MCMP422 Immunology and Biologics

MCMP422 Immunology and Biologics
Immunology is important personally and professionally! Learn the language - use the glossary and index RNR - Read, Notes, Reviewing All materials in Chapters 1-3 are examinable (with exceptions) To commit an item to long term memory you should observe it 3 times over a hour period. So try and skim over material before class, come to class and skim over that night before you go out to party! Go over your notes tonight and just spend a 20 minutes. Then you can go and party.

Summarizes all of immunology Foundation for the rest of the course
Chapter 1 Elements of the Immune System and their Roles in Defense Summarizes all of immunology Foundation for the rest of the course The rest is all details The powerpoint slides are set-up so that you will have to fill in notes from the class. If you don’t come to class you will miss out on a lot of extras. Its sort of like getting the fee demo version of software. We will follow the book very closely in the early chapters - these are the foundation chapters do you need to really understand them well. The rest is all the details

Chapter 1 Concepts What components make up the immune system?
Cells, organs, cytokines and other molecules involved in the immune system What is the goal of the immune system? To clear pathogens in our body How do we classify immune responses? Innate and adaptive immune responses What are the side effects of the immune system? Autoimmune diseases, Allergies, Transplantation Rejection

e.g. bone marrow, thymus, spleen, lymph nodes
Immunology: the science of how the body responds to foreign organisms (e.g. pathogens) or substances (e.g. allergen) Immune system: the organs, cells and molecules that defend and respond to pathogens/allergens 1. Tissues/organs 2. Cells Blood borne proteins We will learn about the many cells and tissues of the immune system in the next few lectures. e.g. bone marrow, thymus, spleen, lymph nodes e.g. lymphocytes, dendritic cells, macrophages, natural killer cells, granulocytes (neutrophils, basophils, eosinophils), mast cells e.g. complement and mannose-binding proteins

Origin of Immunology - individuals who survived a disease seemed to be untouched upon re-exposure
Vaccination/Immunization - procedure where disease is prevented by deliberate exposure to infectious agent that cannot cause disease. Polio?

Figure 1-2 Pathogen - any organism that can cause disease

Diversity of Pathogens
Four Classes Opportunistic pathogens Pathogen-Host relationship Classes of pathogens: four classes of pathogens : Bacteria, Fungi, Viruses, and Parasites. Important because immune system responds to these classes in different ways. Look at the different shapes, sizes, morphology - imagine the different strategies the body needs to use to eliminate these pathogens Opportunistic pathogen - e.g. Pneumocystis carinii - a fungal pathogen that causes disease in people with suppressed immune systems (due drugs or disease). This is an example of opportunistic growth in the lung of a monkey infected with simian virus equivalent to AIDS Host-pathogen relationship is complex - host and pathogen respond to each other in an ongoing war. This relationship can change at varying rates. New pathogens tend to cause more severe disease with associated high mortality. Common diseases - can be overcome by the immune system but not before they spread to a new host.

How Clean are You? Part of body Bacteria Head (scalp) 1,000,000 /cm2
Surface of skin /cm2 Saliva ,000,000 /g Nose mucus 10,000,000 /g Faeces over 100,000,000 /g Faeces made of up to 30% live bacteria

Defenses against Pathogens
Physical Defenses 1. Skin 2. Mucosal surfaces Immune Defenses 1. Innate 2. Adaptive Skin - Important barrier against pathogens - tough, waterproof barrier that is continually making new cell that replace dead cells - most pathogens cannot penetrate the layer by themselves (with the exception of some fungi) - breached if physically broken by wound or mosquito Mucosal - surfaces: line cavities that enter the body (e.g. mouth, lungs) epithelial cells that line these cavities are covered in mucus Mucus: thick fluid layer containing (glycoproteins, proteoglycans, enzymes) that trap and remove microorganisms. - Lungs: Mucus in the lungs traps bacteria and fungal spores. Tiny hairs, called cilia, move the mucus to the back of the throat where it is swallowed - Nose: Mucus traps pathogens which are then swallowed or blown out in coughs and sneezes - Mouth: Friendly bacteria help to prevent the growth of harmful pathogens. Saliva cleans and removes bacteria.

