Chapter 17.1 - Immune Response PDF

CHAPTER 17 The Immune Response PART 1 17.1-1  17.1 | An Overview of the Immune Response Vertebrates are able to develop immunity against invading pathogens The cells of the immune system engage in a type of molecular screening by recognizing “foreign” macromolecul...

CHAPTER 17 The Immune Response PART 1 17.1-1  17.1 | An Overview of the Immune Response Vertebrates are able to develop immunity against invading pathogens The cells of the immune system engage in a type of molecular screening by recognizing “foreign” macromolecules Weapons of the immune system include: Cells that kill or ingest infect or altered cells (including CD8+ cytotoxic T-cells that kill virus infected cells) Soluble proteins that can neutralize, immobilize, agglutinate, or kill pathogens (including antibodies - but there are many more) All the mechanisms used by the body (self) as protection against anything foreign (non-self) Innate Immunity (nonspecific) Adaptive Immunity (acquired – involves T cells and B cells) 17.1-2  Classification of pathogens and some of the human disease they cause FYI only We will focus on the immune response to a bacterial infection 17.1-3  Setting the stage: Two circulatory systems: cardiovascular lymphatic ✓ Positive arterial pressure exerted by the heart pumping results in loss of liquid from the cardiovascular circulatory system into interstitial spaces (the space around cells ✓ Interstitial fluid volume is three times that of circulating blood ✓ Interstitial fluid is returned to the bloodstream via the lymphatic circulatory system ✓ Most of the immune system action (where B-cells make antibodies and T cells become activated) takes place in lymph nodes 17.1-4 Leukocytes (white blood cells) circulate between the blood and the lymph (RBCs do not) These cells include: B-cells that will make antibodies T-cells that help B-cells make antibody T-cells that can kill virus infected cells Q: How do cells of the immune system get into the lymphatic system? A: by squeezing through specialized endothelial Pathogens can also exploit cells in lymph nodes this way of entry 17.1-5 Cells of the immune system All blood cells have limited life spans and need to be regenerated (hematopoiesis) From hematopoetic stem cells in the bone marrow White blood cells (everything in this figure except platelets and erythrocytes) are called Leukocytes We will be focusing on monocytes, macrophages, dendritic cells, 17.1-6 T-cells and B-cells (and a quick mention of Natural Killer cells) Setting the stage: some terminology leukocytes (white blood cells ) can be differentiated by cell surface molecules identified by monoclonal antibodies CD (clusters of differentiation) system of nomenclature recognizes over 200 individual molecules that can be specific for individual populations of cells phases of cell differentiation degree of cell activation because these CD markers may be present at varying levels on several different cell types, it’s the overall profile of 17.1-7 CD markers that defines a subset of lymphocytes example: 2 populations of T cells are distinguished by whether they express CD4 or CD8 Cells of the immune system-monocytes Monocytes from the bone marrow circulate in the blood stream for ~8 hrs until they undergo apoptosis But if needed, they migrate into tissues where they differentiate into tissue specific macrophages differentiation of a monocyte into a macrophage involves: five to ten-fold enlargement in cell size increased complexity and number of intracellular organelles increased phagocytic ability 17.1-8 Cells of the immune system-macrophages Tissue specific resident Macrophages develop during embryogenesis, are long-lived (2-4 months), self-renewing and are the first line of cellular defense against a pathogen In an infection they phagocytose pathogen and secrete signals that recruit monocytes that will then transition into macrophages to reinforce and expand the population of resident macrophages Langerhans cells are macrophages found in epidermal tissue 9you don’t need to know 17.1-9 names of tissue specific macrophages Cells of the immune system-macrophages A macrophage has many receptors on its cell surface Some can recognize patterns on pathogen surfaces These patterns on pathogens = PAMPS pathogen-associated molecular patterns (PAMPS) on pathogens bind to pattern recognition receptors macrophages Pathogens are then phagocytosed thereby activating the macrophage Examples of PAMP receptors: Scavenger receptor Mannose receptor Toll-like receptors (TLR) Other more specific receptors: Fc receptors Complement receptors 17.1-10 Cells of the immune system-macrophages Macrophages remain in a resting state until activated by binding to pathogen 17.1-11 Macrophages are the first cellular line of defense against a break in the epithelium and