Chapter 1 Basic Concepts in Immunology PDF

Basic Concepts in Immunology Literature: Chapter 1, Janeway’s Immunobiology ETH Zürich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024 Take-home messages from Chapter 1 The immune...

Basic Concepts in Immunology Literature: Chapter 1, Janeway’s Immunobiology ETH Zürich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024 Take-home messages from Chapter 1 The immune system defends the host against infection. Most cells of the immune system arise from the bone marrow. Innate immunity serves as a first line of defense and depends on general recognition of pathogenic patterns. Adaptive immunity is based on clonal selection and expansion of pathogen- specific leukocytes that can effectively fight the pathogen. The adaptive immune response also generates increased numbers of memory cells, which enable a more rapid and effective response upon reinfection. 2 Content 1. Introduction to Immunology 2. Principles of innate immunity 3. Principles of adaptive immunity 4. The effector mechanisms of adaptive immunity 5. Lymphoid organs 6. Immune cell types 3 1. Introduction to Immunology The beginnings: Edward Jenner In 1796, Jenner demonstrated that inoculation with cowpox protected the recipient against smallpox. Jenner called the procedure vaccination: Inoculation of healthy individuals with inactivated or attenuated pathogens or pathogenic constituents to induce protective immunity Eradication of smallpox by vaccination (WHO announcement 1979) 4  1. Introduction to Immunology Vaccination: The most effective means of controlling infectious diseases Subacute sclerosing panencephalitis (SSPE): a brain disease that is a late consequence of measles infection in a few patients. 5  1. Introduction to Immunology Main function of the immune system: Protection from infection Leukocytes (immune cells) Lymphoid organs  1. Introduction to Immunology Leukocytes, erythrocytes and platelets arise from pluripotent hematopoietic stem cells in the bone marrow The pluripotent hematopoietic stem cells give rise to: Common lymphoid progenitor T and B lymphocytes natural killer (NK) cells innate lymphoid cells (ILCs) Common myeloid progenitor dendritic cells granulocytes monocytes megakaryocytes => platelets erythrocytes 7  1. Introduction to Immunology The categories of disease-causing microorganisms (pathogens) Size comparison: Different strategies neutrophils: 10-12 µm needed to fight different types of pathogens! T cell: approx. 7 µm macrophages: approx. 20 µm 8  1. Introduction to Immunology The major types of pathogens confronting the immune system and some of the diseases they cause 9  1. Introduction to Immunology Protection against pathogens relies on several levels of defense Body’s epithelial surfaces Chemical and enzymatic systems Rapid cell-mediated innate defense Slower-acting, pathogen- specific adaptive defense  1. Introduction to Immunology Cell-mediated immunity proceeds in a series of steps min - days days days - weeks Potentially life-long at least 5-7 days 2. Principles of innate immunity How are invading pathogens detected? Microbes contain pathogen-associated molecular patterns (PAMPs) that are detected by specific receptors on sensor cells in the tissue or blood In response to pathogenic patterns, sensor cells produce inflammatory mediators, such as cytokines and chemokines Cytokines and chemokines amplify the anti- pathogen response, by inducing antimicrobial / antiviral factors recruitment and activation of other leukocytes 12  2. Principles of innate immunity Sensor cells express pattern recognition receptors (PRRs) that provide an initial discrimination between self and nonself Example: Toll-like receptors (TLRs) expressed on macrophages in the skin TLR-4: Senses lipopolysaccharides (LPS) from Gram-negative and lipoteichoic acids from Gram-positive bacteria What other molecular structures could generally be different between host cells and patho- gens and therefore be recognized as PAMPs (pathogen-associated molecular pattern)? 