Figure 1-4 Physical Barriers
- Lungs: Mucus in the lungs traps bacteria and fungal spores. Tiny hairs, called cilia, move the mucus to the back of the throat where it is swallowed Nose: Mucus traps pathogens which are then swallowed or blown out in coughs and sneezes Mouth: Friendly bacteria help to prevent the growth of harmful pathogens. Saliva cleans and removes bacteria. Eyes: lysozyme in tears help limit bacterial growth Stomach: acid help to neutralize most pathogens Intestine: Friendly bacteria help to stop the growth of harmful pathogens Urogenital tract: Slightly acid conditions in the vagina and urethra help to stop the growth of pathogens

Innate and Adaptive responses
Pathogen independent Immediate (hours) Neutrophils NK cells Macrophages Mast cells Eosinophils Basophils Adaptive Pathogen-dependent Slower (days) Dendritic cells B cells T cells (CD4 or CD8) Both systems “talk” to each other to modulate response

Immunity: Three Basic Parts
Pathogen Recognition (Binding event) (Foreign) Signal Effector mechanisms (Self) Immune disorders Effector Cells Complement Innate immunity - “naïve”, immediate, everyday immunity Acquired immunity - “specialized”, late, immunity Basis of immunity is to recognize self from foreign organisms - this is usually initiated by a binding event - Binding molecules - Antibodies and receptors Destructive mechanisms by which a pathogen is eliminated Innate immunity is entirely determined by the genes a person has. It is the basic immunity that you already have in your genes Acquired immunity is the response to a specific pathogen

Figure 1-5 part 1 of 2 One way Immunity Works Complement Effector cell
Effector cells - engulf bacteria, kill virus infected cells, attack pathogens Complement - blood borne (serum) proteins that tag pathogens, attack in their own right Endocytosis - process by which extracellular material is taken up into cells Complement Effector cell Endocytosis

Figure 1-5 part 2 of 2 One type of effector cell is the phagocyte

Figure 1-6 Innate Immunity Cytokines Inflammation Phagocytosis
Cytokines - soluble proteins that transmit a signal that pathogen is present Inflammation - local accumulation of fluid, cells involved in the immune response Local dilation of blood capillaries = increase of blood to the area = heat (DOES NOT increase blood flow) Vascular dilation (Vasodilation) introduces gaps between the endothelial cells allowing plasma to leak into the cells = swelling = pain (pressure on nerves) Change the adhesiveness of the endothelial tissue allowing white blood cell (neutrophils and monocytes) to attach and migrate into the connective tissue (extravasion) State of Inflammation is induced - increased swelling, pain, heat and redness. Cytokines Inflammation Phagocytosis Inflammatory cells

What if Innate Immunity is not Enough?
Innate immunity keeps us healthy most of the time Some pathogens escape the innate immune process Need a specific system to adapt to a specific pathogen Adaptive immune response Highly specialized defense against one pathogen that has little or no effect against other pathogens.

