Knowledge Objectives in Immunology and Host Defenses

Transcription

1 Seventh Educational Strategies Workshop Teaching Microbiology & Immunology to Medical Students Knowledge Objectives in Immunology and Host Defenses Myrtle Beach, May, 1998 Sponsored by the Association of Medical School Microbiology and Immunology Chairs

2 Preamble Approximately twenty members of the Seventh Educational Strategies Workshop Teaching Microbiology & Immunology to Medical Students participated in the development of this document. As a working model, we reviewed an outline derived from a syllabus provided by Dr. Rod Nairn. The members initially assigned scores to the items listed using the following scoring system: 1 = essential material 2 = nice to know but not essential 3 = not essential At our next meeting, we compared our scoring and arrived at a consensus. We also debated suggested knowledge objectives that members thought we should include. We judiciously added these to the list at our third and last meeting. Ultimately, all items considered non-essential were deleted. Items considered being nice to know but not essential were preserved. These are identified by a double asterisk (**) on the pages that follow. Unmarked items were all considered to be essential. Finally, we surveyed the workshop group to learn how many curriculum hours are devoted to the areas of immunology/host defenses at individual schools. The following information was obtained (n = 19): Mean Median Range Lecture Hours: PBL 1 Hours Wet Lab Hours PBL hours includes POPS, small group teaching

3 1 Summary of Knowledge Objectives in Immunology and Host Defenses 1. Basic Concepts I 2: Basic Concepts II 3: Antigens and Antibody Structure 4: Antigen-Antibody Interactions 5: Antibody Diversity 6: T-Cell Receptor Complex 7: Major Histocompatibility Complex (MHC) 8: Antigen Processing and Presentation 9: B-Cell and T-Cell Activation 10. Regulation of T cells 11: Cells and Organs of the Immune Response 12: Development and Regulation of the Humoral Immune Response 13: Ontogeny of T Lymphocytes 14: Constitutive Defenses and Complement 15: Phagocytic Cells: Recruitment, Activation, Mechanisms of Bacterial Killing 16: Cytokine Networks, Inflammation, Arachidonic Acid Metabolism 17: Autoimmunity 18: Cell-Mediated Immune Reactions 19: Tumor Immunology and Cancer Immunotherapy 20: Ab-Mediated Cell & Tissue Injury: (Classification & Type I) 21: Ab-Mediated Cell & Tissue Injury: II (Types II & III) 22: Atopy, Anaphylaxis & Allergic Reactions 23: Asthma 24: Transplantation 25: Congenital and Acquired Immunodeficiency 26. Immunity to Microbes 1

4 2 1: Basic Concepts I 1. Describe in overall terms what the host defense system, why we need it what it does and how it does it. 2. Compare and contrast innate and adaptive immunity. 3. List several examples of barriers to infection (e.g., skin, mucous, etc.). 4. Describe in overall terms the major components of the inflammatory response. 5. Understand and be able to explain the difference between self and non-self. 6. Describe the clonal selection theory. 7. Compare and contrast antigen-dependent and antigen-independent differentiation of lymphocytes. 8. Describe in general overall terms several negative or damaging effects of the immune response. 9. Describe the significance of immunology in medicine by: (A) Listing several examples of disorders affecting the immune response. (B) Listing several benefits of immunology to medicine. 2

5 3 2: Basic Concepts II 1. Explain the difference between self and non-self. 2. Describe generation of diversity in the immune system. 3. Explain the essential role of gene families in the evolution of antigen recognitionin the immune system. 4. Describe the theory of clonal selection. 5. List the major types of specific immunity. 6. Compare and contrast active and passive immunity. 7. Describe the essential characteristics of humoral and cell-mediated immunity. 8. List the effector cells involved in the immune response. 9. Describe the fundamental characteristics that distinguish an immune response (specificity, diversity, memory, regulation). 10. Describe the phases of an immune response (e.g., cognitive, activation, effector). 11. Describe in general terms the networks regulating the immune response. ** 3

6 4 3: Antigens And Antibody Structure 1. Compare and contrast antigenicity and immunogenicity. 2. List the chemical classes of antigens. 3. Define antigen, antigenic determinant, epitope and hapten and give examples of each. 4. Describe the fundamental difference between B cell and T cell epitopes. 5. Explain the mode of action of adjuvants and recall some examples of adjuvant materials and give examples. 6. Describe the basic structure of the immunoglobulin molecule. 7. Recall the overall chain structure of the major classes and subclasses of immunoglobulins. 8. Recall the overall structure of the major Ig fragments (e.g., Fc) and describe the enzymatic digestion used to obtain these fragments. 9. List the major regions of the Ig molecule (e.g., hinge, variable hypervariable, etc.) and describe their overall structure and function. 10. Diagram the basic domain structure of the Ig molecule and the essential features of the tertiary structure. 11. Describe antigen-antibody interaction as a subset of receptor-ligand type interactions. 4

