 although B-cell receptor rearrangement in the bone marrow is similar to T-cell receptor rearrangement, B cells that bear receptors capable of recognizing self-antigens are not necessarily eliminated in the bone marrow through negative selection. Some of these still-maturing self-reactive B cells exit the bone marrow and relocate peripherally to the spleen, where they reside initially in T cell zones. Allergy and Immunology Review Corner: Chapter 20 of Immunology IV: Clinical Applications in Health and Disease, by Joseph A. Bellanti, MD. Chapter 20: Immune Responses to Cancer Prepared by Monica Bhagat, MD, University of Pennsylvania 1. There are four groups of peptides that classify as TATAs (TAAs) or tumor-associated transplantion antigens. Which of the following is not representative of these four groups? A. Unique tumor-specific antigens B. Over-expressed self-antigen peptides/proteins C. Shared tumor antigens D. Bacterial-associated antigens 2. Which of the following innate immune cells play a key role in tumor immunity by

4 taking up tumor antigens and migrate to lymphoid organs where presentation of processed peptides to T cells occurs? A. Mast cells B. NK cells C. DCs D. Basophils 3. Antibodies can play a direct role in KILLING tumor cells via the activation of what key component of the innate immune system? A. Membrane-attack complex (MAC) B. Dendritic cells C. Mast cells D. Basophils 4. Which of the following is an example of a previously suppressed embryonic antigen? A. CEA B. MAGE tumor-associated antigen C. HPV D. P53 5. The following homeostatic immune actions are favored in the premalignant state by TGF-B EXCEPT: A. Apoptosis of premalignant cells B. Downregulation of tumorigenic inflammation C. Cytostasis D. Inhibition of effector cells 6. Which of the following is FALSE regarding the enzyme Indoleamine-2,3 dioxygenase (IDO)? A. It converts tryptophan to kynurenine B. It is only produced by mast cells C. It plays a role in the inactivation of the tumor suppressor gene Bin1 D. It is upregulated in plasmacytoid DCs leading to the activation of Tregs 7. In pathological differentiation of myeloid cells, immature myeloid cells may differentiate into myeloid-derived suppressor cells (MDSCs). These MDSCs express which of the following immune suppressive factors? A. Arginase 1 B. inos C. ROS D. All of the above 8. T regulatory cells are crucial in cancer immunology, in the sense that regulatory T cell mediated immunosuppression is one of the most crucial tumor immune-evasion mechanisms. Which of the following subset of Treg cells is INCORRECTLY identified by its marker?

5 A. Natural Treg (ntreg) = CD4+CD25+FOXP3+ B. Induced Treg (itreg) = CD4+IL10+FOXP3+ C. TH3 cells = CD4+TGF-B+ D. d. TR1 cells = CD4-CD25+FOXP3+ 9. In conventional immunotherapy, one can aim to mimic cytokines or block cytokines and/or inhibit their particular pathway. Out of the following cytokines, which one do scientists aim to INHIBIT? A. TGF-beta B. IL-5 C. IFN-alpha D. IL Which of the following monoclonal antibodies is INCORRECTLY paired with its target? A. Cetuximab and EGFR B. Trastuzumab and HER2 C. Bevacizumab and VEGF D. Canakinumab and IL-12 Answers 1. D, page 802, Table 20-1 Viral-associated antigens make up the fourth category of TAAs and include HPV, HBV, and EBV. 2. C, page 806 Dendritic cells play a crucial role in the interface between innate immunity and adaptive immunity via such presentation of processed peptides to T cells. Mast cells, macrophages, and even the DCs may be considered sentinel cells that are pre-stationed in tissue where they continuously monitor the microenvironment. 3. A, page 812 Antibody directed to TAA together with the activation of the complement systemc can kill the cancer cell by cytolytic activation of the MAC cascade. However, alternatively, TAA complexed with antibodies as Ag-Ab complexes can interfere with the CTL-killing of a cancer cell by blocking its activity. So antibodies directed against TAAs can either facilitate the killing of tumor cells or paradoxically enhance their growth. 4. A, page , Table 20-1 CEA is a type of tumor antigen that is a part of the category called overexpressed self antigen peptides. These include CEA and Muc-1 (colorectal cancer), Her-2/neu (breast cancer), and EGF receptor (colorectal, lung, head, and neck cancers). MAGE is shared among different tumors and is in the shared tumor antigen category, HPV is in the viral-associated antigen category, and p53 is part of the unique tumor-specific antigen category.

6 5. D, page 820. Fig TGF-B inhibits immune effector cells in the malignant progression stage, when TGF-B is functioning as a tumor promoter. TGF-B is considered a tumor supporter during the metastasis stage. 6. B, page 816 IDO is a key enzyme that converts Trp to Kyn and is involved in tumor growth and immune suppression. It does this by inactivating Bin1 and via the activation of Treg cells and blunting of T effector cell function. It is produced by alternatively activated macrophages and other immunoregulatory cells. 7. D, pages In the setting of infection, trauma, immunosuppression, or autoimmunity, a partial block in IMC differentiation results in their abnormal expansion. Such pathologic conditions can then lead to the differentiation into MDSCs which produce STAT-induced arginase 1, inos, and ROS. MDSCs are defined as CD14-CD11b+ cells that express CD33 but lack expression of markers found on mature cells. Key to note is that in response to tumor derived factors, the MDSCs will differentiate into TAMs (tumor-associated macrophages) which contributes to non-specific T cell suppression. 8. D, page 811, Table T regulatory 1 cells, or TR1 cells, are synonymous with induced Treg cells (itreg). TR1 cells are CD4+IL- 10+FOXP3+. Recall that there are CD4+ based Treg cells and CD8+ Treg cells. Some arise in the thymus, like the ntreg cells, while others arise in the periphery, like the itreg and CD8+IL-10+ Treg cells. 9. A, page 822, Table 20-4 IFN-alpha, along with IL-5, IL-7, and IL-21 have all been studied extensively by seeing if trial administration of such cytokines or recombinant forms of such cytokines can lead to the destruction of cancerous cells. The toxicity of utilizing interferons in general, however, has limited the use of recombinant IFN-alpha. TGF-B plays a pivotal role in tumor development, functioning as a tumor suppressor in the pre-malignant state and evolving to function as tumor promoter and eventually tumor supporter in the metastatic stage. Consequently, research is focused on antagonism of TGF-beta. 10. D, page 821, Table 20-5 Canakinumab targets IL-1 beta and was approved by the FDA in 2009 for use in CAPS (cryopyrin-associated periodic syndromes).