Figure 1-7 Characteristics of Innate vs Adaptive Immunity
1. Innate Immunity a. present BEFORE the pathogen enters the body (rapid response) b. NOT specific for a unique pathogen c. Remains relatively constant during an infection Does NOT impart long term immunity Composed of cells (eg. NK cells) and proteins (eg. complement) circulating in the blood and cells present in tissues (eg., macrophages) 1. Adaptive Immunity a. develops AFTER the pathogen enters the body (slow response) b. IS exquisitely specific for a given pathogen c. Becomes more effective as the immune response progresses d. Imparts long term immunity (basis of vaccination/immunization) -Edward Jenner (1796) rural England doctor (cowpox to immunize against small pox; vaccine is the disease cowpox causes) e. Composed of cells and proteins circulating in the blood and present in tissues -lymphocytes (circulate in blood, lymph and found in tissues) -antibodies (circulate in blood) -cytokines (mostly act locally in tissues, few found in blood) Most of the time the innate response is sufficient to rid the body of daily, unwanted pathogens that normally enter the body (mouth is full of pathogens). Innate immune system functions silently. When it fails and an infection persists, the adaptive immune response (IR) develops with the accompanying symptoms (eg., fever, aches, congestion etc..). During an adaptive IR, the innate and adaptive responses work together to eliminate the pathog Effector mechanisms are similar - The important difference is in the cell surface receptors used by lymphocytes to recognize pathogen. The receptors used to recognize pathogen by the Innate response are There are many types of receptors of innate immunity but they are fixed and cannot be changed - encoded by conventional genes Adaptive immunity - receptors are of the same basic type that is specific for the pathogen. Lymphocytes - white blood cells that increase the immune response to ongoing infection

Innate vs Adaptive Molecular Recognition
Most important difference: Receptors used to recognize pathogens Innate immunity: Receptors recognize conserved structures present in many pathogens Pathogen-associated Molecular Patterns: LPS, peptidoglycan, lipids, mannose, bacterial DNA and viral RNA Adaptive immunity: Receptors recognize a specific structure unique to that pathogen Effector mechanisms are similar - The important difference is in the cell surface receptors used by lymphocytes to recognize pathogen. The receptors used to recognize pathogen by the Innate response are a few highly conserved structures present in many different microorganisms pathogen-associated molecular patterns: LPS from the gram-negative cell wall, peptidoglycan, lipotechoic acids from the gram-positive cell wall, the sugar mannose (common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial DNA, N-formylmethionine found in bacterial proteins, double-stranded RNA from viruses, and glucans from fungal cell wall There are many types of receptors of innate immunity but they are fixed and cannot be changed - encoded by conventional genes Adaptive immunity - receptors are of the same basic type that is specific for the pathogen.

Figure 1-11 part 1 of 2 Flowchart of Hematopoiesis
How are the immune cells made? Common Progenitor to the cells of the immune system (leukocytes) and erythroid cells. Pluripotent hematopoietic stem cell gives rise to hematopoietic cells (hematopoiesis) Self renewal process: divide to give more hematopoietic stem cells Pluripotent stem cells also matures into three cell types Lymphoid, Myeloid, Erythroid

Figure 1-11 Flowchart of Hematopoiesis
Several types of white blood cell (leukocytes) - we will study the function of each Leukocytes develop in the primary lymphoid organs - Bone marrow- B-lymphocytes (B-cells) - thymus - T-lymphocytes (T-Cells) Leukocytes - white blood cells

Myeloid Lineage

Figure 1-9 part 3 of 6 Granulocytes (Myeloid progenitor)
Polymorphonuclear leukocytes (PMLs) Figure 1-9 part 3 of 6 Neutrophils: Most abundant Phagocyte Effector cells of Innate Immunity Short-lived - Pus Eosinophils: Worms/intestinal parasites Amplify inflammation Bind IgE Very Toxic - Pathogen and host Chronic asthma Basophils: Rare Unknown function Bind to IgE Granulocytes - named due to their staining of cytoplasmic granules - also called PMLs due to the morphology of the Nucleus. Neutrophil - eosinophil bind to acid stain eosin - basophil binds to basic stain - neutrophil does not bind to either

Figure 1-9 part 5 of 6 Monocytes - leukocytes that circulate in the blood Bigger than granulocytes All look the same - indented nucleus Circulate in the blood until needed - mature to macrophage Macrophage - main function is to phagocytose pathogens, dead cells and debris - secrete cytokines to recruit neutrophils and other leukocytes

Figure 1-13 Neutrophils are stored in the marrow and move to injury or infection. They only go one round of fighting an infection. Pus is composed of dead neutrophils and cellular debris and bacteria. Macrophages last a long time and will clean up the area.