7 5 4: Antigen-Antibody Interactions 1. Describe the difference between soluble and insoluble immune complexes. 2. Describe a range of tests used in studying human disease that are based on the specificity of antibodies, e.g. Western blot for HIV antigens, competitive binding tests for low molecular antigens such as steroid hormones, etc. 3. Give examples of how different tests are utilized, e.g. immunofluorescence microscopy to detect antigen in tissue sections. 4. Describe in overall terms the general principles of each tests, e.g. ELISA is based on bound antibody being detected by an enzyme-dependent color change reaction, etc. 5. Define affinity, avidity, and describe their role in immune pathogenesis 5

8 6 5: Antibody Diversity 1. Recall the difference classes and subclasses of immunoglobulin molecules. 2. Describe the structural basis of the above classification **. 3. Recall the different types and subtypes of light-chains. 4. Describe the structural basis of the above classification **. 5. Explain the differences between isotype, allotype and idiotype. 5. Describe constant, variable and hypervariable regions with respect to antibody structure. 7. Describe and explain the molecular genetic mechanisms involved in the generation of antibody diversity (e.g., somatic mutation, junctional diversity etc.). 8. Diagram light chain gene organization. 9. Diagram heavy chain gene organization. 10. Explain allelic exclusion with respect to immunoglobulin gene expression. 11. Explain isotype switching. 11. Describe the genetic mechanism used to produce membrane-bound and secreted forms of Ig. 13. Describe the mechanism used to regulate expression of IgD. 6

9 7 6: T-Cell Receptor Complex 1. Describe the overall structure of the TCR molecule. 2. Differentiate between the two types of TCR (alpha/beta, gamma/delta) and distinguish their subsets. 3. Recall the molecular genetic mechanisms used to generate diversity in the TCR. 4. Compare the gene organization of the TCR with Ig.** 5. Recall that unlike for Ig genes, somatic mutation is not a mechanism used to generate diversity in the TCR genes. 6. Diagram the role of the TCR in recognition of antigen on the APC 7. Describe the concept of the immunoglobulin supergene family and list several members of the family (e.g., Ig, TCR, MHC, etc.). 7

10 8 7: Major Histocompatibility Complex (MHC) 1. Describe the function of MHC molecules in antigen presentation and in cellcell interactions in the immune system 2. Explain the concept of transplantation antigen 3. Recall the laws of transplantation 4. Diagram the genetic organization of the HLA complex 4. Recall the similarities and differences between the HLA and H-2 complexes ** 6. Describe the three major classes of MHC gene products 7. List the major structural features of the MHC gene products (e.g., Class I molecules are two chains, a heavy chain and a 2- microglobulin chain. 8. Identify the tissue distributon of class I and classii MHC 9. Recall several examples of MHC/disease correlations and provide a hypothesis to account for this correlation 10. Explain MHC polymorphism and the likely selective advantage of such a system 11. Describe the concept of MHC restriction and provide examples of the functional consequences of the restriction of T cell recognition 12. Define: haplotypes, genotypes, phenotypes, alleles, linkage disequilibrium. 13. Diagram a proposed model of MHC-Ag-TCR interaction 8

11 9 8: Antigen Processing and Presentation 1. Recall that T lymphocytes recognize antigen bound to MHC molecules. 2. Recall that T lymphocytes primarily recognize protein antigens and in fact recognize linear determinants as opposed to the conformational determinants recognized by B cells. 3. Recall that T lymphocytes recognize antigen on the surface of other cells (antigen-presenting-cells (APC s) or target cells). 4. List several examples of APC s (e.g. dendritic cells, macrophages, B cells, etc.). 5. Describe the phenomenon of MHC-restricted antigen recognition and diagram this recognition process for both helper and cytotoxic T lymphocytes. 6. Describe in overall terms the conversion of polypeptides to peptide antigens via antigen processing (e.g. the role of acidic intracellular compartments, proteases, etc.). 7. Diagram the pathway of processing of an exogenous protein antigen. 8. Diagram the pathway of processing of an endogenous protein antigen. 9. Describe the selectivity of binding of peptides antigens to Class I and Class II - MHC. 10. Compare and contrast the presentation of exogenous and endogenous antigens to T lymphocytes. 11. Recall and be able to diagram the process of superantigen recognition by T cells. 12. Explain the physiological significance of MHC-associated antigen presentation and recognition. 9