13  2. Principles of innate immunity Summary: Infection activates pattern recognition receptors on sensory cells (e.g. macrophages) Sensor cells produce inflammatory mediators what leads to local inflammation Vasodilation (reddening), edema (swelling), leukocyte recruitment, more inflammatory mediators (that may cause pain and fever) 14  2. Principles of innate immunity Cell-mediated immunity proceeds in a series of steps min - days days days- weeks Potentially life-long at least 5-7 days 3. Principles of adaptive immunity During an infection (or vaccination) lymphocytes are activated and contribute to the specific and efficient elimination of the pathogen: T-cells: - recognize and destroy infected cells - activate other leukocytes transmembrane antibody secreted antibody B cells: - activated by pathogen-specific T cells to secrete antibodies Antibodies: - bind specifically to foreign structures (antigens) and make them inactive 16  3. Principles of adaptive immunity Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues Dendritic Cells (DCs): Major antigen-presenting cells in the body Take up extracellular material by macropinocytosis (receptor-independent uptake) Migrate via lymphatic vessels to draining lymph nodes Present antigen to T cells Activate antigen-specific T cells 17  3. Principles of adaptive immunity Dendritic cells form a key link between the innate immune system and the adaptive immune system 18  3. Principles of adaptive immunity Circulating lymphocytes encounter antigen in peripheral lymphoid organs, e.g. in lymph nodes Most T lymphocytes constantly recirculate between blood and lymph nodes: blood => lymph node => efferent lymphatic vessels => thoracic duct => blood Make this round several times / day to increase their chances of finding a cognate (specific) antigen Once they find a cognate antigen on an antigen-presenting dendritic cell (DC): T cells proliferate (generate millions of copies) and differentiate into effector or memory cells 19  3. Principles of adaptive immunity Clonal Selection as a guiding principle of adaptive immunity Huge number of pathogens and pathogen-derived antigens needs to be recognized and fought by the adaptive immune system T cells number and diversity in humans: total number of T cells in body: 1 x 1012 theoretical diversity of T cell receptor (TCR) T cell receptor (TCR) sequences: 2 x 1018 BUT: “Fighting” against any pathogen requires an army (=millions!) of antigen-specific (cognate) T cells proliferation => Solution: clonal selection and expansion Arstilla et al., A direct estimate of the human alphabeta T cell receptor diversity, Science 1999, 286(5441):958-61. doi: 10.1126/science.286.5441.958.  3. Principles of adaptive immunity Clonal selection Definitions: Naïve lymphocyte: has not yet encountered its cognate antigen Effector lymphocyte: has acquired effector functions Upon recognizing foreign antigen (on an antigen- presenting cell), the naïve lymphocyte is activated, and proliferates and differentiates. This gives rise to an “army” (millions!) of identical, antigen-specific T cells that can help to fight the invading pathogen. By differentiating, the cells acquire “effector- functions”, e.g. the ability to: - kill target infected cells (CD8+ T cells) - help activate other leukocytes (CD4+ T cells) 21  3. Principles of adaptive immunity Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues Dendritic Cells (DCs): Major antigen-presenting cells in the body Take up extracellular material by macropinocytosis (receptor-independent uptake) Migrate via lymphatic vessels to draining lymph nodes Present antigen to T cells Activate antigen-specific T cells 22  3. Principles of adaptive immunity Clonal selection Definitions: Naïve lymphocyte: has not yet encountered its cognate antigen Effector lymphocyte: has acquired effector functions Upon recognizing foreign antigen (on an antigen- presenting cell), the naïve lymphocyte is activated, and proliferates and differentiates. This gives rise to an “army” (millions!) of identical, antigen-specific T cells that can help to fight the invading pathogen. By differentiating, the cells acquire “effector- functions”, e.g. the ability to: - kill target infected cells (CD8+ T cells) - help activate other leukocytes (CD4+ T cells) 23 4. The effector mechanisms of adaptive immunity During an infection (or vaccination) lymphocytes are activated and contribute to the specific and efficient elimination of the pathogen: T-cells: - recognize and destroy infected cells - activate other leukocytes transmembrane antibody secreted antibody B cells: - activated by pathogen-specific T cells to secrete antibodies Antibodies: - bind specifically to foreign structures (antigens) and make them inactive 24  4. Effector mechanisms Antigen recognition by antibody Epitope or antigenic determinant: a small portion of the Antigen: antigen’s molecular