have two primary functions Activation of signal transduction Phagocytosis and pathway that generate degradation of pathogen inflammatory cytokines 17.1-12 Ligand (pathogen) binding to macrophage receptor(s) induce signal transduction cascades in Macrophages resulting in the secretion of cytokines Cytokines: substances secreted by cells of the immune system that have an effect on other cells Chemokines: a type of cytokine that induce directed chemotaxis Don’t need to know details of what cytokines do You don’t need to know all these details but you should understand what powerful molecules cytokines are and how an inflammatory response is 17.1-13 now being stimulated at the site of pathogen invasion macrophages are antigen presenting cells Macrophages phagocytose pathogen Digest pathogen Present pathogen to Helper T-cells in the context of Class II MHC molecules MHC proteins are synthesized in the ER (Major Histocompatability Complex) Pieces of the pathogen end up in the binding pocket of Class II MHC proteins as the MHC proteins travel to the cell surface of a macrophage via the endomembrane system This is how a macrophage “presents” antigen to other cells of the immune system 17.1-14 Cells of the immune system-neutrophils Released by bone marrow and circulate in blood stream 7-10 days Extravasation into tissue at site of injury (in response to chemical signals secreted by other cells (including macrophages) Neutrophils: most abundant granulocyte recognition of pathogen is similar to macrophages job is to kill pathogens (professional phagocytes) they do not present antigen 17.1-15 Cells of the immune system-neutrophils primary granules and secondary granules After a Neutrophil has contain lytic and exhausted it’s ability to bactericidal substances phagocytose it will spit out a network of extracellular fibers, primarily composed of DNA from which sticks to pathogens = NETs: Neutrophils are neutrophil extracellular traps phagocytosed by macrophages 17.1-16 Cells of the immune system-neutrophils Leucocytosis: transient increase in the number of circulating neutrophils is used as an indication of infection hereditary deficiencies in neutrophil function result in an inability to defend against bacterial infection 17.1-17 Cells of the immune system-eosinophils FYI only slide Eosinophils: Very small numbers present in the blood stream (most are found in tissues) Activation releases toxic granules and free radicals (which can kill microorganisms and parasites –but during inappropriate release in allergic reactions can cause tissue damage) 17.1-18 Cells of the immune system-basophils and mast cells Basophils: FYI only slide Extremely low levels in circulation Upon activation release histamine and interleukins (which can cause problems in an allergic reaction ) Mast Cells: Differentiate when they enter tissues Cytoplasmic granules contain histamine and other pharmacologically active substances 17.1-19 Cells of the immune system-dendritic cells Dendritic cells: get their name from their long membrane extensions that resemble dendrites of nerve cells migrate to peripheral tissue Found under most surface epithelia and in heart and kidneys and other tissues where they remain for variable lengths of time 17.1-20 Cells of the immune system-dendritic cells At the site of infection they engulph pathogen either by phagocytosis (with similar receptors as macrophages and neutrophils) but also by pinocytosis After engulphing pathogen dendritic cells are induced to migrate via the afferent lymphatic vessels to the nearest regional lymph nodes In lymph nodes they lose phagocytosis ability but gain the ability to present antigen to T cells They can present antigen in the context of both Class I MHC and Class II MHC molecules = cross presentation Important link between the innate and adaptive immune system 17.1-21 Cells of the immune system- Natural killer cells Natural killer cells (NK cells): Circulate in the blood as large lymphocytes with distinct cytotoxic granules Lack antigen specific receptors (named natural killer cells because of non-specific cytotoxicity compared to T and B cells) Are often the first line of defense against some viruses (before specific cytotoxic T cells (CTLs) are activated) 17.1-22 Summary of the immune response so far The inflammatory response initiated by cytokine secretion from macrophages causes redness, heat, pain and swelling – all of which are needed to try to contain and eliminate the localize infection At the same time signal are being sent to initiate a stronger immune response (the adaptive immune response of T-cells and B-cells) The adaptive immune response only comes into play if the innate immune response cannot clear the localized infection but the adaptive response needs time to get ready to do this 17.1-23 17.1-24 Cells of the immune