12 10 9: B-Cell and T-Cell Activation 1. Describe the B cell receptor complex and outline the structure of the molecules involved. 2. Recall the difference between transmembrane and secreted immunoglobulin. 3. List several examples of biochemical events triggered in B cells by antigen recognition. 4. Recall that most B cell responses require additional signals to that provided by antigen alone. 5. Describe the T cell receptor CD3 complex and outline the structure of the molecules involved. 6. List several examples of biochemical events triggered in T cells by antigen recognition. 7. Diagram the mechanism of superantigen activation of T cells. 8. Recall the mechanism of inhibition of T cell activation used by several drugs, e.g. cyclosporin A 9. Define the two signal model of T cell activation and the role of costimulatory molecules. 10

13 11 10: Regulation of T cells 1. Define the roles played by mechanisms leading to apoptosis and anergy in the regulation of T cells 2. Recall mechanisms of peripheral tolerance 3. Recall the roles played by cytokines in the regulation of T cells (Th1, Th2) 11

14 12 11: Cells and Organs of the Immune Response 1. Describe in general terms the development of white blood cells from stem cells to progenitor cells to mature cells. 2. Recall the role of growth factors/colony-stimulating factors/cytokines in this process. 3. Describe the different maturational stages of B and T cells (small lymphocyte, blast cell, plasma cell, etc.). 4. List the markers used to distinguish different lineages, subsets and maturational stages of lymphocytes. Be familiar with the functional significance and/or cellular distribution of the following: CD2, 3, 4, 5, 8, 11b, 14, 16, 19, 25, 40, 45, 56, TCR,BCR, B Define the functional subsets of T cells. 6. Describe the characteristics and functions of monocytes and macrophages (phagocytosis, antigen processing, etc.). 7. Describe the characteristics and functions of the granulocytic cells (neutrophils,eosinophils, basophils), mast cells, dendritic cells and natural killer cells. 8. Describe the role of the thymus in maturation and selection of T lymphocytes. 9. Recall and describe the processes of positive and negative selection, programmed cell death (apoptosis), etc., and their roles in the thymus. 10. Describe the role of the bone marrow in lymphocyte origin. 11. Describe the role of the spleen and lymph-nodes as organs of lymphocyte lodging. 12. Describe the function of the secondary lymphoid organs in trapping and processing antigens. 13. Recall the functions of different regions of the spleen and lymph-nodes in lymphocyte 14. Recall the distribution of lymph nodes in the body. 15. Recall the location and function of specialized lymphoid tissues such as the mucosal-associated-lymphoid tissues (Peyer s patches, secretory piece, etc.). 16. Recall the recirculation of lymphs and the role of adhesion molecules in lymphocyte trafficing. 12

15 13 12: Development and Regulation of the Humoral Immune Response 1. Describe the sequence of events in the B cell developmental pathway from stem cell to plasma cell. 2. Diagram the order of rearrangement and expression of Ig heavy chain and light chain genes during development of the B cell. 3. Recall the antigen-independent and antigen-dependent phases in B cell ontogeny. 4. Describe the mechanism of antigen induced B lymphocyte activation. 5. Recall the role of B lymphocytes as antigen-presenting cells (APCs). 6. Compare and contrast the effects of T independent and T dependent antigens. 7. List several examples of T independent antigens and describe the typical characteristics of such antigens (e.g., polyclonal activators). 8. Describe the mechanism of T H -B cell collaboration and explain the observation known as the hapten-carrier effect. 9. Recall the role of cytokines in B lymphocyte differentiation, e.g., the role of IL-4 as a switch factor for IgE synthesis. 10. Diagram the cell-cell interactiosn in a humoral immune response to a protein antigen (e.g., T H, cytokines, APCs interact with B cells, etc.). 11. Recall the role of the germinal center in somatic hypermutation of Ig ** 12. Recall the specialized functions of the human Ig isotypes.list examples of the specific role of different Ig isotypes in host defense, e.g. IgA may neutralize toxins in the gut. 13. Diagram the process by which IgA crosses the epithelium and recall the role of the poly-ig receptor in IgA secretion. 14. Understand the process of antibody feedback in negative regulation of B cells and the roles played by FcRII, ITIM, and ITAM 13