Protein, glycoprotein, structure that is re- and polysaccharide of a pathogen cognized by the antibody Self-antigen: Protein, glycoprotein, and polysaccharide from the own body 25  4. Effector mechanisms Antibodies are composed of constant and variable regions that provide distinct functions Structure: Y-shaped molecule, 150 kD 2 heavy, 2 light chains linked by disulfide bridges Also exists as transmembrane protein on the B cell it originates from Variable region: site of antigen binding Fc different amino acid sequence in different part antibodies Constant region: identical in antibodies of the same subtype (e.g. IgGs) Fc part interacts with phagocytes and NK cells 26  4. Effector mechanisms Antibodies participate in humoral immunity in three main ways Antibodies are found in plasma - the fluid component of blood - and in extracellular fluids. Because body fluids, were once known as humors, immunity mediated by antibodies is know as humoral immunity. Neutralisation: prevent toxins from harming cells prevent viruses from binding to receptors on cells Opsonization: Cover extracellular Cover extracellular bacteria, bacteria, so so the antibody’s can the antibody’s can bind to bind to Fc-receptors Fc-receptors onon macrophages. macrophages. Consequence: phagocytosis Consequence: phagocytosis Complement activation: Cover viruses and bacteria in blood to activate a cascade of proteins with enzymatic activity (complement system). Consequence: pathogen lysis or enhancement of phagocytosis 27  4. Effector mechanisms The course of a typical antibody response Antibody (Ab) titer: Concentration of antibody in the blood In many cases the Ab titer after vaccination decreases over time Do you know any vaccination(s) that need to be given repeatedly to maintain a high antibody titer? Why is this important? 28  4. Effector mechanisms Antibodies and T cell receptors (TCRs) recognize antigens by fundamentally different mechanisms: Antibody: Binds directly to the native antigen (as it occurs in blood or tissue) T cell receptor (TCR): Only recognizes peptide fragments of the antigen when presented on major histocompatibility (MHC) molecules 29  4. Effector mechanisms Antigen recognition by T cell receptor (TCR) TCR usually recognize protein antigen presented on major histocompatibility complex (MHC – a cell surface glycoprotein) 30  4. Effector mechanisms T-cell receptors (TCR) are composed of constant and variable regions that provide distinct functions Structure: 2 chains: TCR α and β chains linked by a disulfide bridge Variable region: site of binding to peptide-MHC molecules different amino acid sequence in different T cell clones Constant region: identical in most T cells 31  4. Effector mechanisms Major Histocompatibility (MHC) molecules on the cell surface display peptide fragments of antigens MHC class I : expressed by virtually all cells in the body present fragments of proteins expressed by the cell itself (i.e. derived from cytosol) recognized by cytotoxic CD8+ T cells MHC class II: expressed by antigen-presenting cells (APC – i.e. DCs, macrophages, B cells) present fragment of proteins that were taken up into the APC from the outside (e.g. by phagocytosis or macropinocytosis) interact with CD4+ T cells 32  4. Effector mechanisms MHC class I molecules present antigen derived from proteins in the cytosol => Recognition or virally infected cells or tumor cells by cytotoxic CD8+ T cells 33  4. Effector mechanisms Cytotoxic CD8+ T cells recognize antigen presented by MHC class I molecules and kill the cell 34  4. Effector mechanisms Major Histocompatibility (MHC) molecules on the cell surface display peptide fragments of antigens MHC class I : expressed by virtually all cells in the body present fragments of proteins expressed by the cell itself (i.e. derived from cytosol) recognized by cytotoxic CD8+ T cells MHC class II: expressed by antigen-presenting cells (APC – i.e. DCs, macrophages, B cells) present fragment of proteins that were taken up into the APC from the outside (e.g. by phagocytosis or macropinocytosis) interact with CD4+ T cells 35  4. Effector mechanisms CD4+ T cells recognize antigen presented by MHC class II molecules Bacterial destruction Antibody production MHCII: presents fragments of proteins that were taken up into the APC from the outside Þ Macrophage took up Þ B cell took up antigen via its B bacteria by phagocytosis cell receptor (Ab on surface) 36  4. Effector mechanisms Effector T cells specialize