Dendritic cells: Star-shaped morphology
Resident in the tissue cellular messengers Cargo cells - carry pathogen materials Mast Cells - in all connective tissue - granules similar to basophil but a different unknown progenitor - degranulation major contributor to inflammation

Lymphoid Lineage Cells

Lymp Figure 1-9 part 2 of 6 Two types - large lymphocytes with a granular cytoplasm and small with little cytoplasm Natural killer cell - Large granular lymphocyte effector cells of innate immunity - infected tissue and kill viral-infected cells - secrete cytokines that interfere with virus infections

Figure 1-9 part 1 of 6 Small lymphocytes - responsible for the adaptive immune response - small because they are dormant and immature - Recognition of a pathogen drives their amplification and maturation - Two types - B cells and T-cell that can be distinguished by their cell surface receptors -structurally similar molecules that are the source of diversity B-cells have immunoglobulins BCR T-cells have T-cell receptors

Erythroid Lineage

Figure 1-9 part 6 of 6

Figure 1-11 part 2 of 2 Lymphoid Myeloid Erythroid

Figure 1-12

Figure 1-14

Figure 1-15 Sites of Lymphoid Tissue Primary and Secondary
Many sites of Lymphoid tissue which is where lymphocytes hang out. Primary - Bone marrow and Thymus - where lymphocytes develop and mature ALL other tissue is Secondary - where mature lymphocytes mature to respond to pathogens GALT - Gut associated lymphoid tissue - Adenoid, tonsil, Peyers, Appendix BALT - Bronchial associated lymphoid tissue - respiratory epithelium MALT- Mucosal associated lymphoid tissue Reason for this - these are the areas of the body that have the most dense and diverse numbers of organisms - most heavily infested is the Mouth 3 billion neutrophils enter the mouth every day - and this is the first step of the inflammatory immune response Lymphatic vessels - collect fluid that leaks out of blood and return it to the blood via the thoracic duct which empties into the left subclavian vein in the neck Junctions of these interconnected network are lymph nodes. Recirculation - lymphocytes cycle through the body. B-cells mature in bone marrow T-cells leave the bone marrow in an immature form then mature some more in the Primary and Secondary GALT, BALT, MALT Lymph Recirculation

Figure 1-16 Draining Lymph node Edema Afferent and Efferent
Recirculation of lymphocytes Draining lymph node - the nearest node to infection point where lymph collects Lymphocytes leave the blood and enter lymph nodes - if activated they will stay in the node and differentiate into effector cells. - no activation they will leave the node and continue to circulate 5 million lymphocytes leave the blood and circulate every minute Dendritic cells will also travel from the injury to the nearest lymph node Edema - vessels are one way valves that relying on movements of the body - if the you are confined to bed for a long time the fluid can accumulate which leads to swelling and edema.

Figure 1-17 part 1 of 2 Lymph node is small kidney shaped organ (1 gram each) packed with cells of the immune system from which lymph percolates through all of them. Afferent vessels bring in the lymph from infected tissue - carrying dendritic cells and pathogens These communicate with the lymphocytes in the lymph node (arriving to the lymph node through the artery) Cells are in predominantly different areas - B-cells in the follicles, T-cells in the central area Follicles develop into germinal centers lymphocytes are activated and need to be expanded

B-cell area (follicle)
Don’t take notes - Please listen - because I will summarize this in the next slide Lymphocytes enter node through artery Tcells with migrate to the T-cell area and if they meet a dendritic cell that is carrying pathogens from an infection site they get activated - to divide into functional effector cells. Some T-cells stay in the lymph node and become T-helper cells - secrete cytokines (soluble proteins) and have receptors that contact B-cells. This helps the B-cells differentiate into plasma cells. Plasma cells stay in the lymph or leave and pump out large amount of antibodies - a soluble form of their cell surface receptor A second type of activated T-cell is the T-helper cell that leaves the node to the infected area and interact with macrophages and amplify inflammation Third type of T-cell is the cytotoxic T-Cell which kill cells infected with pathogen Remember 5 million lymphocytes are entering node every minute and only a few are activated in response to an infection.