16 14 13: Ontogeny of the T Lymphocyte 1. Recall the developmental pathway of T cells in the thymus. 2. Recall that they thymus is the major site of selection and maturation of both helper T cells and CTLs. 3. Describe the overall structure of the TCR (alpha/beta and gamma/delta). 4. Explain the processes of positive and negative selection in the thymus. 5. Describe the development of TCR and CD4/CD8 expression in maturing T cells. 6. Describe the activation of T cells, e.g. the interactions between APCs and T cells leading to T cell activation. 7. List examples of cell adhesion molecules, e.g. ICAM, LFA Describe the process of differentiation of cytotoxic T cells from pre-ctl. 9. Recognize that tolerance is the antigen-induced, immunologically specific inactivation of lymphocytes. 10. Recall that two basic mechanisms exist to induce tolerance: (a) clonal deletion and (b) clonal anergy (or functional inactivation). 14

17 15 14: Constitutive Defenses and Complement 1. Describe the mechanisms by which the complement system is activated and regulated. Chemotaxis, anaphylotoxins, clearance of immune complexes, B cell activation, CR, phagocytosis, opsonization, resp. burst 2. List the effector molecules of complement activation and their biologic function. 3. Recall the role of complement in bacterial clearance and lysis. 4. Explain the effects of specific complement deficiencies on patients. 5. Recall the use of plasma CH50 levels in the assessment of disease processes** 6. Recall the regulation of C3 convertase and MAC 15

18 16 15: Phagocytic Cells: Recruitment, Activation, Mechanisms of Bacterial Killing 1. Describe various phagocytic cells in the body. 2. Define the role of guanine nucleotide binding regulatory proteins (G-proteins) in the activation of inflammatory cells ** 3. Define the role of phospholipases, calcium, protein kinase C and tyrosine kinases in inflammatory cell activation. ** 4. Define the role of transcription factors in the action of inflammatory cells. ** 5. Define the role of cyclic nucleotides (camp and cgmp) in modulating inflammatory cell-mediated tissue injury **. 6. Describe the possible effect of nitric oxide in inflammatory cell-mediated tissue injury. 7. Recall the pathways involved in reactive oxygen burst and the formation of reactive oxygen metabolites following tissue injury. 8. Define the role of Fc receptors and complement receptors in opsonization and phagocytosis. 9. Recall the role of enzymes, scavengers, and anti-proteases in the protective mechanisms against tissue injury **. 10. Define the functional role of cell adhesion molecules including selectins, integrins, and immunoglobulin superfamily members. 11. Recall the role of endothelial cell activation in leukocyte recruitment. 12. List the chemotactic factors involved in the recruitment of various inflammatory cells. 13. Recall the time course of stimulus-induced increased expression of endothelial cell adhesion molecules **. 16

19 17 16: Cytokine Network and Inflammation, Arachidonic Acid Metabolism 1. Recall various roles of cytokines in cell-to-cell communication 3. Describe the general functions of cytokines. (IL-1, 2,3, 4, 5, 6, 8, 10, 12, IFN, GM-CSF, G-CSF, M-CSF, TNFa, TGFb, chemokines) 4. Compare and contrast the individual effect of several cytokines (including IL- 1, TNF, interferons, IL-6 and chemokines) on natural immunity. 5. Discuss the role of several cytokines and cytokine receptors (including IL-2, IL-4, TGF ) in the activation, growth and differentiation of lymphocytes. 6. Recall the role of several cytokines (including IFN-Lymphotoxin, IL-5, IL-12) as regulators of immune-mediated inflammation. 7. List several cytokines that stimulate hematopoiesis. 8. Describe the pathways involved in cytokine regulation of neutrophil function** 9. List the cytokines involved in the acute phase response. ** 10. Discuss the potential therapeutic role of cytokines in cancer. 11. Discuss the potential therapeutic roles of antibodies specific for cytokines and/or their receptors in: Sepsis, Inflammatory Bowel Disease, Rheumatoid Arthritis and Graft-versus-Host Disease. 12. Recall the lipopolysaccharide (LPS)-induced cytokine cascade 17

20 18 17: Autoimmunity 1. List several examples of autoimmune diseases mediated by autoantibodies, e.g. myasthenia gravis, Graves disease, Lupus, etc. 2. List several examples of autoimmune diseases mediated by T cells, e.g. EAE. 3. Describe several mechanisms that help to explain anti-self responses, e.g. immunological cross-reactions, breaking tolerance 4. Describe the role of MHC genes in autoimmunity. 5. Provide several hypotheses to account for the association of autoimmune diseases with MHC genes, e.g. molecular mimicry, etc. 18

21 19 18: Cell Mediated Immune Reactions 1. Diagram the process of CTL-mediated cell lysis, e.g. role of perforin 2. Recall the role of CD4 T cells in activation of macrophages. 3. Recall cell-mediated immune responses induced by:nk responses, ADCC, LAK, DTH and give some clinical examples (e.g. contact sensitivity, intracellular infections, granulomas). 4. Give examples of current therapies for DTH 19