to fight specific types of pathogens (helped by innate immune cells) 37  4. Effector mechanisms Immune responses can be beneficial or harmful, depending on the nature of the antigen 38 Appendix for Self-Study  5. Lymphoid organs 5. Lymphoid organs in the body Central or primary lymphoid organs Generation / maturation of lymphocytes Bone marrow (B cells and initially T cells) Thymus (T cells) Peripheral or secondary lymphoid organs Maintenance of lymphocytes and induction of adaptive immune responses Lymph nodes Spleen Peyer’s patches Appendix 40  5. Lymphoid organs Organization of a lymph node Outermost cortex: B cells follicles, T-cell zones Inner medulla: macrophages, antibody-secreting plasma cells (medullary cords) Follicle containing germinal center: site of B cell activation 41  5. Lymphoid organs Organization of a lymph node and cell entry / exit routes Afferent lymphatic vessels drain fluid from tissues and carry pathogenic constituents (antigen) and antigen- presenting dendritic cells (DCs) from infected tissues to the lymph nodes Specialised blood vessels in the paracortical area, so- HEV (high called high endothelial endothelial venule) venules (HEV) are the entry portals for lymphocytes into the lymph node Efferent lymphatics are the DCs and T cells meet and exit routes for all lymphocytes interact in the paracortical from the lymph node area. DCs are short-lived 42 and eventually die there.  5. Lymphoid organs Organization of the spleen Red pulp White pulp Red pulp: the site of red blood cell destruction / disposal. White pulp: actual immune compartment. Lymphocytes surround the arterioles running through the spleen, forming isolated areas of “white pulp”. periarteriolar lymphoid sheath: T-cell zone in the white pulp, site of DC-T cell interactions, Follicles: B cell zone; a germinal center is surrounded by a B-cell corona and marginal 43 zone,  5. Lymphoid organs Organization of a Peyer’s patch in the gut mucosa The subepithelial dome contains dendritic cells (DCs), T cells, and B cells. Peyer’s patches have no afferent lymphatics, and the antigen enters directly from the gut across a specialized epithelium made up of microfold (M) cells. Lymphocytes enter Peyer’s patches from the blood across the walls of high endothelial venules (not shown), and leave via the efferent lymphatic. 44  6. Cell types Myeloid cells in innate and adaptive immunity Immature Mature 45  6. Cell types Macrophages are resident in almost all tissues Macrophages are long-lived cells that live in tissues, where they take up (phagocytose) and destroy bacteria or dead cells. In the spleen, macrophages of the red pulp help to degrade old red blood cells or immune complexes. Embryonic Adult development Long-lived cells 46  6. Cell types Granulocytes: Neutrophils, basophils and eosinophils Neutrophils are granulocytes (contain characteristic Eosinophils and basophils are less abundant intracellular granules). They are short-lived cells that are than neutrophils, but like neutrophils, they have produced in bone marrow and are rapidly recruited to granules containing a variety of enzymes and sites of infection / inflammation. They an take up and kill toxic proteins, which are released when these pathogens like bacteria or funghi. During and infection, cells are activated. They are important in the neutrophil numbers rapidly increase in blood, as more defense against parasites and also during cells are produced in the bone marrow. allergic responses.  6. Cell types Mast cells Mast cells begin development in the bone marrow, but migrate as immature precursors that mature in peripheral tissues, especially skin, intestines, and airway mucosa. Their granules contain many inflammatory mediators, such as histamine and various proteases, which play a role in protecting the internal surfaces from pathogens, including parasitic worms. Skin Intestines Airway mucosa 48  6. Cell types Dendritic cells are phagocytic when they are immature, and can activate T lymphocytes after maturation 49  6. Cell types Innate lymphocytes and NK cells: effector cells that share similarities with lymphoid lineages of the adaptive immune system NK cells of the innate immune system lack antigen- specific receptors. However, the express Fc receptors, by which they can recognize the Fc portion of Bone marrow antibodies. If the antibody e.g. binds to a virally infected cell or a tumor cell, the NK can destroy it (hence their name: natural killer cell). Blood 50