Figure 1-19 Anatomy of immune function in the Spleen
Spleen is a large lymphoid organ in the upper left of the abdomen - Spleen is the blood filtering organ 1) to remove damaged/ old red cells (red pulp) 2) typical secondary tissue function - remove pathogens and activate lymphocytes (white pulp) Very important for blood borne pathogens - malaria, etc Similar to lymph node but pathogens/lymphocytes enter and leave by blood NOT lymph White pulp transverse sections - similar organization to a lymph node

Figure 1-20 GALT Microanatomy again is similar to lymph node and spleen white pulp - B and T cell area, lymphoid follicles and germinal centers. Except pathogen delivery is mediated by M cells - specialized cells lining the mucosal epithelium Lymphocytes - enter via blood and leave via lymph If activated they stay in the mucosal system but move out to the lamina propria and the mucosal epithelium to perform effector functions.

- recognition modules - BCR, Ab and TCR
Adaptive Immunity Vertebrates only Specificity - recognition modules - BCR, Ab and TCR - gene rearrangement is the source of diversity - clonal selection Small lymphocytes - types and sub-types - functions Effector B cells called plasma cells

Receptor or Antibody molecule
Recognition concept Receptor or Antibody molecule Antigen - structure recognized by an Ab, BCR or TCR Epitope - particular sub-structure of the Ag that is bound Affinity - how much a molecule likes to bind to a structure Receptors and Ig are molecules used as recognition molecules by the immune system

Small lymphocyte sub-types
B-cells BCR is Immunoglobulin (Ig) Plasma cells - effector cells that secrete Ab T-cells Tc = cytotoxic (CD8+) TH = helper T-cells (CD4+) Th1 (inflammation) Th2 (help B-cells make AB) B-cell = effector B-cells called plasma cells secrete soluble forms of immunoglobulins called antibodies.

Recognition modules of Adaptive immunity
Structurally related molecules Immunoglobulins Y shaped immunoglobulin molecule has 2 Hc and 2 Lc Variable regions and constant region with identical amino acids from one BCR to another of from one Ab to another Several sub-types of constant region that target them to different anatomical sites BCR are anchored by a transmembrane region at the C-terminal end of the heavy chain. TCR Alpha and beta chains both anchored to the membrane Variable and Constant regions B cells T cells

B-cells T-cell B and T cells recognize different forms of antigen
B cells can recognize more diverse set of epitopes compared to T cell BCR or Ab can bind to epitopes present on the intact antigen TCR recognizes a short linear sequence of amino acids that is complexed with a membrane glycoprotein called MHC Two step process Antigen is broken down in a process called Antigen Processing - denatured antigen and proteolysed Assembly of the peptide:MHC molecule occurs bound to a major histocompatibility (MHC) molecule presented by another cell - APC, macrophages, dendritic cells, and B cells. MHC molecues can have slight genetic variants between humans - this is called polymorphism and the basis of in transplantation phenomena

Figure 1-25 Extracellular pathogens Intracellular pathogens
Two types of MHC molecules MHC I - present on all nucleated cells of the body except the rbc. Since all the cells of the body can be infected by a virus they need a mechanism to try and stop the virus. They process the pathogen and become APC which then can interact with cytotoxic T cells MHC II - present only on immune cells. These are also called professional Antigen presenting cells they will present peptides present in the extracellular milieu. Dendritic, macrophages, and B cells. Tcells that interact with professional APC are called helper T cells TH1 AND TH2 Extracellular pathogens Intracellular pathogens

Figure 1-26 MHC class I communicates with Tc cells

Figure 1-27 MHC class II communicates with TH cells Macrophage - Th1
B-cell - Th2