system: lymphocytes (T cells, B cells) lymphocytes released from the bone marrow are small cells with very few cytoplasmic organelles and condensed chromatin In this form, lymphocytes are inactive—they have no functional activity until they encounter antigen Encounter with antigen stimulates their proliferation and differentiation They circulate between blood and lymph If they encounter antigen they become effector cells If they don’t encounter antigen they undergo apoptosis 17.1-25 B cells and T cells have unique receptors for antigen (pathogen) The B cell antigen receptor (BCR) is a membrane bound form of the antibody (immunoglobulin or Ig) the B cell will secret after activation and differentiation The T cell antigen receptor (TCR) does not recognize free antigen (pathogen), only antigen (piece of a pathogen) that is bound to an MHC molecule on an antigen-presenting cell Note that help T-cells are Note that cytotoxic T-cells defined by the presence of are defined by the presence the CD4 protein of the CD8 protein 17.1-26 More terminology Antigen (Ag) antibody generator): any molecule or molecular fragment that is either recognized by an antibody or a B-cell receptor or can be bound by an MCH molecule and presented to a T-cell receptor Epitope (antigenic determinant): The portion of an antigenic molecule that is bound by an antibody or that is recognized by a T-cell receptor in the context of presentation by an MHC molecule The MHC molecule is recognizing the epitope 17.1-27 Cells of the immune system: lymphocytes: B cells B lymphocytes (B cells): when activated differentiate into plasma cells that make antibodies The B cell receptor is a membrane bound form of the antibody that the B cell will secrete when it becomes a plasma cell The B cell receptor will initially bind the antigen (pathogen) it is specific for and phagocytose antigen (pathogen) The antigen/pathogen will be degraded and presented on the B cell surface in the context of class II MHC molecules to a helper T cell The helper T-cell helps the B cell make antibodies 17.1-28 Signal Transduction Pathways in Lymphocyte Activation FYI only slide 17.1-29 Antigen Presenting Cells dendritic cells macrophages B-lymphocytes In order to present antigen they must be able to phagocytose neutrophils also phagocytose but they do not present antigen neutrophils and macrophages are professional phagocytes 17.1-30 17.1-31 Cells of the immune system-lymphocytes (T cells) 17.1-28 T lymphocytes (T cells): three main classes upon activation and differentiation Cytotoxic T cells: (CD8+) kill cells infected with virus Helper T cells: (CD4 +) regulate the activities of other white blood cells help activate macrophages, B cells and neutrophils (sometimes CD8+ cells) There are many types of helper T cells Regulatory T cells: suppress the activity of other lymphocytes and help to control immune responses In this course we will only discuss helper T-cells in the context of helping B-cells produce antibodies 17.1-32 Cells of the immune system-lymphocytes (T cells) Big concepts that are coming up in more detail: T cells only recognize antigen when it is presented in the context of MHC protein molecules on the cell surface of an antigen presenting cell There are two important classes of MHC molecules: Class I and Class II Class I MHC is always associated with CD8 and both are found on every nucleated cell in your body – why? Class II MHC is always associated with CD4 and is found only on professional antigen presenting cells: dendritic cells, macrophages and B cells 17.1-33 Tissues and organs of the immune system Primary lymphoid tissue: Bone marrow Thymus All cells of the immune system originate from a hematopoetic stem cell in the bone marrow B cells mature in the bone marrow T cells mature in the thymus Only need to know that lymph nodes are an example of secondary lymphoid organs Everything else is is secondary lymphoid tissue where mature lymphocytes become stimulated to respond to invading pathogen Lymph nodes Spleen Tonsils Appendix Peyer’s patches 17.1-34 Tissues and organs of the immune system We only emphasized lymph node germinal centers in this course– don’t need to know the other areas 17.1-35 Learning objectives: Be clear on the characteristics of innate immunity Be clear on the characteristics of adaptive immunity Be clear on the classification and nomenclature of the cells of the immune system Understand the basic characteristics of the cells of the immune system (This may seem like a lot of information but there are not that many cells and they all have distinguishing characteristics and do interesting things!) Undestand what is meant by antigen presentaton Know the primary lymphoid organs Know what an antigen is Know what an epitope /antigenic determinant is Know what a cytokine is Know what a chemokine is 17.1-36