22 20 19: Tumor Immunity /Cancer Immunotherapy 1. Describe the concept of immunosurveillance. 2. Recall several examples of tumor antigens, e.g. TSTAs, oncogenic vial antigens, etc. 3. Describe the roles of antibody, T cells, NK cells, etc. in tumor immunity. 4. Describe the involvement of MHC molecules in tumor immunity, e.g. the effect of virally induced low MHC expression. 5. List several ways in which tumors evade immune recognition, e.g. antigen modulation. 6. Describe several approaches to tumor immunotherapy, e.g. antibody-toxin conjugates, IL-2, etc. 7. Lymphoproliferative disorders. 20

23 21 20: Antibody Mediated Cell & Tissue Injury: I (Classification & Type I) 1. List the Gell and Coomb s classification 2. Describe the pathophysiologic mechanisms associated with Type I (IgE) - mediated injury 3. Diagram the processs of mast cell degranulation 4. List the primary effector mediators released by mast cells 5. Describe the pathologic changes in tissues during anaphylactic reactions 6. Explain the modulator role of eosinophils in allergic and anaphylactic reactions 7. Correlate the effect of mediators on target organs with clinical expression of allergic reactions 8. Modulation of type I hypersensitivity 9. Describe the clinical expression of anaphylactic reactions and diagnosis via skin tests, RAST, immunoassays, etc. 10. Non-immune mechanisms of type I hypersensitivity 21

24 22 21: Antibody Mediated Cell & Tissue Injury: II (Types II & III) 1. Define type II and type III reactions 2. Compare complement mediated cell lysis and antibody dependent cell cytotoxicity 3. Compare immunopathology of Goodpasture s syndrome and Lupus. 4. Diagram the effects of antibodies on cell surface receptors 5. List the diagnostic techniques used (e.g. immunofluorescence and EM techniques) to evaluate Types II and III tissue injuries 6. List the therapies used for the diseases that involve Type II and II reactions (e.g. immunosuppression, plasmapheresis etc.) 7. Recall drug-induced type I and II hypersensitivity. 8. Recall erythroblastosis fetalis 9. Recall mechanism and histopathology of Arthrus reaction. 22

25 23 22: Atopy, Anaphylaxis & Allergic Reactions 1. List the clinical forms of allergic diseases 2. List the characteristics of atopic conditions 3. Describe the immunologic reaction types encountered in office practice (type I through type IV) 4. Explain skin test reactions 5. Recall the clinical presentation and management objectives for anaphylaxis 6. Explain anaphylactoid reactions 23

26 24 23: Asthma 1. Describe the different forms of asthma, allergic and otherwise 2. List the bronchial wall changes that occur in asthma 3. Recall the physiologic deficits caused by asthma (blood gases, etc.) 4. Describe allergic asthma 5. Describe non-allergic asthma 6. Recall the treatment considerations of various forms of asthma 24

27 25 24: Transplantation 1. Recall the main areas of clinical organ transplantation. 2. Recall that the major molecular targets in graft rejection are the non-self MHC molecules. 3. Describe the difference between major and minor MHC molecules. 4. Recall the overall molecular structure of the MHC Class I and II molecules. 5. Recall the overall genetic organization of the HLA complex. 6. Describe hyperacute, acute and chronic rejection. 7. Compare and contrast the immunological reactions occurring in the above tyeps of host response to a foreign graft. 8. Give examples of tests used to measure tissue histocompatibility. 9. List several approaches to prolonging graft survival (e.g. immunosuppressive drugs). 10. Describe the special immunological complexities that can be associated with bone marrow transplantation (GVHD, etc.). 11. Immunohematology (blood group Ags) 25

28 26 25: Congenital and Acquired Immunodeficiency 1. Explain how experiments of nature confirm results of lab animals (ThyX, DeGeorge, bursectomy, CD40L knockout mice, SCID mice). 2. Define acquired and congenital immunodeficiencies with some examples (HIV, primary deficiencies of T and B cells, phagocyte defects, complement, ancilary deficiencies, aging). 3. Mechanisms for congenital deficiencies (ADA, etc.) 4. Therapies for treating congenital immunodeficiencies. 5. HIV (structure, receptors, immunopathology, infectious diseases). 26

29 27 26: Immunity to Microbes 1. Immunity to extracellular and intracellular microbes (bacteria, parasites, fungi viruses). 2. Vaccination (inactivated, attenuated, recombinant vaccines, DNA vaccines). 3. Active vs. passive immunity to microbes 4. Mechanisms of immune evasion. 27