Expel and/or destroy pathogen
Parasitic infection Parasite + Mast cell Neutralization Opsonization Inflammation Inflammation Mast cell activated Igs subdivided into 5 classes - IgA, IgD, IgE, IgG and IgM - each have unique roles with some overlapping - will learn more about them next week. Immunity due to Ab action is called Humoral immunity Mechanisms of action Neutralization - bind to a toxin or pathogen to prevent their lethality e.g. influenza virus can be bound by Ab’s to block it from binding to a cell and infecting it 2.Opsonization - Facilitate engulfment by coating a pathogen a. direct b. Ab plus complement 3. Some Ab’s are bound to mast cells and when they detect parasite will activate the mast cell - triggering inflammatory reactions Expel and/or destroy pathogen

Principles of Adaptive Immunity Diversity Specificity Memory
Self-tolerance The next four slides will demonstrate four core principles of Adaptive Immunity

Gene Rearrangement is the source of Diversity
Germline configuration Diversity Alternative combinations Imprecise joints Different types of chains B-cells - somatic hypermutation In the absence of antigen Basis of genetic diversity The Ig and TCR genes are in germline configuration - the configuration that you inherit Recombination occurs in the soma. Three red segments and three yellow segments - need to bring the yellow and red together to

Each cell = one receptor Millions of lymphocytes are generated
Clonal Selection Each cell = one receptor Millions of lymphocytes are generated Small subset will recognize a pathogen Proliferation and differentiation Acquired immunity - the adaptive immunity provided by immunological memory Acquired immunity can be present for decades but for some it may be short-lived: eg. Measles vs influenza Clonal selection - a means for amplifying a response that is very specific for the pathogen Small lymphocyte - circulate in the blood in a dormant and immature form Encounter with pathogen activates a cell This cell will proliferate I.e stimulated to divide - thousands of identical daughter cells will result - which means clones. Ofcourse it won’t be just one clone - several clones can recognize a specific antigen because antigens can have several epitopes.

Figure 1-22 After a person has measles they have many antibodies circulating in the blood that bind to the measles virus - these do not have any effect on influenza

Figure 1-30 Primary immune response: Developed from very few lymphocytes so an infection can progress to a much greater extent. During this immune response some lymphocytes include long-lived memory cells the can respond more quickly and vigorously when challenged again. Secondary immune response: can be so efficient that the person has no symptoms This is the basis for vaccination

Figure 1-31

Figure 1-28 Mechanism of Self-tolerance
B-cells with BCR that bind strongly to the constituents of surrounding bone marrow tissue will be programmed to die - apoptosis More complicated scheme of selection for T cells T-cell progenitors - thymocytes- develop in the thymus Positive selection by surrounding epithelial cells (cortex of the thymus) will select for cells with any affinity for self MHC molecules Negative selection by hematopoietic cells in the medulla (macrophages and thymocytes) Mechanism of Self-tolerance

Immunodeficiencies Inherited deficiencies Stress induced
Pathogen caused deficiencies Bubble boy disease Low/poor nutrition Emotional stress HIV - infects the CD4 T lymphocyte - essential for immunity - leads to a complete collapse of the immune system and secondary infections that are not normally seen

Figure 1-32 IgG CD4 TH1 CD8 CTL IgE antibodies get made against innocuous substances eg pollen Pollen binds to IgE and triggers the mast cell to degranulate - releasing histamine and other active substances Leads to inflammation and sneezing

Figure 1-33 Insulin-Dependent Diabetes Mellitus
Insulin dependent diabetes mellitus (IDDM) Beta cells of the islets of Langerhans in the pancreas are attacked. Symptoms don’t show up for a long time Infection by a specific virus has been correlated with higher rate of IDDM Some of the activated CTL and Th1 cells will attack the healthy beta cells IDDM also has been correlated with certain polymorphisms of the MHC molecule.

Figure 1-34

Figure 1-10

MCMP422 Immunology and Biologics

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